The Health Cdnsequences Of Smoking NICOTINE ADDICTION a report of the Surgeon General 1988 US. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health &vke Cmlen for Disease Control Cenlw for Healfh Plomofkn and Educatkn Offke on Smoldng and Health Rockvllk, Maryland 20857 For sale by the Superintendent of Documents, U.S. Government Printing Office Washingtoa, D.C. 20402 The Honorable James Wright Speaker of the House of Representatives Washington, D.C. 20515 Dear Hf. Speaker: I am pleased to transmit to the Congress the 1987 Surgeon General's Report on the health consequences of smoking, as mandated by Section B(a) of the Public Health Cigarette Smoking Act of 1969. The Act requires the Secretary of Health and Human Services to transmit a" annual report to Congress on the health consequences of smoking and such recommendations for legislation as the Secretary may deem appropriate. This report, entitled The Health Consequences of Smoking: Nicotine Addiction, examines the scientific evidence that cigarettes and other forms of tobacco are addicting. The issue of tobacco addiction has been addressed in previous Surgeon General's Reports and in the medical literature beginning in the early 1900s. Because of the recent expansion of research in this area, a thorough review of this topic is warranted. Despite the significant health risks of tobacco use outlined in previous reports, many smokers have great difficulty in quitting. This report concludes that such difficulty is in large part due to the addicting properties of nicotine, which is present in all forms of tobacco. The report further concludes that the processes that determine tobacco addiction are similar to those that determine addiction to other drugs such as heroin and cocaine. Through such understanding, health-care providers may be better able to assist tobacco users in quitting. Private health organizations, health-care providers, community groups. and government agencies should initiate or strengthen programs to inform the public of the addicting nature of tobacco use. A warning label on the addicting nature of tobacco use should be rotated with other health warnings now required on cigarette and smokeless tobacco packages and advertisements. Preventing the initiation of tobacco use must be a priority because of the difficulty in overcoming "icocine addiction once it is firmly established. Because most cases of nicotine addiction begin during childhood and adolescence, school curricula on the prevention of drug use should also include tobacco. Cigarette smoking, the chief avoidable cause of premature death in this country, is responsible for mare than 300,000 premature deaths each year. The disease impact of smoking justifies placing the problem of tobacco use at the top of the public health agenda. The conclusions of this report provide another compelling reason for strengthening our efforts to reduce tobacco use in our society. Sincerely, f$&--- `4.y Otis R. Bane", Y.D. %YPZt*ry Enclosure The Honorable George Bush President of the Senate Washington, D.C. 20515 Deer Hr. Presfdent: I am pleased to transmit t" the Congress the 1987 Surgeon General's Report an the health consequences of smoking, as mandated by Section g(a) of. the Public Health Cigarette Smoking Act of 1969. The Act requires the Secretary of Health and Human Services to transmit an annual report t" Congress on the health consequences of smoking end such recommendations for legislation as the Secretary may deem appropriate. This report, entitled The Health Consequences of Smoking: Nicotine Addiction, examines the scientific evidence that cirarettes and other forma of tobacco are addicting. The issue of tobacco addrction has been addressed in previous Surgeon General's Reports end in the medical literature beginning in the early 1900s. Because of the recent expansion of research in this area, a thorough revi.& of this topic is warranted. Despite the significant health risks of tobacco "se outlined in previous reports, many smokers have great difficulty in quitting. This report concludes that such difficulty is in large part due t" the addicting properties of nicotine, which is present i" all forms of tobacco. The report further concludes that the processes that determine tobacco addiction are similar to those that determine addiction to other drugs such as heroin and cocaine. Through such understanding, health-care providers may be better able to assist tobacco users in quitting, Private health organizations, health-care providers, community groups. and government agencies should initiate or strengthen programs to inform the public of the addicting nature of tobacco use. A vaming label on the addicting "ature of tobacco use should be rotated vith other health warnings now required on cigarette and swkelesa tobacco packages and advertisements. Preventing the initiation of tobacco use must be a priority because of the difficulty in overcoming "icotfne addiction once it is firmly established. Because m"st cases of nicotine addiction begin during childhood and adolescence, school curricula on the prevention of drug use should also include tobacco. Cigarette smoking, the chief avoidable cause of premature death in this country, is responsible for more than 300,000 premature deaths each year. The disease impact of smoking justifies placing the problem of tobacco use at the top of the public health agenda. The conclusions of this report provide another compelling Peas"" for strengthening "UT efforts to reduce tobacco use in our society. Sincerely, C&=5---& Otis R. Boven, H.D. Secretary FOREWORD This 20th Report of the Surgeon General on the health conse- quences of tobacco use provides an additional important piece of evidence concerning the serious health risks associated with using tobacco. The subject of this Report, nicotine addiction, was first mentioned in the 1964 Report of the Advisory Committee to the Surgeon General, which referred to tobacco use as "habituating." In the landmark 1979 Report of the Surgeon General, by which time considerably more research had been conducted, smoking was called "the prototypical substance-abuse dependency." Scientists in the field of drug addiction now agree that nicotine, the principal pharmacologic agent that is common to all forms of t.obacco, is a powerfully addicting drug. Recognizing tobacco use as an addiction is critical both for treating the tobacco user and for understanding why people continue to use tobacco despite the known health risks. Nicotine is a psychoactive drug with actions that reinforce the use of tobacco. Effort,s to reduce tobacco use in our society must address all the major influences that encourage continued use, including social, psychological, and phar- macologic factors. After carefully examining the available evidence, this Report concludes that: o Cigarettes and other forms of t,obacco are addicting. o Nicotine is the drug in tobacco that causes addiction. o The pharmacologic and behavioral processes that determine tobacco addiction are similar to those that determine addiction to drugs such as heroin and cocaine. We must recognize both the potential for behavioral and pharma- cologic treatment of the addicted tobacco user and the problems of withdrawal. Tobacco use is a disorder which can be remedied through medical attention; therefore, it should be approached by health care providers just as other substance-use disorders are approached: with knowledge, understanding, and persistence. Each health care provider should use every available c!inical opportunity to encourage or assist smokers to quit and to help former smokers to maintain abstinence. To maintain momentum toward a smoke-free society, we also must take steps to prevent young people from beginning to smoke. First, we must insure that every child in every school in this country is educated as to the health risks and the addictive nature of tobacco use. Most jurisdictions require that school curricula include preven- tion of drug use; therefore, education on the prevention of tobacco use should be included in this effort. Second, warning labels regarding the addictive nature of t,obacco use should be required for all tobacco packages and advertisements. Young people in particular may not be aware of the risk of tobacco addiction. Finally, parents and other role models should discourage smoking and other forms of tobacco use among young people. Parents who quit set an example for their children. Smoking continues to be the chief preventable cause of premature death in this country. Nicotine has addictive properties which help to sustain widespread tobacco use. It is gratifying to see the decline in reported smoking prevalence and cigarette consumption in the United States during the past 25 years. However, we cannot expect to see a sustained decline in rates of smoking-related cancers, cardiovascular disease, and pulmonary disease without sustained public health efforts against tobacco use. The Public Health Service is committed to preventing tobacco use among youth and to promoting cessation among existing smokers. We hope that this Report will assist the health care community, voluntary health agencies, and our Nation's schools in working with us to reduce tobacco use in our society. Robert E. Windom, M.D. Assistant Secretary for Health ii PREFACE This Report of the Surgeon General is the U.S. Public Health Service's 20th Report on the health consequences of tobacco use and the 7th issued during my tenure as Surgeon General. Eighteen Reports have been released previously as part of the health consequences of smoking series; a report on the health consequences of using smokeless tobacco was released in 1986. Previous Rep0rt.s have reviewed the medical and scientific evi- dence establishing the health effects of cigarette smoking and other forms of tobacco use. Tens of thousands of studies have documented that smoking causes lung cancer, other cancers, chronic obstructive lung disease, heart disease, complications of pregnancy, and several other adverse health effects. Epidemiologic studies have shown that cigarette smoking is responsible for more than 300,000 deaths each year in the United States. As I stated in the Preface to the 1982 Surgeon General's Report, smoking is the chief avoidable cause of death in our society. From 1964 through 1979, each Surgeon General's Report ad- dressed the major health effects of smoking. The 1979 Report provided the most comprehensive review of these effects. Following the 1979 Report, each subsequent Report has focused on specific populations (women in 1980, workers in 19851, specific diseases (cancer in 1982, cardiovascular disease in 1983, chronic obstructive lung disease in 19841, and specific topics (low-tar. low-nicotine cigarettes in 1981, involuntary smoking in 1986). This Report explores in great detail another specific topic: nicotine addiction. Careful examination of the data makes it clear that cigarettes and other forms of tobacco are addicting. An extensive body of research has shown that nicotine is the drug in tobacco that causes addiction. Moreover, the processes that determine tobacco addiction are similar to those that determine addiction to drugs such as heroin and cocaine. Actions of Nicotine All tobacco products contain substantial amounts of nicotine. Nicotine is absorbed readily from tobacco smoke in the lungs and from smokeless tobacco in the mouth or nose. Levels of nicotine in . . . 111 the blood are similar in magnitude in people using different forms of tobacco. Once in the blood stream, nicotine is rapidly distributed throughout the body. Nicotine is a powerful pharmacologic agent that acts in a variety of ways at different sites in the body. After reaching the blood stream, nicotine ent,ers the brain, interacts with specific receptors in brain tissue. and initiates metabolic and electrical activity in the brain. In addition, nicotine causes skeletal muscle relaxation and has cardiovascular and endocrine (i.e., hormonal) effects. Human and animal studies have shown that nicotine is the agent in tobacco that leads to addiction. The diversity and strength of its actions on the body are consistent with its role in causing addiction. Tobacco Use as an Addiction Standard definitions of drug addiction have been adopted by various organizations including the World Health Organization and the American Psychiatric Association. Although these definitions are not identical, they have in common several criteria for establish- ing a drug as addicting. The central element among all forms of drug addiction is that the user's behavior is largely controlled by a psychoactive substance (i.e., a substance that produces transient alterations in mood that are primarily mediated by effects in the brain). There is often compul- sive use of the drug despite damage to the individual or to society, and drug-seeking behavior can take precedence over other important priorities. The drug is "reinforcing"-that is, the pharmacologic activity of the drug is sufficiently rewarding to maintain self- administration. "Tolerance" is another aspect of drug addiction whereby a given dose of a drug produces less effect or increasing doses are required to achieve a specified intensity of response. Physical dependence on the drug can also occur, and is characterized by a withdrawal syndrome that usually accompanies drug absti- nence. After cessation of drug use, there is a strong tendency to relapse. This Report demonstrates in detail that tobacco use and nicotine in particular meet all these criteria. The evidence for these findings is derived from animal studies as well as human observations. Leading national and international organizations, including the World Health Organization and the American Psychiatric Associa- tion, have recognized chronic tobacco use as a drug addiction. Some people may have difficulty in accepting the notion that tobacco is addicting because it is a legal product. The word "addiction" is strongly associated with illegal drugs such as cocaine and heroin. However, as this Report shows, the processes that determine tobacco addiction are similar to those that determine addiction to other drugs, including illegal drugs. In addition, some smokers may not believe that tobacco is addicting because of a reluctance to admit that one's behavior is largely controlled by a drug. On the other hand, most smokers admit that they would like to quit but have been unable to do so. Smokers who have repeatedly failed in their attempts to quit probably realize that smoking is more than just a simple habit. Many smokers have quit on their own ("spontaneous remission") and some smokers smoke only occasionally. However, spontaneous remission and occasional use also occur with the illicit drugs of addiction, and in no way disqualify a drug from being classified as addicting. Most narcotics users, for example, never progress beyond occasional use, and of those who do, approximately 30 percent spontaneously remit. Moreover, it seems plausible that spontaneous remitters are largely those who have either learned to deliver effective treatments to themselves or for whom environmental circumstances have fortuitously changed in such a way as to support drug cessation and abstinence. Treatment Like other addictions, tobacco use can be effectively treated. A wide variety of behavioral interventions have been used for many years, including aversion procedures (e.g., satiation, rapid smoking), relaxation training, coping skills training, stimulus control, and nicotine fading. In recognition of the important role that nicotine plays in maintaining tobacco use, nicotine replacement therapy is now available. Nicotine polacrilex gum has been shown in controlled trials to relieve withdrawal symptoms. In addition, some (but not all) studies have shown that nicotine gum, as an adjunct to behavioral interventions, increases smoking abstinence rates. In recent years, multicomponent interventions have been applied successfully to the treatment of tobacco addiction. Public Health Strategies The conclusion that cigarettes and other forms of tobacco are addicting has important implications for health professionals, educa- tors, and policy-makers. In treating the tobacco user, health profes- sionals must address the tenacious hold that nicotine has on the body. More effective interventions must be developed to counteract both the psychological and pharmacologic addictions that accompa- ny tobacco use. More research is needed to evaluate how best to treat those with the strongest dependence on the drug. Treatment of tobacco addiction should be more widely available and should be V considered at least as favorably by third-party payors as treatment of alcoholism and illicit drug addiction. The challenge to health professionals is complicated by the array of new nicotine delivery systems that are being developed and introduced in the marketplace. Some of these products are produced by tobacco manufacturers; others may be marketed as devices to aid in smoking cessation. These new products may be more toxic and more addicting than the products currently on the market. New nicotine delivery systems should be evaluated for their toxic and addictive effects; products intended for use in smoking cessation also should be evaluated for efficacy. Public information campaigns should be developed to increase community awareness of the addictive nature of tobacco use. A health warning on addiction should be rotated with the other warnings now required on cigarette and smokeless tobacco packages and advertisements. Prevention of tobacco use should be included along with prevention of illicit drug use in comprehensive school health education curricula. Many children and adolescents who are experimenting with cigarettes and other forms of tobacco state that they do not intend to use tobacco in later years. They are unaware of, or underestimate, the strength of tobacco addiction. Because this addiction almost always begins during childhood or adolescence, children need to be warned as early as possible, and repeatedly warned through their teenage years, about the dangers of exposing themselves to nicotine. This Report shows conclusively that cigarettes and other forms of tobacco are addicting in the same sense as are drugs such as heroin and cocaine. Most adults view illegal drugs with scorn and express disapproval (if not outrage) at their sale and use. This Nation has mobilized enormous resources to wage a war on drugs - illicit drugs. We should also give priority to the one addiction that is killing more than 300,000 Americans each year. We as citizens, in concert with our elected officials, civic leaders, and public health officers, should establish appropriate public policies for how tobacco products are sold and distributed in our society. With the evidence that tobacco is addicting, is it appropriate for tobacco products to be sold through vending machines, which are easily accessible to children? Is it appropriate for free samples of tobacco products to be sent through the mail or distributed on public property, where verification of age is difficult if not impossible? Should the sale of tobacco be treated less seriously than the sale of alcoholic beverages, for which a specific license is required (and revoked for repeated sales to minors)? In the face of overwhelming evidence that tobacco is addicting, policy-makers should address these questions without delay. To vi achieve our goal of a smoke-free society, we must give this problem the serious attention it deserves. C. Everett Koop, M.D., Sc.D. Surgeon General vii ACKNOWLEDGMENTS This Report was prepared by the Department of Health and Human Services under the general editorship of the Office on Smoking and Health, Ronald M. Davis, M.D., Director. The Manag- ing Editors were Thomas E. Novotny, M.D., and William R. Lynn, Office on Smoking and Health. Scientific editors were Neal L. Benowitz, M.D., Professor of Medicine, Chief, Division of Clinical Pharmacology and Experimen- tal Therapeutics, San Francisco General Hospital, University of California, San Francisco, California; Neil E. Grunberg, Ph.D., Department of Medical Psychology, Uniformed Services University of the Health Sciences, Bethesda, Maryland; Jack E. Henningfield, Ph.D., Chief, Biology of Dependence and Abuse Potential Assessment Laboratory, Addiction Research Center, National Institute on Drug Abuse, Baltimore, Maryland; and Harry A. Lando, Ph.D., Professor, Department of Psychology, Iowa State University, Ames, Iowa. The following individuals prepared draft chapters or portions of the Report. David B. Abrams, Ph.D., Assistant Professor of Psychiatry and Human Behavior, Brown University Program in Medicine, The Miriam Hospital, Center for Health Promotion, Providence, Rhode Island Timothy B. Baker, Ph.D., Department of Psychology, University of Wisconsin, Madison, Wisconsin Neal L. Benowitz, M.D., Professor of Medicine, Chief, Division of Clinical Pharmacology and Experimental Therapeutics, San Fran- cisco General Hospital, University of California, San Francisco, California Thomas H. Brandon, M.S., Department of Psychology, University of Wisconsin, Madison, Wisconsin Richard F. Catalano, Ph.D., Research Assistant Professor, Center for Social Welfare Research, School of Social Work, University of Washington, Seattle, Washington Larry D. Chait, Ph.D., Research Associate (Assistant Professor), Department of Psychiatry, University of Chicago, Chicago, Illinois Paul B.S. Clarke, Ph.D., Department of Pharmacology and Thera- peutics, McGill University, Montreal, Quebec, Canada ix Richard R. Clayton, Ph.D., Professor, Department of Sociology, University of Kentucky, Lexington, Kentucky Allan C. Collins, Ph.D., Institute for Behavioral Genetics, School of Pharmacy, University of Colorado, Boulder, Colorado Thomas M. Cooper, D.D.S., Professor, Department of Community Dentistry, University of Kentucky, Lexington, Kentucky Lori A. Crane, M.P.H., Division of Cancer Control, Jonsson Compre- hensive Cancer Center, University of California, Los Angeles, California Susan Curry, Ph.D., Center for Health Studies, Group Health Cooperative of Puget Sound, Seattle, Washington D. Layten Davis, Ph.D., Director, Tobacco and Health Research Institute, University of Kentucky, Lexington, Kentucky Ronald M. Davis, M.D., Director, Office on Smoking and Health, Center for Health Promotion and Education, Centers for Disease Control, Rockville, Maryland Edward F. Domino, M.D., Professor, Department of Pharmacology, University of Michigan, Ann Arbor, Michigan John L. Egle, Jr., Ph.D., Department of Pharmacology/Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia Joan Ershler, Ph.D., Research Associate, Mt. Sinai Medical Center, Milwaukee, Wisconsin Raymond Fleming, Ph.D., Assistant Professor, University of Wiscon- sin-Milwaukee, Mt. Sinai Medical Center, Milwaukee, Wisconsin Kathleen A. Fletcher, Ph.D., M.P.H., Consultant, The University of Texas Health Science Center, Houston, Texas Paul J. Fudala, Ph.D., Addiction Research Center, National Institute on Drug Abuse, Baltimore, Maryland C. Gary Gairola, Ph.D., University of Kentucky, Tobacco and Health Research Institute, Lexington, Kentucky David Gilbert, Ph.D., Department of Psychology, Southern Illinois University, Carbondale, Illinois Lewayne D. Gilchrist, Ph.D., Research Associate Professor, School of Social Work, University of Washington, Seattle, Washington Donna M. Goldberg, M.A., Annapolis, Maryland Steven R. Goldberg, Ph.D., Preclinical Pharmacology Research Branch, Addiction Research Center, National Institute on Drug Abuse, Baltimore, Maryland John Grabowski, Ph.D., Department of Psychiatry and Behavioral Science, The University of Texas Health Science Center, Houston, Texas Neil E. Grunberg, Ph.D., Department of Medical Psychology, Uni- formed Services University of the Health Sciences, Bethesda, Maryland X Dorothy K. Hatsukami, Ph.D., Department of Psychiatry, University of Minnesota, Minneapolis, Minnesota J. David Hawkins, Ph.D., Professor, Center for Social Welfare Research, School of Social Work, University of Washington, Seattle, Washington Jack E. Henningfield, Ph.D., Chief, Biology of Dependence and Abuse Potential Assessment Laboratory, Addiction Research Cen- ter, National Institute on Drug Abuse, Baltimore, Maryland. Ronald I. Herning, Ph.D., Addiction Research Center, National Institute on Drug Abuse, Baltimore, Maryland Matthew Owen Howard, M.S., M.S.W., Research Assistant, Center for Social Welfare Research, School of Social Work, University of Washington, Seattle, Washington John R. Hughes, M.D., Departments of Psychiatry, Psychology, and Family Practice, University of Vermont, Burlington, Vermont Edgar T. Iwamoto, Ph.D., Department of Pharmacology, College of Medicine, University of Kentucky, Lexington, Kentucky Murray E. Jarvik, M.D., Ph.D., The Neuropsychiatric Institute and Hospital, School of Medicine, University of California, Los An- geles, Veterans' Administration Medical Center, Brentwood Divi- sion, Los Angeles, California Robert C. Klesges, Ph.D., Associate Professor, Center for Applied Psychological Research, Department of Psychology, Memphis State University, Memphis, Tennessee Lynn T. Kozlowski, Ph.D., Head, Behavioral Research on Tobacco Use, Addiction Research Foundation, Professor of Psychology and of Preventive Medicine and Biostatistics, University of Toronto, Toronto, Ontario, Canada Howard Leventhal, Ph.D., Professor and Chairman, Department of Psychology, University of Wisconsin, Madison, Wisconsin Edythe D. London, Ph.D., Chief, Neuropharmacology Laboratory, Addiction Research Center, National Institute on Drug Abuse, Baltimore, Maryland Scott E. Lukas, Ph.D., Assistant Professor of Psychiatry (Pharmacol- ogy), Harvard Medical School, Department of Psychiatry, Alcohol and Drug Abuse Research Center, McLean Hospital, Belmont, Massachusetts Alfred C. Marcus, Ph.D., Associate Director, Division of Cancer Control, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California Andrew W. Meyers, Ph.D., Professor, Center for Applied Psychologi- cal Research, Department of Psychology, Memphis State Universi- ty, Memphis, Tennessee Thomas E. Novotny, M.D., Medical Epidemiologist, Office on Smok- ing and Health, Center for Health Promotion and Education, Centers for Disease Control, Rockville, Maryland xi Carol Tracy Orleans, Ph.D., Senior Investigator, Behavioral Medi- cine and Director of Smoking Cessation Services, Division of Cancer Control, Fox Chase Cancer Center, Philadelphia, Pennsyl- vania John P. Pierce, MSc., Ph.D., Chief, Epidemiology Branch, Office on Smoking and Health, Center for Health Promotion and Education, Centers for Disease Control, Rockville, Maryland Ovide F. Pomerleau, Ph.D., Behavioral Medicine Program, Universi- ty of Michigan, Department of Psychiatry, Ann Arbor, Michigan Amelie G. Ramirez, M.P.H., Faculty Associate, The University of Texas Health Science Center, Assistant Professor, Baylor College of Medicine, Houston, Texas Jed E. Rose, Ph.D., Veterans' Administration Medical Center, Wadsworth and Brentwood Divisions, Los Angeles, California J.A. Rosecrans, Ph.D., Department of Pharmacology, Medical Col- lege of Virginia, Virginia Commonwealth University, Richmond, Virginia David P.L. Sachs, M.D., Director, Smoking Cessation Research Institute, Palo Alto, California Mary Anne Salmon, Ph.D., Research Associate, Health Services Research Center, University of North Carolina, Chapel Hill, North Carolina Nina G. Schneider, Ph.D., Associate Research Psychologist, Depart- ment of Psychiatry and Biobehavioral Sciences, UCLA School of Medicine, Research Psychologist, Psychopharmacology Unit, Vet- erans' Administration Medical Center, Brentwood Division, Los Angeles, California V.J. Schoenbach, Ph.D., Associate Professor, Department of Epide- miology, Research Associate, Health Services Research Center, University of North Carolina, Chapel Hill, North Carolina Saul Shiffman, Ph.D., Associate Professor, Department of Psycholo- gy, University of Pittsburgh, Pittsburgh, Pennsylvania Victor J. Strecher, Ph.D., Research Associate, Health Services Research Center, Assistant Professor, Department of Health Education, University of North Carolina, Chapel Hill, North Carolina David M. Warburton, Professor, Department of Psychology, Univer- sity of Reading, Whiteknights, Reading, United Kingdom Elizabeth A. Wells, Ph.D., Post-Doctoral Fellow, Center for Social Welfare Research, University of Washington, Seattle, Washington Thomas Ashby Wills, Ph.D., Assistant Professor of Psychology, Assistant Professor of Epidemiology and Social Medicine, Depart- ment of Epidemiology and Social Medicine, Ferkauf Graduate School of Psychology and Albert Einstein College of Medicine, Bronx, New York xii Phillip P. Woodson, Dr.sc.nat., Addiction Research Center, National Institute on Drug Abuse, Baltimore, Maryland The editors acknowledge with gratitude the following distin- guished scientists, physicians, and others who lent their support in the development of this Report by coordinating manuscript prepara- tion, contributing critical reviews of the manuscript, or assisting in other ways. Leo G. Abood, Ph.D., Department of Pharmacology, University of Rochester Medical Center, Rochester, New York John S. Baer, Ph.D., Department of Psychology, University of Washington, Seattle, Washington Timothy B. Baker, Ph.D., Department of Psychology, University of Wisconsin, Madison, Wisconsin Claudia R. Baquet, M.D., M.P.H., Chief, Special Populations Studies Branch, Division of Cancer Prevention and Control, National Cancer Institute, Bethesda, Maryland Glen Bennett, M.P.H., Field Studies Advisor, Office of Prevention, Education, and Control, National Heart, Lung, and Blood Insti- tute, Bethesda, Maryland George E. Bigelow, Ph.D., Associate Professor of Behavioral Biology, Director, Behavioral Pharmacology Research Unit, Department of Psychiatry and Behavioral Sciences, The Johns Hopkins Universi- ty School of Medicine, Baltimore, Maryland Clarice Brown, M.S., Data Analyst, Office of Prevention, Education, and Control, National Heart, Lung, and Blood Institute, Bethesda, Maryland David M. Burns, M.D., Associate Professor of Medicine, Division of Pulmonary and Critical Care Medicine, University of California Medical Center, San Diego, California Donald R. Cherek, Ph.D., Department of Psychiatry and Behavioral Sciences, Mental Sciences Institute, The University of Texas Health Science Center, Houston, Texas Paul B.S. Clarke, Ph.D., Department of Pharmacology and Thera- peutics, McGill University, Montreal, Quebec, Canada Ro Nemeth-Coslett, Ph.D., Psychologist, Prevention Research Branch, Division of Clinical Research, National Institute on Drug Abuse, Rockville, Maryland Thomas J. Crowley, M.D., University of Colorado Health Sciences Center, Denver, Colorado Joseph W. Cullen, Ph.D., Deputy Director, Division of Cancer Prevention and Control, National Cancer Institute, Bethesda, Maryland K. Michael Cummings, Ph.D., M.P.H., Research Scientist, Depart- ment of Cancer Control and Epidemiology, Roswell Park Memorial Institute, Buffalo, New York . . x111 Susan Curry, Ph.D., Center for Health Studies, Group Health Cooperative of Puget Sound, Seattle, Washington Vincent T. DeVita, Jr., M.D., Director, National Cancer Institute, National Institutes of Health, Bethesda, Maryland Sir Richard Doll, University of Oxford, Oxford, England Manning Feinleib, M.D., Dr.P.H., Director, National Center for Health Statistics, Centers for Disease Control, Hyattsville, Mary- land William H. Foege, M.D., Executive Director, The Carter Center of Emory University, Atlanta, Georgia Richard R. Frecker, M.D., Ph.D., Head, Biomedical Research, Department of Pharmacology, Addiction Research Foundation, Toronto, Ontario, Canada K.H. Ginzel, Ph.D., Professor, Department of Pharmacology and Interdisciplinary Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas Russell E. Glasgow, Ph.D., Oregon Research Institute, Eugene, Oregon Nancy P. Gordon, Sc.D., Behavioral Scientist, Division of Research, Kaiser Permanente Medical Group, Oakland, California Roland R. Griffiths, The Johns Hopkins University School of Medicine, Baltimore, Maryland Ellen R. Gritz, Ph.D., Director, Division of Cancer Control, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California Sharon M. Hall, Ph.D., Professor, Department of Psychiatry, Center for Social and Behavioral Sciences, University of California, San Francisco, California Louis S. Harris, Ph.D., Senior Science Advisor, National Institute on Drug Abuse, Alcohol, Drug Abuse, and Mental Health Administra- tion, Rockville, Maryland Ronald I. Herning, Ph.D., Addiction Research Center, National Institute on Drug Abuse, Baltimore, Maryland Dietrich Hoffmann, Ph.D., Associate Director, Naylor Dana Insti- tute, Valhalla, New York Leo Hollister, M.D., Medical Director, Harris County Psychiatry Center, Houston, Texas Enid Hunkeler, Senior Investigator, Kaiser Permanente Medical Care Program, Oakland, California Peyton Jacob III, Ph.D., Division of Clinical Pharmacology, San Francisco General Hospital, University of California, San Francis- co, California Jerome Jaffe, M.D., Director, Addiction Research Center, National Institute on Drug Abuse, Baltimore, Maryland Murray E. Jarvik, M.D., Ph.D., The Neuropsychiatric Institute and Hospital, School of Medicine, University of California, Los An- xiv geles, and Veterans' Administration Medical Center West LOS Angeles, Brentwood Division, Los Angeles, California Martin Jarvis, M.Phil., Senior Lecturer, Addiction Research Unit, Institute of Psychiatry, London, England Chris-Ellen Johanson, Ph.D., Department of Psychiatry, Pritzker School of Medicine, University of Chicago Drug Abuse Research Center, Chicago, Illinois Reese T. Jones, Ph.D., Department of Psychiatry, University of California School of Medicine, San Francisco, California Kenneth J. Kellar, Ph.D., Department of Pharmacology, Georgetown University Medical Center, Washington, D.C. Lynn T. Kozlowski, Ph.D., Head, Behavioral Research on Tobacco Use, Addiction Research Foundation, Toronto, Ontario, Canada Richard J. Lamb, Ph.D., Addiction Research Center, National Institute on Drug Abuse, Baltimore, Maryland Charles L. LeMaistre, M.D., President, University of Texas Systems Cancer Center, Houston, Texas Claude Lenfant, M.D., Director, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland Howard Leventhal, Ph.D., Professor of Psychology, University of Wisconsin, Madison, Wisconsin Edward Lichtenstein, Ph.D., Oregon Research Institute, Eugene, Oregon Donald Ian Macdonald, M.D., Administrator, Alcohol, Drug Abuse, and Mental Health Administration, Rockville, Maryland G. Alan Marlatt, Ph.D., Professor of Psychology, University of Washington, Seattle, Washington William R. Martin, M.D., Chairman, Department of Pharmacology, University of Kentucky College of Medicine, Lexington, Kentucky James 0. Mason, M.D., Dr.P.H., Director, Centers for Disease Control, Atlanta, Georgia J. Michael McGinnis, M.D., Deputy Assistant Secretary (Disease Prevention and Health Promotion), Washington, D.C. A. Thomas McLellan, Ph.D., Substance Abuse Treatment Research Center, Philadelphia Veterans' Administration Medical Center and The University of Pennsylvania, Philadelphia, Pennsylvania Nancy K. Mello, Ph.D., Alcohol and Drug Abuse Research Center, McClean Hospital, Belmont, Massachusetts Gregory J. Morosco, Ph.D., M.P.H., Smoking Education Program Coordinator, National Heart, Lung, and Blood Institute, Bethesda, Maryland Joseph P. Mulholland, Ph.D., Bureau of Economics, Federal Trade Commission, Washington, D.C. Herbert W. Nickens, M.D., M.A., Director, Office of Minority Health, Public Health Service, Washington, D.C. xv Richard Peto, M.A., M.Sc., Imperial Cancer Research Fund, Cancer Studies Unit, Nuffield Department of Clinical Medicine, Radcliffe Infirmary, University of Oxford, Oxford, England Roy W. Pickens, Ph.D., Director, Division of Clinical Research, National Institute on Drug Abuse, Rockville, Maryland John P. Pierce, MSc., Ph.D., Chief, Epidemiology Branch, Office on Smoking and Health, Center for Health Promotion and Education, Centers for Disease Control, Rockville, Maryland John M. Pinney, Executive Director, Institute for the Study of Smoking Behavior and Policy, John F. Kennedy School of Govern- ment, Harvard University, Cambridge, Massachusetts Michael R. Polen, M.A., Research Associate, Division of Research, Kaiser-Permanente Medical Group, Oakland, California William Pollin, M.D., Former Director, National Institute on Drug Abuse, Bethesda, Maryland David C. Ramsey, M.P.H., Health Educator, Division of Health Education, Center for Health Promotion and Education, Centers for Disease Control, Atlanta, Georgia Everett R. Rhoades, M.D., Assistant Surgeon General and Director, Indian Health Service, Rockville, Maryland M.A.H. Russell, F.R.C.P., Addiction Research Unit, Institute of Psychiatry, University of London, London, England Charles R. Schuster, Ph.D., Director, National Institute on Drug Abuse, Rockville, Maryland Burt Sharpe, M.D., Hennepin County Medical Center, Department of Medicine, Minneapolis, Minnesota Donald R. Shopland, Public Health Advisor, Smoking, Tobacco, and Cancer Program, National Cancer Institute, Bethesda, Maryland Jerome E. Singer, Ph.D., Medical Psychology, Uniformed Services University of the Health Sciences, Bethesda, Maryland Maxine L. Stitzer, Ph.D., Associate Professor, Behavioral Biology, The Johns Hopkins School of Medicine, Behavioral Pharmacology Research, Francis Scott Key Medical Center, Baltimore, Maryland David N. Sundwall, M.D., Assistant Surgeon General and Adminis- trator, Health Resources and Services Administration, Rockville, Maryland Dennis D. Tolsma, M.P.H., Director, Center for Health Promotion and Education, Centers for Disease Control, Atlanta, Georgia Frederick L. Trowbridge, M.D., Director, Division of Nutrition, Center for Health Promotion and Education, Centers for Disease Control, Atlanta, Georgia Frank J. Vocci, Jr., Ph.D., Acting Chief, Drug Abuse Staff, Center for Drug Evaluation and Research, Food and Drug Administration, Washington, DC Ronald W. Wilson, M.A., National Center for Health Statistics, Centers for Disease Control, Hyattsville, Maryland xvi Roy A. Wise, Ph.D., Department of Psychology, Concordia Universi- ty, Montreal, Quebec, Canada Faye Wright, Center for Applied Psychological Research, Depart- ment of Psychology, Memphis State University, Memphis, Tennes- see Ernst L. Wynder, M.D., President, American Health Foundation, New York, New York James B. Wyngaarden, M.D., Director, National Institutes of Health, Bethesda, Maryland Tomoji Yanagita, M.D., Ph.D., Preclinical Research Laboratories, Central Institute for Experimental Animals, Kawasaki, Japan Frank E. Young, M.D., Commissioner, Food and Drug Administra- tion, Rockville, Maryland The editors also acknowledge the contributions of the following staff members and others who assisted in the preparation of this Report. Margaret Anglin. Secretary, Office on Smoking and Health, Rock- ville, Maryland Charles Appiah, Project Clerk. Smoking and Health Project,. The Circle, Inc., McLean, Virginia John L. Bagrosky, Associate Director for Program Operations, Office on Smoking and Health, Rockville, Maryland Sonia Balakirsky, Secretary, Office on Smoking and Health, Rock- ville, Maryland Carol Bean, Associate Project Director, Smoking and Health Project, The Circle, Inc., McLean, Virginia Tamara Blair, Production Coordinator, Information Management Department, ATLIS Federal Services, Inc., Rockville, Maryland Catherine E. Burckhardt, Editorial Assistant, Office on Smoking and Health, Rockville, Maryland Gayle Christman, Word Processing Specialist, Smoking and Health Project, The Circle, Inc., McLean, Virginia Carol K. Cummings, Secretary, Office on Smoking and Health, Rockville, Maryland Stephanie D. DeVoe, Programmer, Information Systems Depart- ment, ATLIS Federal Services, Inc., Rockville, Maryland Michael C. Fiore, M.D., M.P.H., Medical Epidemiologist, Office on Smoking and Health, Rockville, Maryland David Fry, Editor, Smoking and Health Project, The Circle, Inc., McLean, Virginia Lynn Funkhauser, Word Processing Specialist, Smoking and Health Project, The Circle, Inc., McLean, Virginia Mary Gardner, Senior Editor, Smoking and Health Project, The Circle, Inc., McLean, Virginia xvii Amy Garson, M.P.H. student, Office on Smoking and Health, Rockville: Maryland -4rnetta G. Glover, Secretary, Office on Smoking and Health, Rockville, Maryland William Groskopf, Library Acquisitions Specialist, Information Management Department, ATLIS Federal Services, Inc., Rock- ville, Maryland Evridiki Hatziandreu, M.D., M.P.H., Epidemic Intelligence Service Officer, Office on Smoking and Health, Rockville, Maryland Susan A. Hawk, Ed.M., M.S., Chief, Technical Information Center, Office on Smoking and Health, Rockville, Maryland Patricia E. Healy, Technical Information Specialist, Office on Smoking and Health, Rockville, Maryland Terri L. Henry, Clerk-Typist, Office on Smoking and Health. Rockville, Maryland Timothy K. Hensley, Technical Publications Writer, Office on Smoking and Health, Rockville, Maryland Shirley K. Hickman, Data Entry Operator, Information Manage- ment Department, ATLIS Federal Services, Inc., Rockville, Mary- land Robert S. Hutchings, Associate Director for Information and Pro- gram Development, Office on Smoking and Health, Rockville, Maryland Karen Jacob, Senior Editor, Smoking and Health Project, The Circle, Inc., McLean, Virginia Sheila Jones, Word Processing Specialist, Smoking and Health Project, The Circle, Inc., McLean, Virginia Rick Keir, Senior Editor, Smoking and Health Project, The Circle, Inc., McLean, Virginia Julie Kurz, Graphics Specialist, Information Management Depart- ment, ATLIS Federal Services, Inc., Rockville, Maryland Diana Lord, Research Assistant, Department of Medical Psychology, Uniformed Services University of the Health Sciences, Bethesda, Maryland Gerri E. Mast, Secretary, Center for Health Promotion and Educa- tion, Centers for Disease Control, Atlanta, Georgia Judy J. Mast, Secretary, Center for Health Promotion and Educa- tion, Centers for Disease Control, Atlanta, Georgia Dixie McGough, Program Manager, Information Management De- partment, ATLIS Federal Services, Inc., Rockville, Maryland Paul G. McGovern, Ph.D., Postdoctoral Research Associate, Smoking Research Group, Department of Psychology, Iowa State Universi- ty, Ames, Iowa Dan McLaughlin, Editorial Assistant, Smoking and Health Project, The Circle, Inc., McLean, Virginia . . . xv111 Nancy Miltenberger, Editor. Smoking and Health Project, The Circle, Inc., McLean, Virginia Cathie O'Donnell, Senior Editor, Smoking and Health Project, The Circle, Inc., McLean, Virginia Ruth C. Palmer, Secretary, Office on Smoking and Health, Rockville, Maryland Russell D. Peek, Library Acquisitions Specialist, Information Man- agement Department, ATLIS Federal Services, Inc., Rockville, Mar.yland Mary B. Pfeiffer, M.L.S., Librarian, Addiction Research Center, National Institute on Drug Abuse, Baltimore, Maryland Margaret E. Pickerel, Public Information and Publications Special- ist, Office on Smoking and Health, Rockville, Maryland Renate Phillips, Desktop Publishing/Graphic Artist, Smoking and Health Project, The Circle, Inc., McLean, Virginia Karen Sherman, Production Assistant, Information Management Department, ATLIS Federal Services, Inc., Rockville, Maryland Linda R. Spiegelman. Administrative Officer, Office on Smoking and Health, Rockville, Maryland Tamara Shipp, Publications Assistant, Smoking and Health Project, The Circle, Inc., McLean, Virginia Evelyn L. Swarr, Systems Management Projects Supervisor, Infor- mation Systems Department, ATLIS Federal Services, Inc., Rock- ville, Maryland Patricia Y. Thomas, Secretary, Addiction Research Center, National Institute on Drug Abuse, Baltimore, Maryland Daniel R. Tisch, Project Director, Smoking and Health Project, The Circle, Inc., McLean, Virginia Louise G. Wiseman, Technical Information Specialist, Office on Smoking and Health, Rockville, Maryland xix TABLE OF CONTENTS Foreword ................................................................. i Preface .................................................................. iii Acknowledgments .................................................... ix I. Introduction, Overview, Summary, and Conclusions . . . . . . . . . . . . . . . . . . ..**............................... 1 II. Nicotine: Pharmacokinetics, Metabolism, and Phar- macodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 III. Nicotine: Sites and Mechanisms of Actions.. ........ .75 IV. Tobacco Use as Drug Dependence ..................... 145 V. Tobacco Use Compared to Other Drug Dependencies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241 VI. Effects of Nicotine That May Promote Tobacco Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377 $11. Treatment of Tobacco Dependence.. . . . . . . . . . . . . . . . . . . .459 Appendix A: Trends in Tobacco Use in the United States . . . . . , . . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . .561 Appendix B: Toxicity of Nicotine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 589 Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . , . . . . . . . . . . 619 xxi CHAPTER I INTRODUCTION, OVERVIEW, SUMMARY, AND CONCLUSIONS CONTENTS Introduction ............................................................ 5 Development and Organization of this Report ......... 5 Overview ................................................................ 6 Major Conclusions .................................................... 9 .__- Brief History Relevant to this Report .......................... 9 Chapter Conclusions ............................................... .13 Chapter II: Nicotine: Pharmacokinetics, Metabo- lism, and Pharmacodynamics ........... .13 Chapter III: Nicotine: Sites and Mechanisms of Actions ........................................ ,14 Chapter IV: Tobacco Use as Drug Dependence.. ... .14 Chapter V: Tobacco Use Compared to Other Drug Dependencies ................................. .15 Chapter VI: Effects of Nicotine That May Promote Tobacco Use .................................. .15 Chapter VII: Treatment of Tobacco Dependence .... .15 Appendix A: Trends in Tobacco Use in the United States .......................................... .16 Appendix B: Toxicity of Nicotine ....................... .16 References ............................................................ .18 3 Introduction Development and Organization of this Report This Report was developed by the Office on Smoking and Health, Center for Health Promotion and Education, Centers for Disease Control, Public Health Service of the U.S. Department of Health and Human Services as part of the Department's responsibility, under Public Law 91-222, to report new and current information on smoking and health to the United States Congress. The scientific content of this Report reflects the contributions of more than 50 scientists representing a wide variety of relevant disciplines. These experts, known for their understanding of and work in specific content areas, prepared manuscripts for incorpora- tion into this Report. The Office on Smoking and Health and its consultants edited and consolidated the individual manuscripts into appropriate chapters. These draft chapters were subjected to an extensive outside peer review (see Acknowledgments for individuals and their affiliations) whereby each chapter was reviewed by up to 11 experts. Based on the comments of these reviewers, the chapters were revised and the entire volume was assembled. This revised edition of the Report was resubjected to review by 20 distinguished scientists inside and outside the Federal Government, both in this country and abroad. Parallel to this review, the entire Report was also submitted for review to 12 institutes and agencies within the U.S. Public Health Service. The comments from the senior scientific reviewers and the agencies were used to prepare the final volume of this Report. This Report contains a Foreword by the Assistant Secretary for Health, a Preface by the Surgeon General of the U.S. Public Health Service, and the following chapters and appendices: Chapter I. Introduction. Overview, Summary, and Conclu- sions Chapter II. Nicotine: Pharmacokinetics, Metabolism, and Pharmacodynamics Chapter III. Nicotine: Sites and Mechanisms of Actions Chapter IV. Tobacco Use as Drug Dependence Chapter V. Tobacco Use Compared to Other Drug Dependencies Chapter VI. Effects of Nicotine That May Promote Tobacco Use Chapter VII. Treatment of Tobacco Dependence Appendix A. Trends in Tobacco Use in the United States Appendix B. Toxicity of Nicotine Overview This Report of the Surgeon General on tobacco and health focuses on the pharmacologic basis of tobacco addiction. Previous Surgeon General's Reports have reviewed the medical and scientific evidence establishing that cigarette smoking and tobacco use in other forms are deleterious to health. Several reports emphasized particular diseases (e.g., 1982 Report on cancer (US DHHS 1982), 1983 Report on cardiovascular disease (US DHHS 1983a), 1984 Report on chronic obstructive lung disease (US DHHS 1984a)); some reports concentrat- ed on specific populations (e.g., 1980 Report on women (US DHHS 1980)); and some reports dealt with particular aspects of smoking (e.g., 1986 Report on involuntary smoking (US DHHS 1986a)). These reports have been important because so many individuals engage in a behavior that causes morbidity and premature mortality. The present Report addresses a central issue of the tobacco and health problem: Why do people smoke and in other ways consume tobacco products? Specifically, this Report reviews the pharmacolog- ic basis of the disease-producing and life-threatening behavior of tobacco use. Psychological and social factors are also important influences on tobacco use, but a detailed review of these factors is beyond the scope of this Report. Reviews of this literature include previous reports of the Surgeon General (US DHEW 1979; US DHHS 1980, 1982, 1983a, 1984a), research monographs from the National Institute on Drug Abuse (NTDA) (Jarvik et al. 1977; Krasnegor 1978, 1979a,b,c; Grabowski and Bell 1983), and articles by scientists who study tobacco use and nicotine (Russell 1971, 1976; Gritz 1980; Henningfield 1984). This Report reviews evidence that tobacco use is addicting and that nicotine is the active pharmacologic agent of tobacco that causes this addictive behavior. Previous Surgeon General's Reports have focused on evidence that cigarette smoking and tobacco use are health hazards. Now that those relationships are well-documented and well-known, this Report addresses addictive properties of cigarette smoking and tobacco use in order to help develop more effective prevention and cessation programs. This Report topic is particularly timely because of recent advances and extensive data gathered in the 1980s relevant to the issue of tobacco addiction. Since the early 1900s scientific literature and historical anecdotes have provided evidence that tobacco use is a form of drug addiction. In the 1970s however, research efforts increased considerably on various aspects of tobacco addiction, including nicotine pharmacokinetics, pharmacodynamics, self-ad- ministration, withdrawal, dependence, and tolerance. In addition, advances in the neurosciences have begun to reveal effects of nicotine in the brain and body that may help to explain why tobacco use is reinforcing and difficult to give up. These issues are addressed 6 in this Report. Finally, recent developments in the use of nicotine replacement in smoking cessation emphasize the importance of pharmacologic aspects of cigarette smoking. Concepts of drug addiction or drug dependence are discussed in detail in Chapters IV and V. It is useful to begin this Report with a brief summary of main points about drug dependence that provide the foundation for the findings of the Report. The terms "drug addiction" and "drug dependence" are scientifi- cally equivalent: both terms refer to the behavior of repetitively ingesting mood-altering substances by individuals. The term "drug dependence" has been increasingly adopted in the scientific and medical literature as a more technical term, whereas the term "drug addiction" continues to be used by NIDA and other organizations when it is important to provide information at a more general level. Throughout this Report, both terms are used and they are used synonymously. The main conclusions of the Report are based upon concepts of drug dependence that have been developed by expert committees of the World Health Organization, as well as in publications of NIDA and the American Psychiatric Association. These concepts were used to develop a set of criteria to determine whether tobacco-delivered nicotine is addicting. The criteria for drug dependence include primary and additional indices and are summarized below. CRITERIA FOR DRUG DEPENDENCE Primary Criteria . Highly controlled or compulsive use . Psychoactive effects . Drug-reinforced behavior Additional Criteria . Addictive behavior often involves: -stereotypic patterns of use -use despite harmful effects -relapse following abstinence -recurrent drug cravings . Dependence-producing drugs often produce: -tolerance -physical dependence -pleasant (euphoriantl ef'fects The primary crit.eria listed above are sufficient to define drug dependence. Highly controlled or compulsive use indicates that drug- seeking and drug-taking behavior is driven by strong, often irresisti- ble urges. It can persist despite a desire to quit or even repeated attempts to quit. Such behavior is also referred to as "habitual" behavior. To distinguish drug dependence from habitual behaviors not involving drugs, it must be demonstrated that a drug with psychoactive (mood-altering) effects in the brain enters the blood stream. Furthermore, drug dependence is defined by the occurrence of drug-motivated behavior; therefore, the psychoactive chemical must be capable of functioning as a reinforcer that can directly strengthen behavior leading to further drug ingestion. Additional criteria are often used to help characterize drug dependence. Several are associated with the drug-taking behavior itself': (1) the behavior may develop into regular temporal and physical patterns of use (repetitive and stereotypic); (2) drug use may persist despite adverse physical, psychological, or social conse- quences; (3) quitting episodes are often followed by resumption of drug use (relapse); (4) urges (cravings) to use the drug may be recurrent and persistent, especially during drug abstinence. Similar- ly, several common effects of dependence-producing drugs can strengthen their control over behavior and increase the likelihood of harm by contributing to the regularity and overall level of drug intake: (1) diminished responsiveness (tolerance) to the effects of a drug occurs, and may be accompanied by increased intake over time; (2) abstinence-associated withdrawal reactions (due to physical dependence) can motivate further drug intake; (3) effects that are considered pleasant (euphoriant) to the drug user can be provided by the drug itself. Dependence-producing drugs can also produce effects that individuals find useful. For example, many addicting drugs have therapeutic uses in medical treatments of various disorders. Most medically approved drugs that are addicting, however, are generally only available by prescription. Effects of a drug considered by the individual to be useful can promote initiation of drug use, strengthen the addiction, and contribute to relapse following cessa- tion of use. Tobacco and nicotine are considered in the Report in light of the above criteria. In brief, the organization of the Report is as follows: review of evidence that tobacco use is accompanied by orderly patterns of uptake of nicotine in the body and brain resulting in the development of tolerance (Chapter II); review of how effects of nicotine in the brain and the rest of the body are chemically mediated (Chapter 1111; review of the evidence that tobacco is addicting and that nicotine is an addicting drug (Chapter IV); comparison of tobacco use with other addictions and of nicotine with other addicting drugs (Chapter VI: review of possible effects of nicotine that may promote the use of tobacco and present impedi- ments to quitting smoking (Chapter VII; review of strategies for 8 helping people to achieve and maintain tobacco abstinence (Chapter VII). In addition, appendices are included that summarize informa- tion regarding trends in tobacco use (Appendix A) and information regarding the toxicity of nicotine itself (Appendix BI. A summary of the main findings of the Report follows. Major Conclusions 1. Cigarettes and other forms of tobacco are addicting. 2. Nicotine is the drug in tobacco that causes addiction. 3. The pharmacologic and behavioral processes that determine tobacco addiction are similar to those that determine addiction to drugs such as heroin and cocaine. Brief History Relevant to this Report Tobacco products have been used for centuries. The tobacco plant was native to the New World. The oldest cited evidence of tobacco use appears on a Mayan stone carving dated from 600 to 900 A.D. There are reports of tobacco smoking in Christopher Columbus' diary in 1492; reports of tobacco smoking appear in the logs of other European explorers of the New World in the 16th century. Since the colonial period, tobacco has been an integral part of the American economy (Robert 19491. Tobacco use permeated the New World and quickly spread throughout the rest of the world during the 16th and 17th centuries. As use of tobacco products spread, so did controversy over the effects of these products. Throughout history, while some persons extolled the virtues of tobacco (including numerous alleged medicinal uses), others condemned its use. George Washington is attributed with exhorting the home front during the Revolutionary War, "If you can't send money, send tobacco." In contrast, Dr. Benjamin Rush condemned tobacco use in his 1798 book Essa,vs. The controversy continued into the 19th century with no convincing scientific or medical evidence to support either position (Robert 1949). In 1856-57 the British medical journal Lancet published opinions of 50 physicians on tobacco use. Many opponents attributed in- creased crime, nervous paralysis, loss of intellectual abilities, and visual impairment to tobacco use-all of these claims lacked convincing evidence. In restating the main arguments of the tobacco proponents, the Lancet editors wrote that tobacco use "...must have some good or at least pleasurable effects; that, if its evil effects were 9 so dreadful as stated the human race would have ceased to exist" (Lancet 1857). While the health-promoting and health-damaging effects of tobac- co products were being debated throughout the 17th and 18th centuries, scientists were trying to determine the chief active ingredient in tobacco. In the early 1800s the oily essence of tobacco was discovered by Cerioli and by Vauquelin. This active substance was named "Nicotianine," after Jean Nicot, who sent tobacco seeds from Portugal to the French court at the end of the 16th century. In 1828, Posselt and Reimann at the University of Heidelberg isolated the pure form of Nicotianine and renamed it, "Nikotin." The chemical's empirical formula, C10H,4N2, was determined in the 184Os, and "nicotine" was synthesized in the 1890s (Robert 1949). Since the late 1800s research on the pharmacologic actions of nicotine has contributed substantially to basic information about the nervous system (Kharkevich 1980; Volle 1980). The classic work by Langley and Dickinson (18891 on nicotine's effects in autonomic ganglia led to the postulates that chemicals transmit information between neurons and that there are receptors on cells that respond functionally to stimulation by specific chemicals. As early as the 1920s and 1930s some investigators were concluding that nicotine was responsible for the compulsive use of tobacco products (Arm- strong-Jones 1927; Dorsey 1936; Lewin 1931). Johnston (1942) concluded that, "smoking tobacco is essentially a means of adminis- tering nicotine, just as smoking opium is a means of administering morphine." Throughout the 20th century, research has continued to investi- gate the role of nicotine in tobacco use. The 1964 Report of the Surgeon General's Advisory Committee on Smoking and Health (US PHS 19641 held that: "The habitual use of tobacco is related primarily to psychological and social drives, reinforced and perpetu- ated by the pharmacologic actions of nicotine on the central nervous system. Nicotine-free tobacco or other plant materials do not satisfy the needs of those who acquire the tobacco habit." The 1964 Report, relying upon a distinction (that is no longer made) between "habituating" and "addicting" drugs. asserted that tobacco was habituating and not addicting. The distinction in 1964 between habituating drugs iincluding cocaine and amphetamines) and addict- ing drugs (including opiates and barbiturates) was based on: (1) whether the drug produced clear physical dependence; (2) whether damage was mainly to the individual user (habituating drugs) or to society (addicting drugs); and (3) the strength of the habitual behavior that developed. There was no question at the time of the 1964 Report that nicotine was the critical pharmacologic agent for tobacco use, but its role was then considered to be more similar to cocaine and amphetamines than to opiates and barbiturates. Later 10 in 1964 the World Health Organization dropped this semantic distinction between habituating and addicting drugs because it was recognized that habitual use could be as strongly developed for cocaine as for morphine. that social damage generally accompanied personal damage, and that behavioral characteristics of drug use could be similar for the so-called habituating and addicting drugs. In an effort to shift the focus to dependent patterns of behavior and away from moral and social issues associated with the term addiction, the term dependence was recommended. It is now clear that even by the earlier distinction in nomencla- ture, cigarettes and other forms of tobacco are addicting and actions of nicotine provide the pharmacologic basis of tobacco addiction. The term "dependence producing" may also be used to describe cigarettes and other forms of tobacco use, analogous to actions of other drugs (e.g., opiates, cocaine). Since 1964, considerable additional evidence has been compiled that substantiates these conclusions. The present Report reviews this information and the relevant literature. Previous Surgeon General's Reports provided current reviews of the health consequences of cigarette smoking particularly relevant to public health. For example, despite the accumulating evidence, in the early 1960s there was little recognition by the public of the health hazards of smoking. Each Report examined specific informa- tion considered to be important for public dissemination. A brief review of topics addressed in these reports provides the background for the present Report. In the late 195Os, the U.S. Public Health Service, the National Cancer Institute, the National Heart Institute, the American Cancer Society, and the American Heart Association appointed a study group to examine the available evidence on smoking and health. This study group concluded that excessive cigarette smoking is a causative factor in lung cancer. In 1962, Surgeon General Luther Terry established an advisory committee on smoking and health. This committee released its Report on January 11, 1964, concluding that cigarette smoking is a cause of lung cancer in men and a suspected cause of lung cancer in women, and increased the risk of dying from pulmonary emphysema. The next Report was issued in 1967 (US PHS 1968a) and stated that "the case for cigarette smoking as the principal cause of lung cancer is overwhelming." Further, the 1967 Report concluded that: "There is an increasing convergence of many types of evidence . . . which strongly suggests that cigarette smoking can cause death from coronary heart disease." The 1967 Report also concluded that "Cigarette smoking is the most important of the causes of chronic non-neoplastic bronchopulmonary disease in the United States." The 1968 and 1969 Reports (US PHS 1968b, 1969) strengthened the conclusions reached in 1967. The 1971 Report provided a detailed 11 review of the evidence to date regarding health consequences of smoking (US DHEW 1971). The subsequent reports (1972 to 1976) continued to review the increasing evidence associating cigarette smoking with many health hazards. The 1972 Report also discussed involuntary or passive smoking (US DHEW 1972). The 1973 Report included some data on the health hazards of smoking pipes and cigars (US PHS 1973). The 1975 Report updated information on the health effects of involuntary or passive smoking (US DHEW 1975). The combined 1977-78 Report discussed smoking-related problems unique to women (US DHEW 1978). At the time of its release, the 1979 Report was the most comprehensive review by a Surgeon General's Report of the health consequences of smoking, smoking behavior, and smoking control. In addition to providing a thorough review of the health consequences of smoking, the 1979 Report discussed the health consequences of using forms of tobacco other than cigarettes (pipes, cigars, and smokeless tobacco). Moreover, the 1979 Report expanded the scope of the previous reports and examined behavioral, pharmacologic, and social factors influencing the initiation, maintenance, and cessation of cigarette smoking. Relevant to the topic of the present Report, the 1979 Report concluded that "it is no exaggeration to say that smoking is the prototypical substance-abuse dependency and that improved knowledge of this process holds great promise for preven- tion of risk." Since the release of the 1979 Report, each subsequent Report has focused on a specific population or setting (women in 1980 (US DHHS 19801, the workplace in 1985 (US DHHS 1985)), a specific topic (health effects of low-tar and low-nicotine cigarettes in 1981 (US DHHS 19811, involuntary smoking in 1986 (US DHHS 1986a)), or a specific disease (cancer in 1982 (US DHHS 19821, cardiovascular diseases in 1983 (US DHHS 1983aL chronic obstruc- tive lung disease in 1984 (US DHHS 1984al). In addition to the previous Surgeon General's Reports, several other developments and publications provide relevant background for the present Report. For example, numerous monographs pre- pared in the 1970s by the National Institute on Drug Abuse (NIDA) considered tobacco use as a form of drug dependence. In 1980, the American Psychiatric Association, in its Diagnostic and Statistical Manual of Mental Disorders, included tobacco dependence as a substance abuse disorder and tobacco withdrawal as an organic mental disorder (APA 1980). The 1987 revised edition of this manual tAPA 1987), in recognition of the role of nicotine, changed "tobacco withdrawal" to "nicotine withdrawal." In 1982, the Director of NIDA testified to Congress that the position of NIDA was that tobacco use could lead to dependence and that nicotine was a prototypic dependence-producing drug. In a 1983 publication, "Why People Smoke Cigarettes," the U.S. Public Health Service supported this position of NIDA regarding tobacco and nicotine (US DHHS 1983133. In the 1984 NIDA Triennial Report to Congress, nicotine was labeled a prototypic dependence-producing drug and the role of nicotine in tobacco use was considered to be analogous to the roles of morphine, cocaine, and ethanol, in the use of opium, coca-derived products, and alcoholic beverages, respectively (US DHHS 1984b3. In 1986, a consensus conference of the National Institutes of Health and the Report of the Advisory Committee to the Surgeon General on the health consequences of using smokeless tobacco concluded that smokeless tobacco can be addicting and that nicotine is a depen- dence-producing (i.e., addicting) drug (US DHHS 1986b). The present Report is the 20th such report issued by the Public Health Service on the health consequences of tobacco use. The deleterious effects of cigarette smoking are now well known. Therefore, this Report focuses on pharmacologic information to help understand why people smoke. Such information will assist health professionals in developing effective strategies to prevent initiation and to promote cessation. The literature reviewed in this Report indicates that tobacco use is an addictive behavior. It is the purpose of this Report to thoroughly review the relevant literature. Chapter Conclusions In addition to the three overall conclusions of this Report, there are many other substantive conclusions. These points are listed under the appropriate Chapter and Appendix headings. Chapter II: Nicotine: Pharmacokinetics, Metabolism, and Phar- macodynamics 1. All tobacco products contain substantial amounts of nicotine and other alkaloids. Tobaccos from low-yield and high-yield cigarettes contain similar amounts of nicotine. 2. Nicotine is absorbed readily from tobacco smoke in the lungs and from smokeless tobacco in the mouth or nose. Levels of nicotine in the blood are similar in magnitude in people using different forms of tobacco. With regular use, levels of nicotine accumulate in the body during the day and persist overnight. Thus, daily tobacco users are exposed to the effects of nicotine for 24 hr each day. 3. Nicotine that enters the blood is rapidly distributed to the brain. As a result, effects of nicotine on the central nervous system occur rapidly after a puff of cigarette smoke or after absorption of nicotine from other routes of administration. 4. Acute and chronic tolerance develops to many effects of nicotine. Such tolerance is consistent with reports that initial 13 use of tobacco products, such as in adolescents first beginning to smoke. is usually accompanied by a number of unpleasant symptoms which disappear following chronic tobacco use. Chapter III: Nicotine: Sites and Mechanisms of Actions 1. Nicotine is a powerful pharmacologic agent that acts in the brain and throughout the body. Actions include electrocortical activation, skeletal muscle relaxation, and cardiovascular and endocrine effects. The many biochemical and electrocortical effects of nicotine may act in concert to reinforce tobacco use. 2. Nicotine acts on specific binding sites or receptors throughout the nervous system. Nicotine readily crosses the blood-brain barrier and accumulates in the brain shortly after it enters the body. Once in the brain, it interacts with specific receptors and alters brain energy metabolism in a pattern consistent with the distribution of specific binding sites for the drug. 3. Nicotine and smoking exert effects on nearly all components of the endocrine and neuroendocrine systems (including catechol- amines, serotonin, corticosteroids, pituitary hormones). Some of these endocrine effects are mediated by actions of nicotine on brain neurotransmitter systems (e.g., hypothalam- ic-pituitary axis). In addition, nicotine has direct peripherally mediated effects (e.g., on the adrenal medulla and the adrenal cortex). Chapter IV: Tobacco Use as Drug Dependence 1. Cigarettes and other forms of tobacco are addicting. Patterns of tobacco use are regular and compulsive, and a withdrawal syndrome usually accompanies tobacco abstinence. 2. Nicotine is the drug in tobacco that causes addiction. Specifi- cally, nicotine is psychoactive ("mood altering") and can provide pleasurable effects. Nicotine can serve as a reinforcer to motivate tobacco-seeking and tobacco-using behavior. Toler- ance develops to actions of nicotine such that repeated use results in diminished effects and can be accompanied by increased intake. Nicotine also causes physical dependence characterized by a withdrawal syndrome that usually accompa- nies nicotine abstinence. 3. The physical characteristics of nicotine delivery systems can affect their toxicity and addictiveness. Therefore, new nicotine delivery systems should be evaluated for their toxic and addictive effects. 14 Chapter V: Tobacco Use Compared to Other Drug Dependen- cies 1. The pharmacologic and behavioral processes that determine tobacco addiction are similar to those that determine addiction to drugs such as heroin and cocaine. 2. Environmental factors including drug-associated stimuli and social pressure are important influences of initiation, patterns of use, quitting, and relapse to use of opioids, alcohol, nicotine, and other addicting drugs. 3. Many persons dependent upon opioids, alcohol, nicotine, or other drugs are able to give up their drug use outside the context of treatment programs; other persons, however, re- quire the assistance of formal cessation programs to achieve lasting drug abstinence. 4. Relapse to drug use often occurs among persons who have achieved abstinence from opioids, alcohol, nicotine, or other drugs. 5. Behavioral and pharmacologic intervention techniques with demonstrated efficacy are available for the treatment of addiction to opioids, alcohol, nicotine, and other drugs. Chapter VI: Effects of Nicotine That May Promote Tobacco Dependence 1. After smoking cigarettes or receiving nicotine, smokers per- form better on some cognitive tasks (including sustained attention and selective attention) than they do when deprived of cigarettes or nicotine. However, smoking and nicotine do not improve general learning. 2. Stress increases cigarette consumption among smokers. Fur- ther, stress has been identified as a risk factor for initiation of smoking in adolescence. 3. In general, cigarette smokers weigh less (approximately 7 lb less on average) than nonsmokers. Many smokers who quit smoking gain weight. 4. Food intake and probably metabolic factors are involved in the inverse relationship between smoking and body weight. There is evidence that nicotine plays an important role in the relationship between smoking and body weight. Chapter VII: Treatment of Tobacco Dependence 1. Tobacco dependence can be treated successfully. 2. Effective interventions include behavioral approaches alone and behavioral approaches with adjunctive pharmacologic treatment. 15 3. Behavioral interventions are most effective when they include multiple components (procedures such as aversive smoking, skills training, group support, and self-reward). Inclusion of too many treatment procedures can lead to less successful out- come. 4. Nicotine replacement can reduce tobacco withdrawal symp- toms and may enhance the efficacy of behavioral treatment. Appendix A: Trends in Tobacco Use in the United States 1. An estimated 32.7 percent of men and 28.3 percent of women smoked cigarettes regularly in 1985. The overall prevalence of smoking in the United States decreased from 36.7 percent in 1976 (52.4 million adults) to 30.4 percent in 1985 (51.1 million adults). 2. In 1985, the mean reported number of cigarettes smoked per day was 21.8 for male smokers and 18.1 for female smokers. 3. Smoking is more common in lower socioeconomic categories (blue-collar workers or unemployed persons, less educated persons, and lower income groups) than in higher socioeconom- ic categories. For example, the prevalence of smoking in 1985 among persons without a high school diploma was 35.4 percent, compared with 16.5 percent among persons with postgraduate college education. 4. An estimated 18.7 percent of high school seniors reported daily use of cigarettes in 1986. The prevalence of daily use of one or more cigarettes among high school seniors declined between 1975 and 1986 by approximately 35 percent. Most of the decline occurred between 1977 and 1981. Since 1976, the smoking prevalence among females has consistently been slightly higher than among males. 5. The use of cigars and pipes has declined 80 percent since 1964. 6. Smokeless tobacco use has increased substantially among young men and has declined among older men since 1975. An estimated 8.2 percent of 17- to 19-year-old men were users of smokeless tobacco products in 1986. Appendix B: Toxicity of Nicotine 1. At high exposure levels, nicotine is a potent and potentially lethal poison. Human poisonings occur primarily as a result of accidental ingestion or skin contact with nicotine-containing insecticides or, in children, after ingestion of tobacco or tobacco juices. 2. Mild nicotine intoxication occurs in first-time smokers, non- smoking workers who harvest tobacco leaves, and people who 16 chew excessive amounts of nicotine polacrilex gum. Tolerance to these effects develops rapidly. 3. Nicotine exposure in long-term tobacco users is substantial, affecting many organ systems (Chapters II and III). Pharmace logic actions of nicotine may contribute to the pathogenesis of smoking-related diseases, although direct causation has not yet been determined. Of particular concern are cardiovascular disease, complications of hypertension, reproductive disorders, cancer, and gastrointestinal disorders, including peptic ulcer disease and gastroesophageal reflux. 4. The risks of short-term nicotine replacement therapy as an aid to smoking cessation in healthy people are acceptable and substantially outweighed by the risks of cigarette smoking. 17 References AMERI(`XN PSYCIII,\TRIC` ASSOCIATION. Diagno,stic und Staf~slic.al Manual of Mental Dtsortlr~ Washington. D.C: American Psychiatric Association, 1980. AMERICAN PSYCHIATRIC ASSOCIATION. nin,onoat;c and Statrstictr/ Manual of Mental D/sortfcv~ Third Editron, Kevijcd. Washington, D.C.: American Psychiatric Association. 1987 ARMSTRONG-JONES, R. Tobacco, its use and abuse. From the nervous and mental aspect. Pro<,titlor:er 118%19. 1927. DORSEY. J.L. Control of the tobacco habit. Arruais ofIntwnaI Medicine 10(4~:628-631, 1936. GRABOWSKI, J.. BELL, C.S. Measltwnzcnt in the Analysis and Treatment ofSmoking Behor,ior. NIDA Researcn Monograph 49. U.S. Department of Health and Human Services. Public Health Service. Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse. DHHS Publication No. (ADM) 83.1285. 1983. GRITZ. E.R. Smoking behavior and tobacco abuse. In. Mello. N.K. ted.1 AdLunces in Substance Abusr. Volume 1. Greenwich, Connecticut: JAI Press, 1980, pp. 91-158. HENNINGFIELD, J.E. Behavioral pharmacology of cigarette smoking. In: Thompson, T Dews. P.B., Barrett, J.E. teds.1 ilrlI,trnces in Beha~~wral Pharmacology, Volume 4. Orlando: Academic Press. 1984. pp. 131-210. clARVIK, M.E.. CIJLLEN, J.W., GRITZ, E.R., \`OGT, T M., WEST, L.J. (eds.1 Research on Smokrn~ Beha~~ior. NIDA Research Monograph 17. U.S. Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, Sational Institute on Drug Abuse. DHEW Publication No. IADM, X-581. 1977. .JOHNSTON, L.M Tobacco smoking and nicotine. Lancet 2:`742, 1942. KHARKEVICH, D.A. ted.1 I1ortdbook of E.rper.imrntu/ Pharmacologic. Berlin: Spring- er-\?erlag. 1980. pp. 1-H. KRASNEGOR, N.A. fed.1 Self-AtfnzrnistrutIon of Abused Sabstance.s: Methods fiu Stud,v. NIDX Research Monograph 20 U.S. Department of Health, Education. and Welfare, Public Hea!th Service. Alcohol, Drug Abuse, and Mental Health Administration. National Institute on Drug Abuse. DHEW Publication No. tADMl 78-727, 1978. KRASNEGOR, N.A. ted.1 R~~hac~ioral Analysis and Trrutrnent 01` Substance Abuse. NIDA Research Monograph 2. 5. U.S. Department of Health, Education, and Welfare, Public Hralth Service. Alcohol, Drug Abuse, and Mental Health Administration. National Institute on Drug Abuse. DHEW Publication No. tADMl 79-839. 1979a. KRASNEGOR, N.A. ced.1 The Bc~har~ioral Aspects of Smokrng. NIDA Research >fIonograph 26. U.S. Department ot Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse. DHEW Publication No. iADMl 79-888, 197913. KRASNEGOR. NA led.1 (`i,qarrtfr Snrnkin~ ns o Dqxwdc~nw Process. NIDA Research Monograph 23 U.S. Department of Health. Education. and Welfare, Public Health Service. Alcohol, Drug Abuse. and Mental Health Administration. National Institute on Drug Abuse. DHEW Publication No. !ADMl 79-800. 1979c. LANCET (Editorial I :%70. .March 15, 1857. LANGLEY. J.N.. DICKINSON. W.L On the local paralysis of the peripheral ganglia and on the connexion of different classes of nerve fibers with them. Proc. Roy11 .`+K~. Londm 46:4'3-431. 1889. LEWIS. L. Phanfostic~a: .\-arrvtrc- and Strmulating Drags. Their Use and Abuse. London: Paul. Trench, Trubner. 1931. ROBERT, J 0. The Stan, of Tobacco in Anrerrca. Chapel Hill: University of North Carolina Press. 1949. 18 RUSSELL, M.A.H. Cigarette smoking. Natural history of a dependence of disorder. British Journal of Medical Psychology 4411):1-16. May 1971. RUSSELL, M.A.H. Tobacco smoking and nicotine dependence. In: Gibbins. R.J.. Israel. Y.. Kalant. H., Popham, R.E.. Schmidt, W , Smart, R.G. teds.1 Research Adcbances in Alcohol and Drug Problems. New York: John Wiley and Sons, 1976. pp. 1-47 U.S DEPARTMENT OF HEALTH AND HUMAN SER\`ICES. The Health C;mse- quences of Smoking for Women. A Report of the Sur~cw CerlwaI. U S. Department of Health and Human Services, Public Health Service, Office of the Sissistant Secretary for Health, Office on Smoking and Health. 1980. U.S. DEPARTMENT OF HEALTH AND HlJhIAS SER\.ICES The Health (hnse- quences ofSmoklng: The Changing Cigarette. A Report of the Surgeon General. L1.S. Department of Health and Human Services, Public Health Service. Office of the Assistant Secretary for Health, Office on Smoking and Health. DHHS Pubiication No. !PHS, 81-50156, 1981. U.S. DEPARTMENT OF HEALTH AND HUM.4S SERVICES. The Health Cor~w quences of Smoking: Cancer. A Report of the Sur;peon (;efrerul. U.S. Department of Health and Human Services, Public Health Service, Office on Smoking and Health. DHHS Publication No. ~PHSI 82-50179. 1962. US. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse- quences of Smoking: Cardiocascular Disease. A Report of the Surgeon General. U.S. Department of Health and Human Services, Public Health Service, Office on Smoking and Health. DHHS Publication No. IPHS~ 84-50204, 1983a. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. Why People Smoke Cigarettes. U.S. Department of Health and Human Services, Public Health Service. 1983b. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse- quences of Smoking. Chronic Obstructilse Lung Disease. A Report of the Surgeon General. U.S. Department of Health and Human Services. Public Health Service, Office on Smoking and Health. DHHS Publication No. (PHSI 8450205. 1984a. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. Drug 4buse and Drug Abuse Research, Triennial Report to Congress from the Secretup, Department of Health and Human Ser[,ices. U.S. Department of Health and Human Services, Public Health Service, Alcohol. Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse. DHHS Publication No. IADMI 85-1372, January 1984b. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse- quences of Smoking: Cancer and Chronic Lung Disease in the Workplace. A Report of the Surgeon General. IJ.S. Department of Health and Human Services, Public Health Service, Office on Smoking and Health. DHHS Publication No. tPHS, 8% 50207, 1985. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse- quences of Inuoluntayv Smoking. A Report of the Surgeon General. US. Depart- ment of Health and Human Services, Public Health Service. Office on Smoking and Health. DHHS Publication No. lCDCi 87-8398, 1986a. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse- quences of Using Smokeless Tobnrcu. .4 Report of the Adc,woyl, Committee to the Surgeon General. U.S. Department of Health and Human Services, Public Health Service. National Institutes of Health. NIH Publication No. 862874, 1986b. U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE The Health Consequences of Smoking. A Report of the Surgeotl Gner-ol: 1971. U.S Department of Health, Education, and Welfare, Public Health Service. Health Services and Mental Health Admmistration. DHEW Publication No. `IISMi 71-7.513. 1971. 19 U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE. The Health Conseywtzces of Smoking. A Report of the Surgeon General: 1972. U.S. Department of Health, Education, and Welfare, Public Health Service, Health Services and Mental Health Administration. DHEW Publication No. lHSM) 72-7516, 1972. US. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE. The Health Conseyrrences of Smoking, 1975. U.S. Department of Health, Education, and Welfare, Public Health Service, Center for Disease Control. DHEW Publication NO. (CDCj 77-8704. 1975. U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE. The Health Consequences of Smoking, 1977.1978. U.S. Department of Health, Education, and Welfare, Public Health Service, Office of the Assistant Secretary for Health, Office on Smoking and Health. DHEW Publication No. (PHS) 7950065, 1978. U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE. Smoking and Health: A Report of the Surgeon General. U.S. Department of Health, Education, and Welfare, Public Health Service, Office of the Assistant Secretary for Health, Office on Smoking and Health. DHEW Publication No. (PHS) 79-50066, 1979. U.S. PUBLIC HEALTH SERVICE. Smoking and Health. Report of the Advisory Committee to the Surgeon General of the Public Health Service. U.S. Department of Health, Education. and Welfare, Public Health Service, Center for Disease Control. PHS Publication No. 1103, 1964. U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking. A Public Sercice Reuiewt 1967. US. Department of Health, Education, and Welfare, Public Health Service, Health Services and Mental Health Administration. PHS Publica- tion No. 1696 Revised, 1968a. US. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking, 1968. Supplement to the 1967 Public Health Seruice Review. U.S. Department of Health, Education, and Welfare, Public Health Service, Health Services and Mental Health Administration. DHEW Publication No. 1696, 1968b. U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking 1969. Supplement to the 1967 Public Health Service Review. Department of Health, Education, and Welfare, Public Health Service, Health Services and Mental Health Administration. DHEW Publication No. 1969-2, 1969. U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking. A Report of the Surgeon General. U.S. Department of Health, Education, and Welfare, Public Health Service, Health Services and Mental Health Administration. DHEW Publication No. (HSM) 73-8704, 1973. U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking, 1974. U.S. Department of Health. Education, and Welfare, Public Health Service, Center for Disease Control. DHEW Publication No. (CD0 74-8704, 1974. U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking. A Reference Edition: 1976. U.S. Department of Health, Education, and Welfare, Public Health Service, Center for Disease Control. DHEW Publication No. (CDC) 78-8357, 1976. VOr,LE, R.L. Nicotinic ganglion-stimulating agents. Pharmacologv of Gangglionic Transmission 9:281-307. 1980. 20 CHAPTER II NICOTINE: PHARMACOKINETICS, METABOLISM, AND PHARMACODYNAMICS CONTENTS ___ Introduction ........................................................... 25 ~-~ Nicotine and Other Alkaloids in Various Tobacco Prod- ucts ................................................................... 26 Pharmacokinetics and Metabolism of Nicotine ............ .29 Absorption of Nicotine ..................................... .29 Distribution of Nicotine in Body Tissues ............. ..3 1 Elimination of Nicot.ine 33 ....................................... Pathways of Nicotine Metabolism ................ 34 Rate of Nicotine Metabolism ........................ .37 Renal Excretion ....................................... .37 Nicotine and Cotinine Blood Levels During Tobacco Use .............................................................. 37 Nicotine Levels ........................................... 37 Cotinine Levels ........................................... 38 Intake of Nicotine ............................................. 40 Cigarette Smoking ...................................... .40 Elimination Rate as a Determinant of Nicotine Intake by Cigarette Smoking .................... .40 Biochemical Markers of Nicotine Intake ........ .41 Analytical Methods for Measuring Nicotine and Cotinine in Biological Fluids ............................ .42 Pharmacodynamics of Nicotine ................................. .43 General Considerations ....................................... 43 Dose-Response .................................................. .44 Tolerance ......................................................... 44 Acute Sensitivity .............................................. .46 Human Studies ........................................... 46 Animal Studies ........................................... 46 Mechanisms of Differences in Acute Sensitivity. .............................................. 47 Tachyphylaxis (Acute Tolerance) ......................... .47 Human Studies .......................................... .47 Animal Studies ........................................... 49 Mechanisms of Tachyphylaxis ...................... .49 Chronic Tolerance ............................................. .50 Human Studies. ......................................... .50 23 Animal Studies ........................................... 51 Mechanisms of Chronic Tolerance ................. .53 Pharmacodynamics of Nicotine and Cigarette Smok- ing ............................................................... 55 Constituents of Tobacco Smoke Other Than Nicotine With Potential Behavioral Effects .......................... .56 Minor Tobacco Alkaloids .................................... .56 "Tar" and Selected Constituents of Tobacco Smoke Which Contribute to Taste and Aroma .............. .58 Carbon Monoxide ............................................... 59 Acetaldehyde and Other Smoke Constituents ......... .60 Summary and Conclusions ....................................... .60 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .62 24 introduction Chemicals with behavioral and physiological activity are delivered to tobacco users when they smoke a cigarette or use other tobacco products. Whether these chemicals are absorbed in quantities that are of biological significance and whether such absorption is related to the behavior of the tobacco user are critical issues in understand- ing their role in addictive tobacco use. The scientific study of the absorption processes, distribution within the body, and elimination from the body of drugs and chemicals is called pharmacokinetics. The study of drug and other chemical actions on the body, over time, is called pharmacodynamics. Pharmacokinetic and pharmacodynamic studies can be done separately or together. An example of the latter is when a drug is administered and its concentrations in the blood and its behavioral and physiological actions are measured over time. Such studies can reveal relationships among the dose of a drug, levels in the blood, and effects on body functions. The pharmacokinetics and pharmacodynamics of some tobacco smoke constituents, particularly nicotine and carbon monoxide, have been extensively studied. These studies show an orderly relationship between the use of tobacco and the absorption of nicotine. Similarly, the effects on behavioral and physiological functions, although complex, are orderly and related to the pharmacokinetics of nicotine. These data will be reviewed in this Section. Research shows that nicotine is well absorbed from tobacco; that it is distributed rapidly and in biologically active concentrations to body organs, including the brain; and that nicotine is the major cause of the predominant behavioral effects of tobacco and some of its physiologic conse- quences. One effect of nicotine, development of tolerance to its own actions, is similar to that produced by other addicting drugs. Tolerance refers to decreasing responsiveness to a drug or chemical such that larger doses are required to produce the same magnitude of effect. Tolerance to many actions of nicotine occurs in animals and humans. Evidence for tolerance to nicotine and mechanisms of tolerance development will be reviewed in this Chapter (see also Chapter VI). Although nicotine has long been considered as the primary pharmacologic reason for tobacco use, and the source of a number of the physiological effects of tobacco, thousands of other chemicals are present in tobacco. Most of these are delivered in such small quantities that they appear to have little OF no behavioral conse- quence. However, a few chemicals do appear to have behavioral effects and there is a potential for numerous chemical interactions that conceivably could have behavioral consequences. This Chapter will conclude with an examination of tobacco smoke constituents 25 other than nicotine that rnay contribute to behavioral effects of cigarette smoking. The toxicity of nicotine is discussed in detail in Appendix B. Nicotine and Other Alkaloids in Various Tobacco Products Nicotine is a tertiary amine composed of a pyridine and a pgrrolidine ring (Figure 1). Nicotine may exist in two different three- dimensionally structured shapes, called stereoisomers. Tobacco contains only (S)-nicotine (also called l-nicotine), which is the most pharmacoloqicaliy active form. Tobacco smoke also contains the less potent (Rj-nicotine (also called d-nicotine) in quantities up to 10 percent of the total nicotine present (Pool, Godin, Crooks 1985). Presumably some racemization occurs during the combustion pro- cess. The nicotine yield of cigarettes, as determined by standardized smoking machine tests, is available for most brands. However, the amount of nicotine in cigarettes or other tobacco products is not specified by manufacturers. Because tobacco is a plant product, there are differences in the amount of nicotine among and within different types and strains of tobacco, including variations in different parts of the plant, as well as differences related to growing conditions. Table 1 shows concentrations of nicotine and other alkaloids in several different tobacco leaves used in making commercial tobacco prod- ucts. Witliin a tobacco plant, leaves harvested from higher stalk positions have higher concentrations of nicotine than from lower stalk positions; ribs and stems of the leaves have the least (Rath- kamp, Tso, Hoffmann 19731. Combining different varieties of tobacco and different parts of the plant is a way to change the nicotine concentration of commercial tobacco. In a study of amounts of nicotine in the tobacco of 15 American cigarette brands of differing machine-determined yields (Benowitz, Hall et al. 19831, tobacco contained on average 1.5 percent nicotine by weight. Nicotine yield of the cigarettes, as defined by Federal Trade Commission smoking machine tests, was correlated inversely with nicotine concentrations in the tobacco. Thus. tobacco of lower- yield cigarettes tended to have higher concentrations of nicotine than did tobacco of higher-yield cigarettes. However, lower-yield cigarettes also contained less tobacco per cigarette, so the total amount of nicotine contained per cigarette, averaging 8.4 mg, was similar in different brands. Thus, low-yield cigarettes are low yield not because of lower concentrations of nicotine in the tobacco, but because they contain less tobacco and have characteristics which remove tar and nicotine by filtration or dilution of smoke with air. Concentrations of nicotine in commercial tobacco products are summarized in Table 2. 26 NICOTINE NORNICOTINE N'-NITROSONORNICOTINE NICOTINE N-OXIDE (OXYNlCOTINEl ANATAGINE ANABASINE N'-METHYLANATABINE N`-METHYLANABASINE NIMTYRINE NORNICOTYRINE COTININE 6'.OXOANABASINE ANABASEINE 2.3'.DIPYPIDYL METANICOTINE PSEUDCOXYNICOTINE FIGURE L-Chemical structures of nicotine and minor tobacco alkaloids sOL'K(`E IRIP IY*:i Although the major alkaloid in t.obacco is nicotine, there are other alkaloids in tobacco which may be of pharmacologic importance. These include nornicotine, anabasine, myosmine, nicotyrine, and anatabine (Figure 1). These substances make up 8 to 12 percent of the total alkaloid content of tobacco products (Table 1) (Piade and Hoffmann 1980). In some varieties of tobacco, nornicotine concentra- tions exceed those of nicotine (Schmeltz and Hoffmann 1977). Typical quantities of the minor alkaloids in the smoke of one cigarette are: nornicotine (27 to 88 pg), cotinine (9 to 50 pg), anabasine (3 to 12 pgl, anatabine (4 to 14 pg). myosmine (9 pg), and 2,3' dipyridyl (7 to 27 pg). N'-methylanabasine, nicotyrine, nornicoty- rine, and nicotine-N'-oxide have also been identified in cigarette smoke (Schmeltz and Hoffmann 1977). Puffing characteristics, especially puff frequency, influence the delivery of the component alkaloids (Bush, Griinwald, Davis 1972). 27 TABLE l.-Alkaloid content of various tobaccos (mg/kg, dry basis) Dar-k commercial tobacco Anstabme 360 3x0 570 600 Anabasine 140 150 99 150 cotlnlne 195 140 90 40 M\oam,ne 45 50 60 30 2.3 -Dlpwld~l 1w 110 30 10 TABLE 2.-Nicotine content of various tobacco products Nornicotine and anabasine have pharmacologic activity qualita- tively similar to that of nicotine, with potencies of 20 to 75 percent compared with that of nicotine, depending on the test system and the animal (Clark, Rand, Vanov 1965). In addition to direct activity, some of the minor alkaloids may influence the effects of nicotine. For example, nicotyrine inhibits the metabolism of nicotine in animals (Stalhandske and Slanina 1982). The pharmacology of the minor tobacco alkaloids is discussed in more detail in the last section of this Chapter. 28 Pharmacokinetics and Metabolism of Nicotine Absorption of Nicotine Nicotine is distilled from burning tobacco and is carried proximal- ly on tar droplets (mass median diameter 0.3 to 0.5 urn) and probably also in the vapor phase (Eudy et al. 19851, which are inhaled. Absorption of nicotine across biological membranes depends on pH (Armitage and Turner 1970; Schievelbein et al. 1973). Nicotine is a weak base with a pKa (index of ionic dissociation) of 8.0 (aqueous solution, 25oC). This means that at pH 8.0, 50 percent of nicotine is ionized and 50 percent is nonionized. In its ionized state, such as in acidic environments, nicotine does not rapidly cross membranes. The pH of tobacco smoke is important in determining absorption of nicotine from different sites within the body. The pH of individual puffs of cigarettes made of flue-cured tobacco, the predominant tobacco in most American cigarettes, is acidic and decreases progres- sively with sequential puffs from pH 6.0 to 5.5 (Brunnemann and Hoffmann 1974). At these pHs, the nicotine is almost completely ionized. As a consequence, there is little buccal absorption of nicotine from cigarette smoke, even when it is held in the mouth (Gori, Benowitz, Lynch 1986). The smoke from air-cured tobaccos, the predominant tobacco in pipes, cigars, and in a few European cigarettes, is alkaline with progressive puffs increasing its pH from 6.5 to 7.5 or higher (Brunneman and Hoffmann 1974). At alkaline pH, nicotine is largely nonionized and readily crosses membranes. Nicotine from products delivering smoke of alkaline pH is well absorbed through the mouth (Armitage et al. 1978; Russell, Raw, Jarvis 1980). When tobacco smoke reaches the small airways and alveoli of the lung, the nicotine is rapidly absorbed. The rapid absorption of nicotine from cigarette smoke through the lung occurs because of the huge surface area of the alveoli and small airways and because of dissolution of nicotine at physiological pH (approximately 7.4), which facilitates transfer across cell membranes. Concentrations of nic- otine in blood rise quickly during cigarette smoking and peak at its completion (Figure 2). Armitage and coworkers (19751, measuring exhalation of radiolabeled nicotine, found that four cigarette smok- ers absorbed 82 to 92 percent of the nicotine in mainstream smoke, another smoker presumed to be a noninhaler absorbed 29 percent, and three nonsmokers (who were instructed to smoke as deeply as possible) absorbed 30 to 66 percent. Chewing tobacco, snuff, and nicotine polacrilex gum are of alkaline pH as a result of tobacco selection and/or buffering with additives by the manufacturer. The alkaline pH facilitates absorp- tion of nicotine through mucous membranes. The rate of nicotine absorption from smokeless tobacco depends on the product and the 29 M Cigarettes A-----A Oral snuff O--Q Chewing tobacco F--O Nicotine gum N=lo -10 0 30 60 90 120 Minutes FIGURE 2.-Blood nicotine concentrations during and after smoking cigarettes (1 l/3 cigarettes), using oral snuff (2.5 g), using chewing tobacco (average, 7.9 g), and chewing nicotine gum (two 2-mg pieces) `0, `I<(`?: Ht.ni.x!:, ,` /h`,,' !,.`A' /PI, 1 . :11,1 1, 10 I, SW ,I 11, ,111 :! 1$11,,1 o, 13, c,~z,w,~P, da>. blood ..1,11~1~?, nrrr <1?llrrlK ,.1-l !W11111~ !I ? 11?\1 .l.!>l~l:ilA x IL,i'i'!`.' SOL'K(`E Rrnm\,t/ ir;~i( .l,ic ,h l'lhl 39 throughout the day than in nicotine concentrations. As expected, there is a gradual increase in cotinine levels during the day, peaking at the end of smoking and persisting in high concentrations overnight. Intake of Nicotine Cigarette Smoking Nicotine intake from single cigarettes has been measured by spiking cigarettes with "C-labeled nicotine (Armitage et al. 1975). That study of eight subjects, each smoking a single filter-tipped cigarette, indicated an intake range of 0.36 to 2.62 mg. Intake was higher in smokers than in nonsmokers. Intake of nicotine from smoking a single cigarette or with daily cigarette smoking has been estimated by methods similar to those used in drug bioavailability studies (Benowitz and Jacob 1984; Feyerabend, Ings, Russell 1985). Metabolic clearance of nicotine was determined after i.v. injection. Metabolic clearance data were then used in conjunction with blood and urinary concentrations of nicotine measured during a period of smoking to determine the intake of nicotine. In five subjects, average intake of nicotine per cigarette was 1.06 mg (range, 0.58 to 1.49 mg) (Feyerabend, Ings, Russell 19851. In 22 cigarette smokers, 13 men and 9 women who smoked an average of 36 cigarettes/day (range 20 to 621, the average daily intake was 37.6 mg, with a range from 10.5 to 78.6 mg (Benowitz and Jacob 1984). Nicotine intake per cigarette averaged 1.0 mg (range 0.37 to 1.56 mg). Intake per cigarette did not correlate with yields obtained by smoking machine using standard Federal Trade Commission methods. This is because smoking machines smoke cigarettes in a uniform way, using a fixed puff volume (35 mL1, flow rate (over 2 secl, and interval (every minute). Smokers smoke cigarettes differently, changing their puffing behav- ior to obtain the desired amount of tobacco smoke and nicotine. Elimination Rate as a Determinant of Nicotine Intake by Cigarette Smoking There is considerable evidence that smokers adjust their smoking behavior to try to regulate or maintain a particular level of nicotine in the body (Gritz 1980; Russell 1976). For example, when the availability of cigarettes is restricted, habitual smokers can increase intake of nicotine per cigarette 300 percent compared with the intake of unrestrict,ed smoking (Benowitz, Jacob, Koslowski et al. 1986). Techniques for measuring daily intake of nicotine (Benowitz and Jacob 1984) have been applied to study the influence of elimination on nicotine intake. The rate of renal elimination of nicotine was manipulated by administration of ammonium chloride or sodium 40 bicarbonate to acidify or alkalinize the urine: respectively (Benowitz and Jacob 1985). Compared with daily excretion during placebo treatment (3.9 mg nicotine/day), acid loading increased (to 12 mglday) and alkaline loading decreased (to 0.9 mglday) daily excretion of nicotine. The total intake of nicotine averaged 38 mg/day. Average blood nicotine concentrations were similar in placebo and bicarbonate treatment conditions but were 15 percent lower during ammonium chloride treatment. Daily intake of nicotine was 18 percent higher during acid loading, indicating compensation for increased urinary loss. The compensatory increase in nicotine consumption was only partial, replacing about half of the excess urinary nicotine loss. Bicarbonate treatment had no effect on nicotine consumption, consistent with the small magnitude of effect on excretions of nicotine in comparison to total daily intake. These results seem compatible with the suggestion of Schachter (1978) that emotional stress, which results in more acidic urine, might accelerate nicotine elimination from the body and thereby increase cigarette smoking. But caution must be exercised in applying these findings to usual smoking situations. These studies were performed under conditions of extreme urinary acidification or alkalinization, so that the changes in renal clearance would be maximized, Even with extreme differences in urinary pH, differ- ences in overall nicotine elimination rate and smoking behavior were modest. This is because renal excretion is a minor pathway for elimination of nicotine; most is metabolized. Smaller changes in urinary pH, such as occur spontaneously throughout the day or that might be related to stressful events, would not be expected to substantially influence nicotine elimination or smoking behavior. Biochemical Markers of Nicotine Intake Absorption of nicotine from tobacco smoke provides a means of verification and quantitation of tobacco consumption. The general strategy is to measure concentrations of nicotine, its metabolites (such as cotinine), or other chemicals associated with tobacco smoke in biological fluids such as blood, urine, or saliva. Different measures vary in sensitivity, specificity, and difficulty of analysis. Different investigators have used blood or urinary nicotine concentrations, blood or salivary or urinary cotinine concentrations, expired carbon monoxide or carboxyhemoglobin concentrations, or plasma or sali- vary thiocyanate (a metabolite of hydrogen cyanide, a vapor phase constituent) concentrations as measures of tobacco smoke consump- tion. Relationships among daily intake of nicotine, daily exposure to nicotine (that is, blood concentrations of nicotine integrated over 24 hr), various parameters of cigarette consumption, and different measures of nicotine intake have been examined experimentally 41 during ad libitum cigarette smoking on a research ward (Benowitz and Jacob 1984). The best biochemical correlate to nicotine intake and exposure in this study was a random blood nicotine concentra- tion measured at 4 p.m. This level did not depend on when the last cigarette was smoked. This finding is consistent with the observation that nicotine levels accumulate throughout the day and plateau in the early afternoon (see Figure 5). At steady state, with regular smoking throughout the day, there should be a reasonably good correlation between nicotine concentrations and daily intake. Car- boxyhemoglobin (COHb) concentrations in the afternoon were the next best markers of nicotine intake. Also, morning (8 a.m.) levels of nicotine and COHb correlated with intake, presumably reflecting persistence of nicotine and COHb in the blood from exposure on the previous day. Although cotinine is a highly specific marker for nicotine expo- sure, blood levels of cotinine across subjects in this study did not correlate as closely with nicotine intake as did blood levels of nicotine or COHb (Benowitz and Jacob 1984). This is probably due to individual variability in fractional conversion of nicotine to cotinine and in the elimination rate of cotinine itself. Because of its relatively long half-life, cotinine levels are less sensitive than nicotine levels to smoking pattern, that is, when the last cigarette was smoked. For longitudinal within-subject studies, the cotinine level would be expected to be a good marker of changes in nicotine intake. Cotinine measurements have become the most widely accepted method for assessing the intake of nicotine in long- term studies of tobacco use (see also Chapter V). As expected by the known variation in renal clearance due to effects of urinary flow and pH, urinary concentrations of nicotine did not correlate well with nicotine intake (Benowitz and Jacob 1984). In contrast, urinary cotinine, which is less influenced by urinary flow or pH, was as good a marker as blood cotinine concentration. Salivary and urinary cotinine concentrations correlate well (r = 0.8 to 0.9) with blood cotinine concentrations (Haley, Axelrad, Tilton 1983; Jarvis et al. 1984). Therefore, salivary or urine cotinine concentrations should be almost as useful as blood levels in indicating nicotine intake. Analytical Methods for Measuring Nicotine and Cotinine in Biological Fluids Determination of nicotine concentrations in biological fluids requires a sensitive and specific method, because concentrations of nicotine in smokers' blood are generally in the low nanogram per milliliter range and a number of metabolites are also present. Cotinine concentrations in blood are generally about tenfold greater than nicotine concentrations, and as a result, less sensitive analyti- 42 cal methodology may be acceptable. Methods with adequate sensitiv- ity for determination of nicotine and cotinine in smokers' blood include gas chromatography (GC) (Curvall, Kazemi-Vala, Enzell 1982; Davis 1986; Feyerabend, Levitt, Russell 1975; Hengen and Hengen 1978; Jacob, Wilson, Benowitz 1981; Vereby, DePace, Mule 1982), radioimmunoassay (RIA) (Langone, Gjika, Van Vunakis 1973; Castro et al. 1979; Knight et al. 1985), enzyme-linked immunosorbent assay (ELISA) (Bjercke et al. 1986), high performance liquid chroma- tography (HPLC! (Machacek and Jiang 1986; Chien, Diana, Crooks, in press), and combined gas chromatograph-mass spectrometry (GC- MS) (Dow and Hall 1978; Gruenke et al. 1979; Jones et al. 1982; Daenens et al. 1985). For reasons of sensitivity, specificity, and economy, GC and RIA are the most frequently used methods. GC-MS is a highly sensitive and specific technique, but the expense has discouraged its routine use. HPLC is less sensitive than GC for nicotine and cotinine determination. Although recently reported methods (Machacek and Jiang 1986; Chien, Diana, Crooks, in press) appear to have adequate sensitivity for determining concentrations in plasma, relatively large sample volumes are required. Concentra- tions of nicotine and cotinine in urine are tenfold to hundredfold greater than concentrations in plasma or saliva (Jarvis et al. 1984), and a variety of chromatographic and immunoassay techniques meet sensitivity requirements. The choice of a particular method depends on the biological fluid to be assayed; the need for sensitivity, precision, and accuracy; and economic considerations. Chromatographic methods, particularly those utilizing high-resolution capillary columns and specific detec- tors such as nitrogen-phosphorus detectors or a mass spectrometer, provide the greatest specificity. On the other hand, immunoassay techniques are operationally simpler, generally require smaller samples, and may be less expensive than chromatographic methods. A drawback to immunoassay methods is the potential for cross- reactivity of the antibody with metabolites or endogenous sub- stances. There is generally a good correlation between results obtained by GC and RIA for plasma cotinine concentrations (r = 0.94) (Gritz et al. 1981; Biber et al. 1987). In an interlaboratory comparison study (Biber et al. 19871, cotinine concentrations in smokers' urine measured by RIA were generally higher than concentrations deter- mined by GC, whereas in nonsmokers' urine spiked with cotinine RIA and GC values were similar. These results suggest that nicotine metabolites cross-react with the antibody against cotinine, at least in some of the RIA methods. Pharmacodynamics of Nicotine General Considerations This Section will focus on the relationship between nicotine levels in the body and their effects on behavior and physiological function 43 (pharmacodynamics). These data show how pharmacodynamic fac- tors determine some of the consequences of cigarette smoking, Two issues are particularly relevant in understanding the pharmacody- namics of nicotine: a complex dose-response relationship and the level of tolerance that is either preexisting or is produced by administration of nicotine. Dose-Response The relationship between the dose of nicotine and the resulting response (dose-response relationship) is complex and varies with the specific response that is measured. In pharmacology textbooks, nicotine is commonly mentioned as an example of a drug which in low doses causes ganglionic stimulation and in high doses causes ganglionic blockade following brief stimulation (Comroe 1960). This type of effect pattern is referred to as "biphasic." Dose-response characteristics in functioning organisms (in vivo) are often biphasic as well, although the mechanisms are far more complex. For example, at very low doses, similar to those seen during cigarette smoking, cardiovascular effects appear to be mediated by the CNS, either through activation of chemoreceptor afferent pathways or by direct effects on the brain stem (Comroe 1960; Su 1982). The net result is sympathetic neural discharge with an increase in blood pressure and heart rate. At higher doses, nicotine may act directly on the peripheral nervous system, producing ganglionic stimulation and the release of adrenal catecholamines. With high doses or rapid administration, nicotine produces hypotension and slowing of heart rate, mediated either by peripheral vagal activation or by direct central depressor effects (Ingenito, Barrett, Procita 1972; Porsius and Van Zwieten 1978; Henningfield, Miyasato, Jasinski 1985). Tolerance A second pharmacologic issue of importance is development of tolerance; that is, after repeated doses, a given dose of a drug produces less effect or increasing doses are required to achieve a specified intensity of response. Functional or pharmacodynamic tolerance can be further defined as where a particular drug concentration at a receptor site (in humans approximated by the concentration in blood) produces less effect than it did after a prior exposure. Dispositional or pharmacokinetic tolerance refers to accelerated drug elimination as a mechanism for diminished effect after repeated doses of a drug. Behavioral tolerance refers to compensatory behaviors that reduce the impact of a drug to adversely affect performance. Such tolerance can occur following intermittent exposures to a drug such that there is minimal development of functional or dispositional tolerance. 44 Most studies of drug tolerance have focused on tolerance which develops as a drug is chronically administered. If the tolerance develops within one or two doses, it is referred to as acute tolerance or tachyphylaxis. If tolerance develops after more prolonged use, the tolerance is referred to as acquired or chronic tolerance. Individual differences in sensitivity to the first dose of a drug also frequently exist. Those individuals who exhibit a reduced response to a specified drug dose or require a greater dose to elicit a specified level of response are said to be tolerant to the drug. This form of tolerance is referred to as first-dose tolerance, drug sensitivity, or innate drug responsiveness. For sake of clarity, this Report will reserve the term tolerance to describe reduction in the response to nicotine during the course of or following a previous exposure and will use acute drug sensitivity to describe responsiveness to an initial dose. Studies of tolerance to nicotine began in the late 19th century. In a series of studies of fundamental importance to the understanding of the nervous system, as well as to understanding the pharmacology of nicotine, Langley (1905) and Dixon and Lee (1912) studied the effects of repeated nicotine administration on a variety of animal species and on in vitro tissue preparations. Several findings emerged which have been widely verified and extended to other species and responses. These include: (1) With repeated dosing, responses dimin- ished to nearly negligible levels; (2) After tolerance occurred, responsiveness could be restored by increasing the size of the dose; (3) After a few hours without nicotine, responsiveness was partially or fully restored. After smoking a cigarette, people who have not smoked before ("naive smokers") usually experience a number of effects that become generally uncommon among experienced smokers. For example, retrospective reports by smokers indicate that initial exposure to tobacco smoke produced dizziness, nausea, vomiting, headaches, and dysphoria, effects that disappear with continued smoking and are rarely reported by chronic smokers (Russell 1976; Gritz 1980). Tolerance may also develop to toxic effects, such as nausea, vomiting, and pallor, during the course of nicotine poisoning, despite persistence of nicotine in the blood in extremely high concentrations (200 to 300 ng/mL! (Benowitz, Lake et al. 1987). A systematic analysis of the various forms of tobacco smoke tolerance has not been carried out. There are a few studies comparing the effects elicited by an acute exposure to tobacco in nonsmokers and smokers. Clark and Rand (1968) studied the effect of smoking cigarettes of varying nicotine content on the knee-jerk reflex and reported that high-nicotine cigarettes suppressed this reflex to a greater degree than did low-nicotine cigarettes. This effect was more pronounced at each nicotine dose in nonsmokers and light smokers compared to heavy smokers. These findings suggested that 45 tolerance is due to altered sensitivity to nicotine. Tolerance to nicotine is not complete because even the heaviest smokers experi- ence symptoms such as dizziness, nausea, and dysphoria when they suddenly increase their smoking rates (Danaher 1977). Evidence indicates that the majority of the psychological actions of tobacco smoke result from nicotine (Russell 1976; Chapter VII). Thus, most of the tolerance to effects of tobacco smoke that occurs following chronic tobacco use is due to the development of tolerance to nicotine. Acute Sensitivity Human Studies Studies which have indicated that individuals differ in response to tobacco smoke or nicotine have used smokers as the experimental subjects. Consequently, whether individual differences are due to differences in acute sensitivity to nicotine that have persisted during chronic tobacco use or are due to differences in the development of tolerance is unknown. Nesbitt (1973) and Jones (1986) noted that individual smokers differ with respect to the effects of smoking a standard cigarette on heart rate, but it is not clear from these studies whether these differences in responsiveness are due to differences in sensitivity to nicotine or to differences in the dose and kinetics of nicotine. Benowitz and colleagues (1982) observed individual differences in the effects of iv. injections of nicotine on heart rate, blood pressure, and fingertip skin temperature. Differences were not explained by differences in blood levels, indicating differential sensitivity to nicotine. Animal Studies Studies using laboratory animals indicate that differences in acute sensitivity to nicotine exist. Inbred rat and mouse strains differ in sensitivity to the effects of nicotine on locomotor activity (Garg 1969; Battig et al. 1976; Schlatter and Battig 1979; Hatchell and Collins 1980; Marks, Burch, Collins 1983b). Mouse strains also differ in the direction of the effect (increased or decreased activity). The mouse strains that differ in sensitivity to the effects of injected nicotine on locomotor activity also differ in the magnitude of response to a standard dose of tobacco smoke (Baer, McClearn, Wilson 1980). Inbred mouse strains also differ in sensitivity to the effects of nicotine on body temperature, heart rate, and acoustic startle response (Marks, Burch, Collins 1983a; Marks et al. 1985, 1986), as well as in sensitivity to nicotine-induced seizures (Tepper, Wilson, Schlesinger 1979; Miner, Marks, Collins 1984, 1986). These findings indicate that genetic factors may influence the sensitivity of rats and 46 mice to the first dose of nicotine. The importance of genetically determined differences in human sensitivity to the effects of nicotine administered in tobacco smoke remains to be determined. Mechanisms of Differences in Acute Sensiticit? Differences between inbred mouse and rat strains in sensitivity to the effects elicited by a single injected dose of nicotine do not appear to result from differences in rate of nicotine metabolism (Petersen, Norris, Thompson 1984) or from differences in brain nicotine concentration following intraperitoneal injection !Hatchell and Collins 1980; Rosecrans 1972; Rosecrans and Schechter 1972). Thus, rat and mouse strains differ in tissue sensitivity to the effects of nicotine. Differences among mouse strains in sensitivity to nicotine do not appear to be due to differences in the number or affinity of brain nicotine receptors that are measured via the binding of 3H- nicotine (Marks, Burch, Collins, 1983b). Mouse stocks that are more sensitive to nicotine-induced seizures do have greater numbers of hippocampal nicotine receptors that bind "`1-bungarotoxin (BTX) (Miner, Marks, Collins 1984, 1986). Some of the differences in sensitivity to nicotine between genetically defined stocks of animals may be related to differences in the number of nicotine receptors in specific regions of the brain. Tachyphylaxis (Acute Tolerance) Human Studies Systematic studies of tachyphylaxis or acute tolerance to effects of tobacco in nonsmokers have not been reported. There is evidence that tachyphylaxis does develop to effects of tobacco and nicotine in humans. Smokers frequently report that the first cigarette of the day is the best and that subsequent cigarettes are "tasteless" (Russell 1976; Henning-field 1984). Smoking a single standard cigarette after 24 hr of abstinence increases heart rate, whereas smoking an identical cigarette during the course of a normal day fails to change heart rate (West and Russell 19871. Fewer standard puffs were required to produce nausea at the beginning of the day (following 8 to 10 hr of tobacco abstinence) or from high-nicotine cigarettes than at the end of the day or from low-nicotine cigarettes (Henningfield 1984). Complete tolerance to nausea and vomiting developed over 8 hr in a woman in the course of an accidental nicotine poisoning, despite persistently toxic blood levels of nicotine (Benowitz, Lake et al. 1987). These findings suggest that tolerance which is lost and regained during short periods of abstinence from tobacco is tolerance to nicotine. Tolerance develops very rapidly to several effects of nicotine. Rosenberg and colleagues (1980) studied the effects of i.v. nicotine 47 injections on arousal level, heart rate, and blood pressure. In these experiments, six healthy smokers, 21 to 35 years of age, received six series of nicotine injections spaced 30 min apart. Each series of injections consisted of 10 2+g/kg injections spaced 1 min apart. Subjects reported a pleasant sensation after the first series of injections, but this response was not observed thereafter. Heart rate and blood pressure values remained above baseline, but there was little increment with successive injections, despite nicotine blood level increases which were similar to those observed after the first series of injections, In contrast, skin temperature fell progressively during the period of nicotine dosing, gradually returning to baseline at the end of the study. These data indicated rapid development of tolerance to subjective effects and heart rate and blood pressure responses, but tolerance was not complete because heart rate and blood pressure remained above baseline. Henningfield (1984) also assessed subjective responses of human subjects after i.v. injections with nicotine at lo-min intervals. The subjective response of "liking" the effects of nicotine was lost after five or six injections. Benowitz and coworkers (1982) studied the effect of a 30-min infusion of nicotine at a rate of 1 to 2 ug/kg/min. Shortly after initiation of infusion, heart rate and blood pressure increased, but the increase did not continue even though plasma nicotine concentrations continued to rise during the continuous infusion. Maximal cardiovas- cular changes were seen within 5 to 10 min, whereas maximal plasma nicotine levels were not reached until 30 min. These findings indicate that tachyphylaxis to the effects of nicotine may develop in humans within 5 to 10 min, the time required to smoke one cigarette. In contrast to heart rate, skin temperature (reflecting cutaneous vascular tone) declined and rose in association with changes in blood nicotine concentrations, showing no evidence of tolerance. The above studies indicate rapid development of tolerance to some (but not all) actions of nicotine in people. These studies were performed with cigarette smokers who had abstained from smoking the night before the study. Since significant quantities of nicotine persist in the body even after overnight abstinence, there is probably some persistence of tolerance. Experimental data supporting this conclusion were obtained in a study of cardiovascular responses to infused nicotine in smokers following either an overnight or 7-day tobacco abstinence (Lee, Benowitz, Jacob 1987). Heart rate and blood pressure responses were significantly greater after more prolonged abstinence. However, within 60 to 90 min, the blood concentra- tion-effect relationship in subjects after brief abstinence approxi- mated that observed after prolonged abstinence. Thus, a significant level of tolerance persists throughout the daily smoking cycle, but is lost with prolonged abstinence. Tolerance, at least after abstinence for one week, is rapidly reestablished with subsequent exposure. 48 Animal Studies Many studies demonstrate that acute tolerance or tachyphylaxis develops very quickly to actions of nicotine. Barrass and coworkers (1969) demonstrated that pretreatment of mice with a single i.v. dose (0.8 mg/kg) of nicotine resulted in an increase in the LD,, (dose which is lethal to 50 percent of animals) for nicotine. Maximal protection was seen 5 min after the injection, but this protection diminished steadily over the next hour. Tachyphylaxis develops to the effects of nicotine on locomotor activity. Stolerman, Bunker, and Jarvik (1974) noted that pretreating rats with a 0.75-mg/kg dose of nicotine 2 hr before challenge doses of nicotine (0.25 to 4.0 mg/kg) resulted in a shift of the nicotine dose-response curves, indicating reduced sensitivity. The ED,, values (doses that are effective in producing the measured response in 50 percent of animals) for nicotine-induced decreases in locomotor activity were nearly 2.4-fold greater in nicotine-pretreated rats than in saline-pretreated animals. Nicotine pretreatment also results in tachyphylaxis to the effects of nicotine on body temperature (hypothermia) in cats (Hall 1972), water-reinforced operant responding in rats (Stitzer, Morrison, Domino 1970), discharge of lateral geniculate neurons of cats (Roppolo, Kawamura, Domino 1970), repolarization of sartorius muscle in frogs (Hancock and Henderson 19721, blood pressure elevation in rats (Wenzel, Azmeh, Clark 19711, contraction of aortic strips in rabbits (Shibata, Hattori, Sanders 1971), respiratory stimu- lation in cats (McCarthy and Borison 19721, and gastrointestinal contraction in squid (Wood 1969) and guinea pigs (Hobbiger, Mitchel- son, Rand 1969). More recent studies have demonstrated that pretreatment with as little as one dose of nicotine will attenuate nicotine-induced elevations of plasma corticosterone (Balfour 1980) and adrenocorticotropic hormone (ACTH) (Sharp and Beyer 1986) levels in rats (see also Chapter III). The interval between the pretreatment and challenge doses of nicotine is a critical factor that determines whether tachyphylaxis is observed. Aceto and coworkers (1986) examined the effect of iv. nicotine infusion on heart rate and blood pressure in the rat. Tolerance did not develop when the interval between pretreatment and challenge doses was 30 min; marked tolerance was detected when the interval was reduced to 1 min. However, Stolerman, Fink, and Jarvik (1973) observed that after a single intraperitoneal dose of nicotine to rats, acute tolerance to a second dose did not become maximal until 2 hr after the initial injection. Mechanisms of Tachyphylaxis Although tachyphylaxis has been described for a wide variety of nicotine's effects, very little is known about mechanisms. A nicotine 49 metabolite may play a role in the development of tachyphylaxis. Barrass and colleagues (1969) argued that nicotine metabolites may block nicotine receptors and thereby antagonize nicotine's lethal effects. This argument was made because pretreatment with nic- otine-N'-oxide protected mice from the lethal effects of large doses of nicotine. LD,, values were increased approximately ninefold by pretreatment with nicotine-N'-oxide. These authors hypothesized that this protection may involve conversion of nicotine-N'-oxide to hydroxynicotine. Their results indicated that injection of a reduction product of cotinine, believed to be hydroxynicotine, gave immediate protection, whereas maximum protection was not seen until 40 min after injection of nicotine-N'-oxide. Thus it appears that metabolism, possibly to hydroxynicotine, is required for the protective action of nicotine-N'-oxide. Another hypothesis is that tachyphylaxis is the result of desensiti- zation of nicotine receptors. Desensitization of the receptor involves a conformational change that results in increased affinity of the nicotinic receptor for agonists coupled with decreased ability of the receptor to transport ions (Weiland et al. 1977; Sakmann, Patlak, Neher 1980; Boyd and Cohen 1984). Desensitization of nicotinic receptors at the motor end-plate was first described by Katz and Thesleff (1957) and has since been studied by a large number of investigators, using either skeletal muscle or the electric organs of the eel, Torpedo californica. Although tachyphylaxis has been commonly suggested as being due to desensitization of brain nicotinic receptors, the role of desensitization in tachyphylaxis to specific behavioral effects of nicotine has not been studied. This is because concentrations of nicotinic receptors in specific areas of the brain corresponding to the behavioral effects being measured are not high enough to use available methods. Chronic Tolerance Human Studies Chronic tolerance to tobacco and nicotine has not been studied systematically in human subjects, but it is clear, as noted previously, that some tolerance does develop. Tolerance is not complete; symptoms of nicotine toxicity such as nausea appear when smokers increase their normal tobacco consumption by as little as 50 percent (Danaher 1977). These findings are consistent with the observations that smokers increase their tobacco consumption and intake of nicotine with experience. Such escalating dose patterns may be observed for several years after initiation of either cigarette smoking or smok- eless tobacco use. Cigarette smokers may achieve such increases by augmenting the number of cigarettes smoked and by increasing the amount of nicotine extracted from each cigarette. For users of 50 smokeless tobacco, switching to products with greater nicotine delivery may also contribute to nicotine dose escalation (US DHHS 1986). Animal Studies Animal studies have proved useful in establishing the actual development of tolerance to nicotine, the magnitude of such toler- ance, and mechanisms that underlie this tolerance. The majority of these studies have used the rat and mouse as experimental subjects. Most of the chronic tolerance studies using the rat have focused on the effects of nicotine on locomotor activity. Depression of locomotor activity typically occurs following the injection of nicotine in doses exceeding 0.2 mg/kg in drug-naive rats. Tolerance to this depression develops following chronic treatment (Keenan and Johnson 1972; Stolerman, Fink, Jarvik 1973; Stolerman, Bunker, Jarvik 1974). The magnitude of this tolerance is influenced by the dose and dosing interval. Tolerance persists for greater than 90 days when nicotine is injected chronically. Tolerance to the effects of injected nicotine on depression of locomotor activity could also be produced with nicotine administered in the rats' drinking water or through subcutaneously implanted reservoirs (Stolerman, Fink, Jarvik 1973). Under certain experimental conditions, rats treated chronically with nicotine exhibit an increase in locomotor activity following nicotine challenge (Morrison and Stephenson 1972; BaA5ttig et al. 1976; Clarke and Kumar 1983a,b). A careful analysis of the response to an acute challenge dose of nicotine demonstrated that soon after the first dose of nicotine, depressed locomotor activity was observed; after 40 min or more, increased locomotor activity became apparent (Clarke and Kumar 1983b). Chronically injected rats exhibited this enhanced activity progressively earlier postinjection. More recently, Ksir and others (1985, 1987) demonstrated that chronic nicotine injections may result in enhanced locomotor activity immediately after nicotine injection if the rats were acclimated to the test apparatus for 1 hr before nicotine injection. These findings indicate that in the rat, tolerance develops to the depressant effects of nicotine and that this tolerance uncovers a latent stimulatory action. If mice are injected chronically with nicotine, tolerance develops to the locomotor depressant effects elicited by a challenge dose of nicotine (Hatchell and Collins 1977). The degree and rate of development of tolerance appear to be influenced by the sex, as well as the strain, of the animals. Tolerance development has been studied by continuously infusing mice of several inbred strains with nicotine and assessing tolerance by measuring locomotor activity, body temperature, respiratory rate, heart rate, and acoustic startle response following nicotine challenge. Such studies have demon- strated that: (1) Tolerance to nicotine increases with the nicotine 51 infusion dose (Marks, Burch, Collins 1983a); (2) Tolerance is specific for nicotinic cholinergic agonists in that nicotine-infused animals are not cross-tolerant to the muscarinic cholinergic agonist oxotremo- rine (Marks and Collins 1985); (3) Maximal tolerance is attained within 4 days following the initiation of infusion and is lost within 8 days following the cessation of infusion (Marks, Stitzel, Collins 1985); (4) Tolerance development varies between inbred mouse strains, with some strains exhibiting marked tolerance and other strains showing very little (Marks, Romm et al. 1986); and (5) Mouse strains that fail to develop tolerance to nicotine are also relatively insensitive to the effects elicited by an acute injection of nicotine (Marks, Stitzel, Collins 1986). More recently these investigators compared the effects of continuous and pulse infusions of nicotine on tolerance develop- ment (Marks, Stitzel, Collins 1987). Pulse infusion was used to simulate the conditions obtained when tobacco is smoked. Although the total dose infused was the same in continuously infused and pulse-infused animals, marked differences in tolerance were seen. The pulse-infused animals exhibited a greater degree of tolerance. The degree of tolerance was most correlated with peak nicotine concentrations. Chronic nicotine administration results in tolerance to a number of other nicotinic effects. Tolerance develops to depression of operant responding elicited by high doses of nicotine, such that after sufficient chronic t.reatment, enhanced rather than depressed oper- ant responding is seen (Clarke and Kumar 1983c; Hendry and Rosecrans 1982). Attenuation of the effects of nicotine on electroen- cephalogram (EEG) activity is seen in the rat following chronic injection (Hubbard and Gohd 1975). These altered EEG responses paralleled the development of tolerance to behavioral effects de- scribed by these authors as "arousal." In contrast to the findings of Hubbard and Gohd (1975), other studies indicate that chronic tolerance does not develop to the behavioral stimulation effect of nicotine (Battig et al. 1976; Morrison and Stephenson 1972; Clarke and Kumar 1983a,c). Likewise, little or no tolerance to nicotine- induced prostration after i.v. administration was observed after chronic exposure in rats (Abood et al. 1981, 1984). In addition, tolerance has been reported to develop to nicotine- induced increases in plasma corticosterone, but not adrenal catechol- amine release in rats (Balfour 1980; Van Loon et al. 1987). Anderson and colleagues (1985) studied the effects of chronic exposure to cigarette smoke on neuroendocrine function of the rat hypothala- mus. These researchers observed that chronic exposure to cigarette smoke over a period of 9 days did not result in tolerance to the ability of acute intermittent exposure to cigarette smoke to reduce serum levels of prolactin, luteinizing hormone, and follicle stimulating hormone. 52 Mechanisms of Chronic Tolerance Chronic tolerance to drugs may be due to an increase in the rate of drug metabolism or to a decrease in sensitivity of the tissue to the drug. Considerable differences exist among humans in the rate of nicotine metabolism (Benowitz et al. 1982). Metabolism is faster (shorter half-life) in smokers than in nonsmokers (Schievelbein et al. 1978; Kyerematen et al. 1982; Kyerematen, Dvorchik, Vesell 1983). The contribution of enhanced nicotine metabolism to the develop- ment of nicotine tolerance in humans is unclear. Studies of rats which clearly demonstrate that chronic nicotine treatment results in tolerance to nicotine also indicat,e that chronic nicotine administra- tion does not increase the rate of nicotine metabolism in rats (Takeuchi, Kurogochi, Yamaoka 1954) or mice (Hatchell and Collins 1977; Marks, Burch, Collins 1983b). These findings indicate that tolerance to nicotine primarily involves reduced sensitivity of target tissues. Chronic tolerance to nicotine may be due to alterations in brain nicotinic receptors (see Chapter III for further discussion of nicotine receptors). At least two types of nicotinic receptors exist in rodent brain (Marks and Collins 1982). One of these receptor types may be measured with 3H-nicotine or `H-acetylcholine (3H-ACh) (Marks, Stitzel et al. 1986; Martino-Barrows and Keller 19871, while the other type may be measured with "`1-bungarotoxin (BTX). The nicotine- binding site has higher affinity for nicotine than does the BTX site (Marks and Collins 1982). Chronic nicotine injection, once or twice daily for approximately 7 days, increased the number of 3H-nic- otine/3H-ACh-binding sites in the brain (Ksir et al. 1985, 1987; Morrow, Lay, Creese 1985; Schwartz and Kellar 1983, 1985). This increase in nicotine-binding sites appeared to correlate with the emergence of nicotine-induced increases in locomotor activity in the rat. Studies of tolerance to nicotine in one inbred mouse strain (DBA) also demonstrated that chronic nicotine treatment elicits an increase in the number of brain nicotinic receptors as measured with both 3H- nicotine and BTX as the ligands (Marks, Burch, Collins 1983a; Marks and Collins 1985; Marks et al. 1985, 1986; Marks, Stitzel, Collins 1985,1986, 1987). These studies have also shown that the number of 3H-nicotine-binding sites increases at lower doses of nicotine than do the BTX-binding sites. An increase in 3H-nicotine binding (Marks, Burch, Collins 1983a) paraliels development of tolerance to various responses during chronic infusion, In chronically infused DBA mice, tolerance acquisition and disappearance parallel the up-regulation and return to control, respectively, of brain 3H-nicotine binding (Marks, Stitzel, Collins 1985). These findings suggest that the increase in 3H-nicotine binding is related to the development of tolerance to nicotine. However, further studies indicate that factors other than receptor number must also be considered, because mouse 53 strains that do not develop tolerance to nicotine also demonstrate up- regulation of nicotinic receptors following chronic infusion (Marks et al. 1986; Marks, Stitzel, Collins 1986). That chronic nicotine treatment results in a decrease in response to the drug (tolerance) and an increase in the number of nicotinic receptors was an unexpected finding. Marks, Burch, and Collins (1983a) and Schwartz and Kellar (1985) have suggested that chronic nicotine treatment results in chronic desensitization of nicotinic receptors. Chronic desensitization of the nicotinic receptor is compa- rable to chronic treatment with an antagonist and could be the stimulus for up-regulation of the receptors. According to this hypothesis, there is an increase in number of brain nicotinic receptors but a decrease in the absolute number of "activatable" (nondesensitized) receptors. This would result in a decreased re- sponse to nicotine (tolerance). Marks and coworkers suggest that inbred mouse strains failing to exhibit tolerance to nicotine, under the procedures used by these investigators, have brain nicotinic receptors that resensitize more rapidly than do those strains that do exhibit tolerance. By treating rats chronically with the acetylcholinesterase inhibi- tor disulfoton, Costa and Murphy (1983) have found a decrease in rat brain 3H-nicotine binding. Disulfoton-treated rats were also tolerant to the antinociceptive effects of nicotine. Thus, tolerance to nicotine effects may be seen when the number of nicotinic receptors is increased or decreased by chronic drug treatment. The observation that tolerance to at least one effect of nicotine can be obtained by a technique that decreases brain nicotinic receptor numbers supports the idea that chronic nicotine treatment results in an increase in the total number of receptors but a decrease in those that may be activated by nicotine; that is, a high fraction of the up-regulated receptors are desensitized. In contrast to the studies reviewed above, some investigators have found no change in the number or affinity of 3H-nicotine-binding sites in the brains of rats chronically exposed to nicotine (Abood et al. 1984; Benwell and Balfour 1985). Other potential neurochemical explanations for tolerance to nicotine have been considered. Several reports (Westfall 1974; Giorguieff et al. 1977; Arqueros, Naquira, Zunino 1978; Giorguieff- Chesselet et al. 1979) indicate that nicotine stimulates dopamine release in vitro, and a recent study demonstrated that nicotinic agonists are less effective in stimulating dopamine release in slices of striatum obtained from rats that had been chronically treated with the nicotinic agonist dimethylphenylpiperazinium (DMPP) (Westfall and Perry 1986). These findings are consistent with the idea that chronic nicotinic agonist treatment results in a decrease in the absolute number of receptors that can be activated. 54 Pharmacodynamics of Nicotine and Cigarette Smoking As the foregoing review has shown, the intensity of nicotine's effects is related to the dose given, the time since the last dose, and the level of preexisting or acquired tolerance. Since nicotine can produce effects that lead to further use (reinforcing effects! (Hen- ningfield and Goldberg 1983, and can also produce effects that limit use (aversive effects, usually at higher dose levels) (Danaher 19771, the strength of the effect of a given dose can determine whether more or less nicotine will be subsequently taken. Thus, factors such as tolerance can affect the manner in which nicotine controls behavior (Chapter IV). Similarly-, an individual's ability to develop tolerance to the toxic actions may be critical in determining whether smoking will occur and, if smoking is initiated, whether there will be an increase in the number of cigarettes consumed each day. Pharmacodynamic considerations may help explain the pattern of cigarette smoking throughout the da)-. Intervals between smoking cigarettes may be determined at least in part by the time required for tolerance to disappear. With regular smoking there is accumula- tion of nicotine in the body resulting in a greater level of tolerance. Transiently high brain levels of nicotine following smoking individu- al cigarettes may partially overcome tolerance. But the effects of individual cigarettes tend to lessen throughout the day. Overnight abstinence allows considerable resensitization to effects of nicotine, and the daily smoking cycle begins again. Pharmacodynamic observations with i.v. dosing of nicotine explain the pattern of cardiovascular changes observed in cigarette smokers. That brief infusions of nicotine increase heart rate to a maximum suggests that heart rate will increase most with the first few cigarettes of the day, but subsequently will not vary in relation to the amount of nicotine consumed. That only partial tolerance develops to heart rate acceleration due to nicorine suggests that effects on heart rate may persist as long as significant levels of nicotine persist, including overnight. These predictions were con- firmed in a study in which volunteer cigarette smokers smoked either high- or low-yield nonfilter research cigarettes or abstained from smoking (Benowitz, Kuyt. Jacob 1984). Full compensation for the low-yield research cigarettes, which contained only small amounts of nicotine, was impossible. Resultant nicotine blood levels were different by fourfold. As predicted, heart rate (assessed by continuous ambulatory electrocardiogram (EKG) monitoring) in- creased in the morning-more on smoking than nonsmoking days- and the increase occurred with the first few cigarettes of the day. Subsequently, heart rate followed a normal circadian pattern, but was always higher during smoking than during abstinence. Also, as predicted, heart rate was no different during the smoking of low- 55 yield or high-yield cigarettes, despite the fourfold difference in blood nicotine concentration. Pharmacodynamic aspects of the actions of nicotine may explain in part how cigarette smoking causes coronary heart disease (US DHHS 1983). As noted before, because of the accumulation of nicotine and its dose-response characteristics, heart rate is increased during cigarette smoking for 24 hr a day. Plasma catecholamine concentrations and urinary catecholamine excretion remain in- creased as well (Benowitz 1986c), consistent with the theory that cigarette smoking produces sympathetic neural activation 24 hr each day. Persistent sympathetic activation could result in the following effects: (1) Alteration in lipid metabolism, resulting in a more atherogenic lipid profile; (2) Promotion of platelet aggregation and hypercoagulability; (3) Induction of vasoconstriction and coronary spasm; and (4) Increased heart rate and myocardial contractility, thereby an increase in the oxygen demands of the heart and of circulating catecholamines, which can promote cardiac arrhythmias. These factors could accelerate atherosclerosis and contribute to acute myocardial infarction in a person with preexisting coronary atherosclerosis (Benowitz 1986a) (see also Appendix B). There is no apparent correlation between acute coronary events and the time at which a person smokes a cigarette, perhaps because of the persistent effects of nicotine throughout the day. Constituents of Tobacco Smoke Other Than Nicotine With Potential Behavioral Effects Tobacco smoke contains more than 4,000 constituents, many of which may have biological activity (US DHHS 1983). Although nicotine is the major pharmacologic factor which determines the use of tobacco, other constituents may also be involved. The behavioral effects of tobacco constituents other than nicotine are described in the Section below and in Chapter IV. This Section focuses more on the chemicals that may be involved, whereas Chapter IV focuses more on cigarette smoking behavior. Minor Tobacco Alkaloids Most of the research on the minor tobacco alkaloids has been directed to determining physiological effects, such as the effect on blood pressure and other cardiovascular responses and toxicological effects, rather than the potential for behavioral effects. The pharma- cologic effects of alkaloids of the nicotine group have been discussed by Bovet and Bovet-Nitti (1948) and Clark, Rand, and Vanov (1965). Nornicotine and anabasine were found to have qualitatively similar actions but to be less potent than nicotine. Larson and Haag (1943) 56 reported that the potency of nornicotine as determined by effects on blood pressure in dogs was about one-twelfth that of nicotine. Nicotine analogs have been studied for discriminative stimulus effects by using animal models (Chance et al. 1978) (see also Chapter IV). The only chemical shown to produce a positive response in that test system was 3-methylpyridylpyrrolidine. Recent research has focused on binding at specific brain receptor sites. Martin and coworkers compared binding characteristics of nicotine-related com- pounds (Martin et al. 1986; Sloan et al. 1985). Lobeline, anabasine, and cytisine were evaluated for effects on heart rate, blood pressure, respiration rate, minute volume, and tidal volume (Sloan et al. 1987). Lobeline and anabasine bound to low-affinity sites in the brain, whereas cytisine bound only at a high-affinity site. The binding data are consistent with the pharmacologic data, indicating that lobeline and anabasine have different pharmacologic actions than cytisine. Kanne and others (1986) and Abood and Grassi (1986) evaluated two nicotine analogs, including a new radioligand, to study brain nicotinic receptors. Kachur and others (1986) studied the pharmaco- logic effects of a bridged-nicotine analog (methylene bridge between the methyl of the pyrrolidine ring and the a-position of the pyridine ring). The magnitude of pressor effect depended on the particular enantiomer and dosage. These results emphasize that compounds other than nicotine may act at the nicotine receptors; however, there may be subpopulations of receptors to which different agonists and antagonists bind (Chapter III). N-Methylated derivatives of nicotine, including nicotine isometho- nium ion IN-methylnicotinium ion, NMNj, have been shown to have pressor and neuromuscular effects in some species (Shimamoto et al. 1958). Nicotine isomethonium ion was first reported to be a metabolite of nicotine present in smokers' urine by McKennis and coworkers in the 1960s and its presence in smokers' urine has been recently confirmed (Neurath et al. 1987). Recently Crooks and coworkers (Cundy, Godin, Crooks 1985) have shown that only the (Rj- isomer of nicotine is converted to nicotine isomethonium ion in vitro in guinea pig tissue homogenates or in vivo in guinea pigs. Consequently, it is uncertain as to whether the nicotine isomethoni- urn ion present in smokers' urine arrives from the small amount of (Rj-nicotine present in tobacco smoke, or whether the human enzyme systems have different specifications than the guinea pig enzymes. Because little if any nicotine isomethonium ion penetrates the blood- brain barrier (Pool 1987; Aceto et al. 1983j, it would appear that this met.abolite could have behavioral actions only if it were formed in the CNS. These findings emphasize the complexity of the pharmacol- ogy of nicotine-related compounds. It can be concluded from research on these compounds that some do bind to specific brain receptors and may result in centrally mediated physiological changes. However, 57 there is inadequate evidence to date that any of these compounds produces either aversive or rewarding effects in human smokers. "Tar" and Selected Constituents of Tobacco Smoke Which Contribute to Taste and Aroma "Tar" is used to describe the dry particulate matter without t,he nicotine in tobacco smoke ~Pillsbury et al. 1969). The possible role of tar in t.he maintenance of the cigarette smoking habit has been considered. Goldfarb and coworkers (19761 studied the effects of the tar cont.ent (determined by cigarette smoking machine testing) on the subjective reactions to cigarette smoking. Ratings of strength were not related to the tar index of the cigarettes. The results were interpreted as indicating that tar did not have a role in the maintenance of cigarette smoking behavior. In a later study, Sutton and coworkers (1982) found that when nicotine yield was held constant, smokers of lower-tar cigarettes puffed more smoke and had higher drug plasma levels. These results suggested that smokers were compensating for reduced delivery of tar by inhaling a greater volume of smoke. Because these two studies used different experi- mental designs, it is difficult to draw a conclusion as to the role of tar in relation to smoking behavior. However, based on knowledge about the taste and aroma constituents of cigarette smoke, it is likely that some of the chemicals in the tar fraction contribute to tobacco use, if only by providing distinct sensory stimuli (Chapter VI). Consistent with this possibility, minimal levels of tar are held by tobacco manufacturers to be important to the taste characteristics of tobacco smoke. Several thousand compounds have been isolated from tobacco and tobacco smoke (Dube and Green 1982), and many of these may be biologically active (IARC 1986). The precursors to the carotenoids and diterpeniods, selected nitrogenous and sulfur constituents, waxes and lipids, and phenolics and acids contribute to the taste and aroma of tobacco (Enzell and Wahlberg 1980: Heckman et al. 1981; Davis, Stevens, Jurd 19763. A number of the isoprenoid corripounds that. influence the taste and aroma of smoke may be formed by sequential oxidation, rearrangement, and reduction reactions (Davis, Stevens, Jurd 1976). Enzell and Wahlberg (1980) described several norisoprenoid comp:iunds which are derived from the cyclic carot- enoids and are important to smoke aroma. The particular taste and aroma of a cigarette can be influenced by the selection of the grade (quality and leaf position on the plant! and type of tobacco used in the blend. Taste and smell receptors in the pharynx, larynx, and nose provide the first sensory input to the smoker as he or she lights up, an experience which is generally perceived as pleasurable (Rose et al. 1985). The taste and smell of tobacco smoke may be important reinforcers for tobacco smoking (Jarvik 1977tat least following repeated association with the reinforcing effects of nicotine adminis- tration (Chapter VII. By such behavioral conditioning, sensory cues provided by tar and flavor additives could come to control the tobacco-consuming behavior of the tobacco user. Changes in smoking patterns when brands are switched and brand selection may be a response in part to the particular flavor and aroma of the product (Thornton 19781. Carbon Monoxide The mainstream and sidestream carbon monoxide (CO) deliveries of cigarettes are influenced by cigarette design and puffing charac- terist.ics of the smokers. Depending upon these factors, the main- stream delivery usually ranges from 10 to 20 mg/cigarette. In a study of 29,000 blood donors in 18 locations around the United States, smokers were found to have median carboxyhemoglobin (COHb) levels ranging from 3.2 to 6.2 percent (Stewart et al. 1974). Anderson, Rivera, and Bright (1977) found the COHb levels in 50 smokers to vary from 3.9 to 14.0 percent, with the mean of 8.1 percent. The mean increment in COHb immediately after smoking 1 cigarette was 0.64 percent. COHb levels gradually decrease in blood after cessation of smoking. Carbon monoxide is eliminated in expired air. The rate of elimination depends on pulmonary blood flow and ventilation. The half-life of COHb is 2 to 4 hr during daytime hours, but as COHb is related to the level of exercise, the half-life may be as long as 8 hr during sleep (Wald et al. 1975). For these reasons, many smokers awaken in the morning with substantial levels of COHb, despite not smoking overnight (Benowitz, Kuyt, Jacob 1982). Persons smoking cigarettes with lower nicotine and CO yields have only slightly lower levels of COHb when compared with those smoking higher-yield products (Wald et al. 1980, 1981; Sutton et al. 1982; Hill, Haley, Wynder 1983; Benowitz, Jacob, Yu et al. 1986). Benowitz and colleagues (1986) studied tar, nicotine, and CO exposure in smokers switched from their usual brand to low-, high-, and ultra-low-yield cigarettes. This study indicated that there were no differences in exposure comparing low- and high-yield, but tar and nicotine exposure were reduced by about 50 percent and CO by 36 percent while smoking ultra-low-yield cigarettes. Switching from a high to lower yield cigarette does not significantly reduce blood COHb although switching to ultra low cigarettes has been shown to lead to a significant reduction. The toxic effects of high CO levels are well documented (US DHHS 1983). Some studies have tried to determine whether CO levels in the blood similar to those observed in smokers can affect behavior. Beard and Wertheim (1967) and Wright, Randell, and Shephard (1973) reported performance decrements with COHb levels below 5.0 59 percent; however, Guillerman, Radziszewski, and Caille (1978) found no psychomotor performance effects at COHb levels of 7 and 11 percent. Thus, the data are inconclusive with regard to the possible influence of CO on psychomotor performance at levels normally encountered in smokers. Acetaldehyde and Other Smoke Constituents Acetaldehyde is a major constituent of tobacco smoke, with mainstream smoke levels in commercial cigarettes ranging from 0.5 to 1.2 mg/cigarette (IARC 1986). The delivery of volatile aldehydes is influenced by cigarette design, with reductions achieved by specific filtration and air dilution techniques. Yields over 5.9 mg have been reported for large cigars (Hoffmann and Wynder 1977). Acetalde- hyde is the primary metabolite of ethanol, and its toxic potency is 20 to 30 times that of ethanol. Acetaldelhyde has been suggested to have an adverse effect on the heart (James et al. 1970). Acetaldehyde and acrolein, another important aldehyde in the gas phase of cigarette smoke, activate the sympathetic nervous system (Egle and Hudgins 1974). Acetaldehyde, by releasing norepinephrine, results in a pressor effect (Kirpekar and Furchgott 1972; Green and Egle 1983). Depressor effects occur at high doses of the aldehydes in guanethidine-pretreated hypertensive rats. Frecker (1983) indicated that condensation products of acetaldehyde may be active on endogenous opioid systems. Torreilles, Guerin, and Previero (1985) reviewed the synthesis and biological properties of beta-carbolines, the condensation products of tryptophan and indole alkylamines with aldehydes. Beta-carbolines occur as plant constituents, includ- ing minor constituents in tobacco. For example, harman (l-methyl+- carboline) has been identified in tobacco and tobacco smoke (Snook and Chortyk 1984). Carbolines from other plant species have been used as hallucinogens. The research conducted to date indicates a potential pharmacologic effect of the aldehydes, especially with regard to cardiovascular physiology; however, the evidence is inadequate to determine if these volatile smoke constituents in the doses delivered in tobacco smoke contribute to the behavioral effects of cigarette smoking. Summary and Conclusions 1. All tobacco products contain substantial amounts of nicotine and other alkaloids. Tobaccos from low-yield and high-yield cigarettes contain similar amounts of nicotine. 2. Nicotine is absorbed readily from tobacco smoke in the lungs and from smokeless tobacco in the mouth or nose. Levels of nicotine in the blood are similar in people using different forms of tobacco. With regular use, levels of nicotine accumulate in the body during the day and persist overnight. Thus, daily tobacco users are exposed to the effects of nicotine for 24 hr each day. 3. Nicotine that enters the blood is rapidly distributed to the brain. As a result, effects of nicotine on the central nervous system occur rapidly after a puff of cigarette smoke or after absorption of nicotine from other routes of administration. 4. Acute and chronic tolerance develops to many effects of nicotine. Such tolerance is consistent with reports that initial use of tobacco products, such as in adolescents first beginning to smoke, is usually accompanied by a number of unpleasant symptoms which disappear following chronic tobacco use. 61 References XBOOD. L.G GRASSI. S. [3H]Methylcarbamylcholine, a new radioligand for studying brain nicotinlc receptors. Biochemical Pharmacology 35(23):4199-4202, December 1. 1986. ABOOD, L.G., GRASSI, S., COSTANZO, M., JUNIG, J. Behavioral and biochemical studies in rats after chronic exposure to nicotine. In: Sharp, C.W. ied.) Mechanisms of Toleranrr tind Ikpendence. NIDA Monograph 54. U.S. Department of Health and Human Services, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration. DHHS Publication NO. (ADM) 84-1330, 1984, pp. 348-355. ABOOD, L.G., REYNOLDS, D.T., BOOTH, H., BIDLACK, J.M. Sites and mechanisms for nicotine's action in the brain. &uroscience Biobehacioral Recliews 5(4):479-486, Winter 1981. ACETO. M.D., AWAYA, H., MARTIN, B.R.. MAY, E.L. Antinociceptive action of nicotine and its methiodide derivatives in mice and rats. British ~Journal of Pharmacology 79(4):869-876, August 1983. ANDERSON, W.H., RIVERA, C., BRIGHT, M. Carboxyhemoglobin blood levels after smoking one cigarette in relation to puff profile. In: 1975 Symposium Nicotine and Carbon Monoxide, Proceedings-Z, University of Kentucky, Lexington, Kentucky, June 1977, pp. 13@136. ANDERSSON, K., ENEROTH, P., FUXE, K., MASCAGNI, F., AGNATI, L.F. Effects of chronic exposure to cigarette smoke on amine levels and turnover in various hypothalamic catecholamine nerve terminal systems and on the secretion of pituitary hormones in the male rat. Neuroendocrinology 41(6):462-466, December 1985. ARMITAGE, A.K., DOLLERY, C.T., GEORGE, C.F., HOUSEMAN, T.H., LEWIS, P.J., TURNER, D.M. Absorption and metabolism of nicotine from cigarettes. British Medicul Journal 4(5992):313-316, November 8, 1975. ARMITAGE. A.K., DOLLERY, C.T., HOUSEMAN. T.H.. KOHNER, E.M., LEWIS, P.J.. TURNER, D.M. Absorption of nicotine from small cigars. Clinical Pharmacol- og~ and Therapeutics 23(2):143-150, February 1978. ARMITAGE, A.K., TURNER, D.M. Absorption of nicotine in cigarette and cigar smoke. ivatrrru 226(5252):1231-1232, June 27, 1970. ARQUEROS, L., NAQUIRA, D., ZUNINO, E. Nicotine-induced release of catechol- amines from rat hippocampus and striatum. Biochemical Pharmacology 271"3):9667-2674, 1978. 1 - BAER, D.S.. McCLEARN. G.E., WILSON, J.R. Effects of chronic administration of tobacco smoke to mice: Behavioral and metabolic measures. Ps.whophormacologv 67~131-137. 1980. BALFOUR, D.J K. Studies on the biochemical and behavioral effects of oral nicotine. .?rchices Infernationales de Pharmacodwamie et de Theraple 245(1):245:95-103, 1980. BARRASS. B.C.. BLACKBURN, J.W., BRIMBLECOMBE, R.W., RICH, P. Modifica- tion of nicotine toxicity by pretreatment with different drugs. Biochemical Pharrrlnco/og>~ l&9):2145-2152, September 1969. BATTIG. K.. DRISCOLL, P.. SCHLATTER, J., USTER. H.J. Effect of nicotine on the exploratory locomotion patterns of female Roman high- and low-avoidance rats. Pharmwo1og.v Biochemist? and Behaclior 4:435-439, April 1976. BEARD, R.R., WERTHEIM, G.A. Behavioral impairment associated with small doses of carbon monoxide. ilmerican Journal of Public Health 57(1):2012-2022, Novem- ber 1967. BECKETT, A.H.. GORROD. .J.W., JENNER. P. Absorption of (-)-nicotine-1'.N-oxide in man and its reduction in the gastrointestinal tract. (Letter). Journal of Pharmacy nntl Piznmzucolo~~ 22(9):722-723, September 1970. 62 BECKETT. AH., GORROD. J.W.. JESSER. P. Th e ,inal)sis of nicotine-1'.N-oxide in urine, in the presence of nicotine and cotinine. and its application IL the study of in viva nicotine metabolism in man. .7o1rrrrnI or` Pharmnc:\ c~rld Phnr~tlc~c~r~lo,~~~ 23~Supplementt:55S-61S. December 19713. BECKETT. X.H.. GORROD. J.W.. JESNER. P The effect of smoking on nicotine metabolism in viva in man. .7ocrrr1nl of' Phnr-mat,>, ourI Phtrrmncolop~ 23iSupplement 1:62S-6%. December 197 1 b. BENOWITZ. N.L. Clinical pharmacology of nicotine :l,l,lrrczl Hc~~~rrc~ of .Ilcdrcirzr 3;:21-32, 1986a. BENOWITZ. N.L. Human pharmacology of nicotine. In Cappell. H.1). et al 1eds.i Research Adr,ancrs in Alcohol nrzc/ I)r-rrg f'rr~hlerrrs. Volume 9. New York. Plenum Press, 1986b. BENOWITZ, N.L. Increased 24.hour energy expenditure in cigarette smokers. 1Letter.1 lvctc, Enplar~d ,Journa/ of' Jlctf~crr~c~ 3141251 lfX--1631, June 19. 1986c. BENOWITZ, N.L.. HALL. S.M., HERNING. RI. J.1COB. P. III. JONES. RT.. OSMAN. A.-L. Smokers of low yield cigarettes do not consume le>j nicotine. .X'err, England -louma/ of Mcdlcrrle 309(31:139-142, July 21. 198:3 BENOWITZ. N.L.. JACOB, P. III. Daily intake of nicutine during cigarette smoking Clintcal Pharmatolv~~~~ nnd Th~rapeotrcs 35141:49%504. Apnl 1984. BENOWITZ. N L.. JACOB. P III. Nicotine renal excretion rate intluences nicotine intake during cigarette smoking. .JournnI of Pharmocolog~ und E.xperrmental Therapeutics 234(13:153-155. July- 1985, BENOWITZ. N.L.. JACOB, P. III. JONES. R.T.. ROSENBERG, J. Interindividual variability in the metabolism and cardiovascular effects of nicotine in man. ,Journal of Pharmacolog.~ and ErlJerimental Thempeutfcs 221(21.368-372. 1982. BENOWITZ, N.L.. JACOB. P. III. KOZLOWSKI. L.T.. YU. L. Influence of smoking fewer cigarettes on exposure to tar, nicotine. and carbon monoxide. AX'eVercs Eng/~d ~Jortrnal of Medicine 31~5r21):131~1313. November 20, 1986. BENOWITZ. N.L., JACOB, P. III. YC, L.. TALCOTT, R., HALL. S., JONES, R.T. Reduced tar, nicotine, and carbon monoxide exposure while smoking ultralow- but not low-yield cigarettes. .Journal (if the, rlmerican Mc,dicaI Associulron 25612,:241-246. 1986. BENOWITZ, N.L., KUYT, F., JACOB, P. III. Circadian blood nicotine concentrations during cigarette smoking. C'linicnI Pharmaco/ngy and Therapeuttcs 3216):75&764, December 1982. BENOWITZ, N.L., KUYT, F., JACOB, P. III. Influence of nicotine on cardiovascular and hormonal effects of cigarette smoking. Clinical Pharmacologv uud Therapeu- tics 36(1):74-81, 1984. BENOWITZ, N.L.. KUYT, F.. JACOB. P. III, JONES, R.T., OSMAN, A.-L. Cotinine disposition and effects. Clinical Pharmacolog: and Therapeutzcs 309:139-148, 1983. BENOWITZ, N.L., LAKE. T., KELLER, K.H., LEE, B.L. Prolonged absorption with development of tolerance to toxic effects following cutaneous exposure to nicotine. Clinical Pharmacolog> and Therapeutics 42( 11:119-120. 1987. BENOWITZ. N.L., PORCHET. II., SHEINER, L., JACOB, P. Nicotine absorption and cardiovascular effects with smokeless tobacco use: Comparison with cigarettes and nicotine gum. Clinical Pharmacology and Therupeutiw. in press. BENWELL, M.E.M., BALFOUR. D.J.K. Nicotine binding to brain tissue from drug- naive and nicotine-treated rats. ,Journa/ of Pharmuc,? and Phnr-maco/og), 37:405-409. 1985. BIBER. A., SCHERER. G., HOEPFNER. I., ADLKOFER. F.. HELLER. VV:D.. HADDOW. J.E., KNIGHT, G.J. Determination of nicotine and cotinine in human serum and urine: An interlaboratory study. Tor,cr~/og,x L~ttcw 35-45-52. 1987. 63 BJERCKE, R.J.. COOK, G., RYCHLIK, N., GJIKA, H.B., VAN VUNAKIS, H., LANGONE, J.J. Stereospecific monoclonal antibodies to nicotine and cotinine and their use in enzyme-linked immunosorbent assays. Journal of Immunological Methods 90(2):203213, June 24, 1986. BOOTH, J., BOYLAND, E. The metabolism of nicotine into two optically active stereoisomers of nicotine-l'oxide by animal tissues in vitro and by cigarette smokers. Biochemistry and Pharmacology 1%31:73%742, March 1970. BOVET. D., BOVET-NITTI, F. Structure et Activite Pharmacadynamique des Medicaments du Systeme Nerveux Vegetatif: Paris: S. Karger, 1948, pp. 526616. BOWMAN, E.R.. MCKENNIS, N. Jr. Studies on the metabolism of (-)-cotinine in the human, Journal of Pharmacology and Experimental Therapeutics 135(3):306311, 1962. BOYD, N.D., COHEN, J.B. Desensitization of membrane-bound Torpedo acetylcholine receptor by amine noncompetitive antagonists and aliphatic alcohols: Studies of ("H) acetylcholine binding and 22Na+ ion fluxes. Biochemistry 23(18):40234033, August 1984. BRUNNEMANN, K.D., HOFFMANN, D. The pH of tobacco smoke. Food and Cosmetics Toxicology 12(11:11!%124, February 1974. BUSH, L.P., GRUNWALD, C., DAVIS, D.L. Influence of puff frequency and puff volume on the alkaloid content of smoke. Journal of Agricultural and Food Chemistry 20(31:676-678, January-February 1972. CASTRO, A., MONJI, N., MALKUS, H., EISENHART, W., MCKENNIS, H. Jr., BOWMAN, E.R. Automated radioimmunoassay of nicotine. Clinica Chimica Acta 95(3):473481, August 1979. CHANCE, W.T., KALLMAN, M.D., ROSECRANS, J.A., SPENCER, R.M. A compari- son of nicotine and structurally related compounds as discriminative stimuli. British Journal of Pharmacology 63(41:609-616, August 1978. CHIEN, C.-Y., DIANA, J.N., CROOKS, P.A. High performance liquid chromatography with electrochemical detection for the determination of nicotine in plasma. Journal of Pharmaceutical Sciences, in press. CLARK, M.S.G., RAND, M.J. Effect of tobacco smoke on the knee-jerk reflex in man. European Journal of Pharmacology X41:294-302, July 1968. CLARK, M.S.G., RAND, M.J., VANOV, S. Comparison of pharmacological activity of nicotine and related alkaloids occurring in cigarette smoke. Archives Znternatio- nales de Pharmacodynamie et de Therapie X%(2):363-379, 1965. CLARKE, P.B.S., KUMAR, R. The effects of nicotine on locomotor activity in non- tolerant and tolerant rats. British Journal of Pharmacology 78f2):329-337, 1983a. CLARKE, P.B.S., KUMAR, R. Characterization of the locomotor stimulant action of nicotine in tolerant rats. British Journal of Pharmacology 80(3):587-594, Novem- ber 1983b. CLARKE, P.B.S., KUMAR, R. Nicotine does not improve discrimination of brain stimulation reward by rats. Psychopharmacology 7%213):271-277, February 1983c. COMROE, J.H. The pharmacological actions of nicotine. Annals of the New York Academy of Sciences 90(1):48-51, September 27, 1960. COSTA, L.G.. MURPHY, S.D. [3H]Nicotine binding in rat brain: Alteration after chronic acetylcholinesterase inhibition. Journal of Pharmacology and Experimen- tal Therapeutics 226(2):392-397, August 1983. CINDY, KC., GODIN, C.S., CROOKS, P.A. Stereospecific in vitro N-methylation of nicotine in guinea pig tissues by an Sadenosylmethionine-dependent N-methyl- transferase. Biochemical Pharmacology 34:281-284, 1985. CLJRVALL, M.. KAZEMI-VALA, E., ENZELL, C.R. Simultaneous determination of nicotine and cotinine in plasma using capillary column gas chromatography with nitrogen-sensitive detection. Journal of Chromatography 232:28%293, 1982. 64 DAENENS, P.. LXRL'ELLE. L.. CALLEWXERT, K., SCHEPPER, P., GALEAZZI, R., VAN ROSSUM. J. Determination of corinine in biological fluids by capillary gas cl:romatograph~-mass spectrometry-selected-ion monitoring. Journal o/ Chroma- tograph? 342:79-U. 1985. DAJANI. R.M.. GORROD, J M'., BECKETT. AH In vitro hepatic and extrahepatic reduction of I-I-nicotine-1'.N-oxide in rats. Riochcrnical Pharmacology 24:109-117, 197%. DAJXNI, R.M. GORROD, J.W., BECKETT, AH. Reduction in vivo of l-l-nicotine-l'- N-oxide by germ-free and conventional rats. Biochemical Pharmacology 24:648-650, 1975b DANAHER, B.G. Research on rnpld smoking: Interim summary and recommenda- tions. Addictiw Behariorr; L':151-166. 1977. DAVIS. D.L., STEVENS, K.L . JURD, L. Chemistry of tobacco constituents. Oxidation of a-ionone and the acid catalvzed rearrangement of 5-keto-a-ionone. ,Journal of &riculturul onci fixed Chemistrl, 2411 ):lP7-189. .January-February 1976. DAVIS. R.A. The determination of nicotine and cotinine in plasma. Journal of Chrvnl(!trJfi,nphi~ SC ienw 2414):134-141. April 1986. DIXON, W.E., LEE. W.E. Tolerance to nicotine. J Exp. Ph,wwl. (Londonl 5:373-383, 1912. DUBE, M.F., GREEN, C.R. Methods of collection of smoke for analytical purposes. Recent rldi,ar!res in Tobacco Sc!cwcr 8:42-102. October 1982. EGLE. J.L. Jr., HUDGINS, P.M Dose-dependent sgmpathomimetic and cardioinhibi- tory effects of acrolein and formaldehyde in the anesthetized rat. Toxicology and Applied Pharmau~1og.s 28:358-366, 1974. ENZELL. C.R.. WAHLBERG. !. Leaf composition in relation to smoking quality and aroma. Recent AdL,anws in Tobacco Sclenw 6:64-122, October 1980. EUDY. L.W.. THOME, F.A.. HEA\-NER. D.L.. GREEN. C.R., INGEBRETHSEN, B.J. Studies on the Vapor Partrtalate-Phase Distribution of En[sironmental Nicotine by Selected Trapping and Detection Methods. Paper presented at the 79th Tobacco Chemists' Research Conference, Montreal, October 2-5. 1985. FAULKNER, J.M. Nicotine poisoning by absorption through the skin. Journal of the American Medica/ Association 100(211:1664-1665, May 27, 1933. FEYERABEND, C.. INGS. R.M., RUSSELL, M.A.H. Nicotine pharmarokinetics and its application to intake from smoking. British Journa! of Clinical Pharmacology 19(2):239-247. February 1985. FEYERABEND, C.. LEVITT. T.. RUSSELL, M.A.H. A rapid gas-liquid chromato- graphic estimation of nicotine in biological fluids. Journal of Pharmacy and Pharmacology 27(61:434-436. June 1975. FRECKER, R.C. Eye movement measurement and the pharmacodynamics of tobacco dependence. In: Prowedings of the 5th World Conference on Smoking and Health l:l'l-129. 1983. GARG. M. Variation in effects of nicotine in four strains of rats. Ps.vchopkarmacologia 14:432-438, 1969. GEHLBXCH. S.H., WILLIAMS, W.A.. PERRY, L.D.. FREEMAN, J.I., LANGONE, J.J.. PETA. L.V., \:AN VUNAKIS. H. Nicotine absorption by workers harvesting green tobacco. Lancet 1(79051:478-480, March 1. 1975. GIORGUIEFF. M.F., Le FLOC'H, M.L., GLOWINSKI, J., BESSON, M.J. Involvement of cholinergic presynaptic receptors of nicotinic and muscarinic types in the control of the spontaneous release of dopamine from striatal dopaminergic terminals in the rat. -Journal of Pharmacolog? and Experimental Therapeutics 20013):535-544. 1977. GIORGUIEFF-CHESSELET, M.F.. KEMEL. M.L., WANDSCHEER. D., GLOWINSKI, J Regulation of dopamine release by presynaptic nicotinic receptors in rat striatal slices: Effect of nicotine in a low concentration. Life Science 25(14):1257-1262, 1979. 65 GOLDFARB, T.L.. GRJTZ. E.R., JARVJK. M.E.. STOLERMAN I.P. Reactions to cigarettes as a function of nicotine and "tar". Clinical Pharmacology and Thwapcatzcs 19i61:767-772. June 1976. GORI. G.B., BENOWITZ, N.L.. LYNCH, C.J. Mouth versus deep airways absorption of nicotine in cigarette smokers. Pharmacolog.v Blochemistq and Behavior 25t6):1181-1184. December 1986. GREEN, M.A., EGLE. J.L. Jr. The effects of acetaldehyde and acrolein on blood pressure in guanethidine-pretreated hypertensive rats. Toxicology and Applied Pharmacologv 69(11:29-36, June 15. 1983. GRITZ. E.R. Smoking behavior and tobacco abuse. In: Mello. N.K. (ed.) Advances in Substance Abuse, Volume 1. Greenwich. Connecticut: JAI Press, 1980, pp. 91-158. GRITZ, E.R., BAER-WEISS, V.. BENOWITZ, N.L.. VAN VUNAKIS. H., JARVIK, M.E. Plasma nicotine and cotinine concentrations in habitual smokeless tobacco users. Clinica/ Pharmacology and Therapeutics 30(2):201-209, August 1981. GRUENKE. L.D.. BEELEN, T.C., CRAIG, J.C., PETRAKIS, N.L. The determination of nicotine in biological fluids at picogram levels by selected ion recording. Analytical Biochemistn 94t2):411-416, April 15, 1979. GUILLERMAN, R.. RXDZJSZEWSKJ, E., CAILLE, J.E. Effects of carbon monoxide on performance in a vigilance task (automobile driving). In: Thornton, R.E. (ed.) Smoking Behacxior. Ph.wiological and P,s~chological Influences. London and New York: Churchill Livingstone, 1978. HALEY, N.J., AXELRAD. C.M.. TILTON, K.A. Validation of self-reported smoking behavior: Biochemical analyses of cotinine and thiocyanate. American Journal of Pubhc Health 73(101:1204-1207. October 1983. HALEY, N.J., HOFFMANN, D. Analysis for nicotine and cotinine in hair to determine cigarette smoker status. Clinical Chemistq 31~103:159~1600, October 1985. HALL, G.H. Changes in body temperature produced by cholinomimetic substances injected into the cerebral ventricles of unanaesthetized cats. British Journal of Pharmacology, 4414):634-641. April 1972. HANCOCK, J.C., HENDERSON. E.G. Antinicotinic action of nicotine and lobeline on frog sartorius muscle. 1Zhlln~n-Schmiedeber~~`s Archic fur Pharmakologie 272(31:307-324, 1972. HATCHELL, P.C., COLLINS, A.C. Influences of genotype and sex on behavioral tolerance to nicotine in mice. Phamcacologv Biochemisty and Behavior 6(1):25-30, January 1977. HATCHELL. P.C., COLLINS, A.C. The influence of genotype and sex on behavioral sensitivity to nicotine in mice. Ps.vchopharmacology 71(1,:45-49. 1980. HECKMAN, R.A., DUBE, M.F., LYNN, D.. RIVERS, J.M. The role of leaf precursors in cigarette flavor. In: Tobacco Leaf Chemist?: Its flrigin. Understanding and Current Trends. Recent Advances in Tobacco Science. Volume 7. Proceedings of the 35th Tobacco Chemists Research Conference, Winston-Salem, North Carolina, 1981. pp. 107-153. HENDRY, J.S.. ROSECRANS. J.A. The development of pharmacological tolerance to the effects of nicotine on schedule-controlled responding in mice. Psychopharma- co1og.v 77(4):339-343, 1982. HENGEN. N., HENGEN, M. Gas-liquid chromatographic determination of nicotine and cotinine in plasma. ClintcaI Chemistp 24(1):50-53, 1978. HENNINGFJELD. J.E. Behal ioral pharmacology of cigarette smoking. In: Thompson, T., Dews, P.B. leds I Adc,anccs ln Reharsloral Pharmacology. Volume 4. New York: Academic Press, 1984, pp. 131-210. HENNISGFJELD, J.E., GOLDBERG. S.R. Nicotine as a reinforcer in human subjects and laboratory animals. Pharmacologv Biochemistp and Behavior 19(6):989-992. 1983. 66 HENNINGFIELD, J.E., MIYASATO. K., JASINSKI, D.R. Abuse liability and pharmacodynamic characteristics of intravenous and inhaled nicotine. Journal of Pharmacology and Experimental Therapeutics 234(1):1-12, July 1985. HERNING. R.I., JONES, R.T., BENOWITZ, N.L.. MINES, A.H. How a cigarette is smoked determines nicotine blood levels. CZlnical Pharmacolog>, and Therapeutics 33(1):84-90, January 1983. HIBBERD, A.R., GORROD, J.W. Enzymology of the metabolic pathway from nicotine to cotinine, in vitro. European ?Journal of Drug Metabolism and Pharmacokinetics 8(2):151-162, 1983. HIBBERD, A.R., O'CONNOR, V., GORROD. J.W. Detection of nicotine, nicotine-l'-N- oxide and cotinine in maternal and foetal body fluids. In: Gorrod, J.W. ied. Biological Oxidation ofNitrogen. Amsterdam: Elsevier/North-Holland Biomedical Press, 1978. pp. 353-361. HILL, P., HALEY, N.J., WYNDER. E.L. Cigarette smoking: Carboxyhemoglobin, plasma nicotine, cotinine and thiocyanate vs self-reported smoking data and cardiovascular disease. Journal of Chronic Diseases 36(6):439449, 1983. HILL, P., WYNDER, E.L. Nicotine and cotinine in breast fluid. Cancer Letters 6:251-254, 1979. HOBBIGER, F., MITCHELSON, F., RAND, M.J. The actions of some cholinomimetic drugs on the isolated taenia of the guinea-pig caecum. British Journal of Pharmacology 36:53-69, 1969. HOFFMANN, D., WYNDER, E.L. Smoke of cigarettes and little cigars. An analytical comparison. Science 178:1197-1199, 1977. HUBBARD, J.E., GOHD. R.S. Tolerance development to the arousal effects of nicotine. Pharmacology Biochemistry and Behatlior 3(3):471-476, MayJune 1975. INGENITO, A.J., BARRETT, J.P., PROCITA, L. Direct central and reflexly mediated effects of nicotine on the peripheral circulation. European ?JournaZ of Pharmacolo- gy 17(3):375-385, March 1972. INTERNATIONAL AGENCY FOR RESEARCH ON CANCER. Tobacco Smoking, IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans, Volume 38. World Health Organization, International Agency for Research on Cancer, 1986. ISAAC, P.F., RAND, M.J. Cigarette smoking and plasma levels of nicotine. Nature 236(5345):308-310, April 7, 1972. JACOB, P. III, BENOWITZ, N.L., SHULGIN, A.T. Recent studies of nicotine metabolism in humans. Pharmacology Biochemist? and BehaLGor 1988. JACOB, P. III, BENOWITZ, N.L., YU. L., SHULGIN. A.T. Determination of nicotine N-oxide by gas chromatography following thermal conversion to 2-methyl-6-(3- pyridylttetrahydro-1,2 oxazine. Analytical Chemistry 58(11!:2218-2221, September 1986. JACOB, P. III, WILSON, M.. BENOWITZ, N.L. improved gas chromatographic method for the determination of nicotine and cotinine in biologic fluids. Journal of Chromatography 222(1):61-70, January 2, 1981. JAMES, T.N., BEAR, E.S., LANG, K.F., GREEN, E.W., WINKLER, H.H. Adrenergic mechanisms in the sinus node. Arckitjes of International Medicine 125513-547, March 1970. JARVIK, M. Biological factors underlying the smoking habit. In: Jarvik, M.E., Cullen, J.W., Griz, E.R.. Vogt, T.M., West, L.J. teds.) Research on Smoking Behat,ior, NIDA Research Monograph 17. U.S. Department of Health and Human Services, Public Health Service, Alcohol, Drug Abuse. and Mental Health Administration, Nation- al Institute on Drug Abuse. DHEW Publication No. (ADM) 78-581, 1977, pp. 122-146. 67 JARVIS, M., TUNSTALL-PEDOE, H., FEYERABEND, C., VESEY, C., SALLOOJEE, Y. Biochemical markers of smoke absorption and self reported exposure to passive smoking. .Journal of Epidemiology and Community Health 38(4):335-339, Decem- ber 1984. JENNER, P., GORROD, J.W., BECKETT, A.H. The absorption of nicotine-l'-N-oxide and its reduction in the gastro-intestinal tract in man. Xenobiotica 3(6):341-349, 1973. JONES, D., CURVALL, M., ABRAHAMdSON, L., KAZEMI-VALA, E., ENZELL, CR. Quantitative analysis of plasma nicotine using selected ion monitoring at high resolution. Biomedical Mass Spectrometry 9(121:539-545, 1982. JONES, R.A. Individual differences in nicotine sensitivity. Addictive Behaviors 11(4):435-438, 1986. KACHUR, J.F., MAY, E.L., AWAYA, H., EGLE, J.L., JR., ACETO, M.D., MARTIN, B.R. Pharmacological effects of 1,2,3,5,6,10b-hexahydropyrido[2,3-glindolizine, a bridged-nicotine analog. Life Sciences 38(41:323-330, January 27, 1986. KANNE, D.B., ASHWORTH, D.J., CHENG, M.T., MUTTER, L.C., ABOOD, L.G. Synthesis of the first highly potent bridged nicotinoid. 9-Azabicylo[4.2.l]nona[2,3- clpyridine (Pyrido[3,4-blhomotropane). fJournal of the American Chemical Society 108:7864-7865, 1986. KATZ, B., THESLEFF, S. A study of the "desensitization" produced by acetylcholine at the motor end-plate. Journal of Physiology (London1 138:63-80, 1957. KIRPEKAR, SM., FURCHGOTT, R.F. Interaction of tryamine and guanethidine in the spleen of cat. Journal of Pharmacology and Experimental Therapeutics 180:3846, 1972. KNIGHT, G.J., WYLIE, P., HOLMAN, MS., HADDOW, J.E. Improved "`1 radioim- munoassay for cotinine by selective removal of bridge antibodies. Clinical Chemistry 31(1):118121, January 1985. KSIR, C., HAKAN, R.L., KELLAR, K.J. Chronic nicotine and locomotor activity: Influences of exposure dose and test dose. Psychopharmacology 92:25-29, 1987. KSIR, C.J., HAKAN, R., HALL, D.P. Jr., KELLAR, K.J. Exposure to nicotine enhances behavioral stimulant effect of nicotine and increases binding of [3H]acetylcholine binding to nicotinic receptors. Neuropharmacology 24:527-532. 1985. KYEREMATEN, G.A., DAMIANO, M.D., DVORCHIK, B.H., VESELL, E.S. Smoking- induced changes in nicotine disposition: Application of a new HPLC assay for nicotine and its metabolites. Clinical Pharmacology and Therapeutics 32(6):769-780, December 1982. KYEREMATEN, G.A., DVORCHIK, B.H., VESELL, E.S. Influence of different forms of tobacco intake on nicotine elimination in man. Pharmacology 26(41:205-209, April 1983. LANGLEY, J.N. On the reaction of cells and of nerve-endings to certain poisons, chiefly as regards the reaction of striated muscle to nicotine and to curari. Journal of PkUysiology (London, 33:374-413, 1905. LANGONE, J.J., GJIKA, H.B., VAN VUNAKIS. H. Nicotine and its metabolites. Radioimmunoassays for nicotine and cotinine. Biockemistrv 12(241:50255030, November 20, 1973. LANGONE, J.J.. V.4N VUNAKIS, H., HILL, P. Quantitation of cotinine in sera of smokers. Research Communications tn Chemzcal Pathology and Pharmacology 1011):21-28, January 1975. LARSON. P.S., HAAG, H.B. Studies on the fate of nicotine in the body III. On the pharmacology of some methylated and demethylated derivatives of nicotine. Journal Pharmacology Experimental Therapeutics 77:343-349, 1943. LEE, B.L., BENOWITZ, N.L., JACOB, P. III. Influence of tobacco abstinence on the disposition kinetics and effects of nicotine. Clinical Pharmacology and Therapeu- tics 41(4):474479, 1987. 68 LUCK, W., HANSEN, R., STELDINGER. R., NAU, H. Nicotine and cotinine-Two pharmacologically active substances as parameters for the strain on fetuses and babies of mothers who smoke. Journal ofPerinata1 Medicine 1@52):107-108, 1982. MACHACEK, D.A., JIANG, N. Quantification of cotinine in plasma and saliva by liquid chromatography. Clinical Chemistry 32(6):979-982, June 13, 1986. MARKS, M.J., BURCH, J.B., COLLINS, A.C. Effects of chronic nicotine infusion on tolerance development and nicotinic receptors. Journal of Pharmacology and Experimental Therapeutics 226(3!817-825, 1983a. MARKS, M.J., BURCH, J.B., COLLINS, A.C. Genetics of nicotine response in four inbred strains of mice. Journal of Pharmacology and Experimental Therapeutics 226(1):291-302, 1983b. MARKS, M.J., COLLINS, A.C. Characterization of nicotine binding in mouse brain and comparison with the binding of a-bungarotoxin and quinuclidinyl benzilate. Molecular Pharmacology 22(31:554-564. November 1982. MARKS, M.J., COLLINS, A.C. Tolerance, cross-tolerance, and receptors after chronic nicotine or oxotremorine. Pharmacolog.? Biochemistry and Behavior 22(2):283-291. 1985. MARKS, M.J., ROMM, E., BEALER, S., COLLINS, A.C. A test battery for measuring nicotine effects in mice. Pharmacology Biochemistry and Behavior 23(2):325-330, August 1985. MARKS, M.J., ROMM. E., GAFFNEY, D.K., COLLINS, A.C. Nicotine-induced tolerance and receptor changes in four mouse strains. Journal of Pharmacology and Experimental Therapeutics 237(3):809-819, 1986. MARKS, M.J., STITZEL, J.A., COLLINS, A.C. Time course study of the effects of chronic nicotine infusion on drug response and brain receptors. Journal of Pharmacology and Experimental Therapeutics 235(3):619-628, December 1985. MARKS, M.J., STITZEL, J.A., COLLINS, A.C. Dose-response analysis of nicotine tolerance and receptor changes in two inbred mouse strains. Journal ofPharmacol- ogy and Experimental Therapeutics 23%2):358-364, November 1986. MARKS, M.J., STITZEL, J.A., COLLINS, A.C. Influence of kinetics on nicotine administration on tolerance development and receptor levels. Pharmacology Biochemistry and Behavior 27:505-512, 1987. MARKS, M.J., STITZEL, J.A., ROMM, E., WEHNER, J.M., COLLINS, A.C. Nicotinic binding sites in rat and mouse brain: Comparison of acetylcholine, nicotine and cr- bungarotoxin. Molecular Pharmacology 3Ot5k427-436, November 1986. MARTIN, W.R., SLOAN, J.W., HOOK, R., KAPLAN, E., WASH, C. Fourth ventricle effects of nicotine, 2-methylpiperidine and cytisine in dogs. Pharmacology Bio- chemistry and Behavior 25(4):843-848, October 1986. MARTINO-BARROWS, A.M., KELLAR, K.J. [3H]Acetylcholine and [3HX-)nicotine label the same recognition site in rat brain. Molecular Pharmacology 31:169-174, February 1987. MAZIERE, M., COMAR, D., MARZANO, C., BERGER, G. Nicotine-`IC: Synthesis and distribution kinetics in animals. European Journal of Nuclear Medicine 1:255-258, 1976. MCCARTHY, L.E., BORISON, H.L. Separation of central effects of CO, and nicotine on ventilation and blood pressure. Respiratory Physiology 15(3):321-330, July 1972. McCUSKER, K., McNABB, E., BONE, R. Plasma nicotine levels in pipe smokers. Journal of the American Medical Association 248(5):577-578, August 1982. McKENNIS, H. Jr., SCHWARTZ, S.L., BOWMAN, E.R. Alternate routes in the metabolic degradation of the pyrrolidine ring of nicotine. Journal of Biological Chemistry 239(11):399&3996, November 1964. McKENNIS, H. Jr., TURNBULL, L.B., BOWMAN, E.R. N-Methylation of nicotine and cotinine in viva. *Journal of Biological Chemistry 238:719-723, 1963. 69 . McKENNIS, H. Jr., TURNBULL, L.B., BOWMAN, E.R., TAMAKI, E. The synthesis of hydroxycotinine and studies on its structure. Journal of Organic Chemistry 28(1):383-387, February 1963. MINER, L.L., MARKS, M.J., COLLINS, A.C. Classical genetic analysis of nicotine induced seizures and nicotinic receptors. Journal of Pharmacology and Experimen- tal Therapeutics 231(3):54&554, December 1984. MINER, L.L., MARKS, M.J., COLLINS, A.C. Genetic analysis of nicotine-induced seizures and hippocampal nicotinic receptors in the mouse. Journal of PharmacoZo- gy and Experimental Therapeuttcs 239(3):853-860, 1986. MORRISON, C.F., STEPHENSON, J.A. The occurrence of tolerance to a central depressant effect of nicotine. British Journal of Pharmacology 46(1):151-156, September 1972. MORROW, A.L., LOY, R., CREESE, I. Alteration of nicotinic cholinergic agonist binding sites in hippocampus after fimbria transection. Brain Research 334(2):309-314, May 20, 1985. NESBI'IT, P.D. Smoking, physiological arousal, and emotional response. Journal of Personality and Social Psychology 25(1):137-144, January 1973. NEURATH, G.B., DUNGER, M., ORTH, D., PEIN, F.G. Trans-3'-hydroxycotinine as a main metabolite in urine of smokers. International Archives of OccupationaE and Environmental Health 5%2):199-201, February 1987. OLDENDORF, W.H. Lipid solubility and drug penetration in the blood-brain barrier. Proceedings of the Society for Experimental Biology and Medicine 147:813-816, 1974. PETERSEN, D.R., NORRIS, K.J., THOMPSON, J.A. A comparative study of the disposition of nicotine and ita metabolites in three inbred strains of mice. Drug Metabolism and Disposition 12(6):725731, November-December 1984. PETERSON, L.A., TREVOR, A., CASTAGNOLI, N. Jr. Stereochemical studies on the cytochrome P-450 catalyzed oxidation of (S&nicotine to the @)-nicotine Ai'fs"- iminium species. Journal of Medicinal Chemistry 30(2):249-254, February 1987. PETRAKIS, N.L., GRUENKE, L.D., BEELEN, T.C., CASTAGNOLI, N., CRAIG, J.C. Nicotine in breast fluid of nonlactating women. Science 199(4326):303-305, January 20, 1978. PIADE, J.J., HOFFMANN, D. Chemical studies on tobacco smoke LXVII. Quantita- tive determination of alkaloids in tobacco by liquid chromatography. Journal of Liquid Chromatography 3(10):150&1515, 1980. PILLSBURY, H.C., BRIGHT, C.C., O'CONNOR, K.J., IRISH, F.W. Tar and nicotine in cigarette smoke. Journal of the Association of Official Analytical Chemists 52(3):458-462, May 1969. POOL, W.F. R-(+I-N-Methylnicotinium Zon and Nicotine Metabolism. Doctoral Dissertation. University of Kentucky, Lexington, Kentucky, 1987. POOL, W.F., GODIN, C.S., CROOKS, P.A. Nicotine racemization during cigarette smoking. (Abstract.) Toxicologist 5:232, 1985. PORSIUS, A.J., VAN ZWIETEN, P.A. The central actions of nicotine on blood pressure and heart rate after administration via the left vertebral artery of anesthetized cats. Distribution of nicotine into the brain after central application. Arzneimittel-Forschung/Drug Research 28(9):1628-1631, 1978. RATHKAMP, G.. TSO, T.C., HOFFMANN, D. Chemical studies on tobacco smoke. XX: Smoke analysis of cigarettes made from bright tobaccos differing in variety and stalk positions. Beitrage zur Tobakforschung 7(3):179-189, November 1973. ROPPOLO. J.R., KAWAMURA, H., DOMINO, E.F. Effects of choline@ agonists and antagonists on lateral geniculate nucleus neurons. (Abstract.) Pharmacoldgist 12(2):270, Fall 1970. ROSE, J.E., TASHKIN, D.P., ERTLE, A., ZINSER, M.C., LAFER, R. Sensory blockade of smoking satisfaction. Pharmacology Biochemistry and Behavior 23(2):289-293, August 1985. 70 ROSECRANS, J.A. Brain area nicotine levels in male and female rats with different levels of spontaneous activity. Neuropharmacology 11(6):863-870, November 1972. ROSECRANS, J.A., SCHECHTER, M.D. Brain area nicotine levels in male and female rats of two strains. Archives Internationales de Pharmacodwmmie et de Therapie 19646-54, 1972. ROSENBERG, J., BENOWITZ, N.L., JACOB, P., WILSON, K.M. Disposition kinetics and effects of intravenous nicotine. Clinical Pharmacology and Therapeutics 28(4):517-522, October 1980. RUSSELL, M.A.H. Tobacco smoking and nicotine dependence. In: Gibbins, R.J., Israel, Y., Kalant, H., Popham, R.E., Schmidt, W., Smart, R.G. feds.1 Research Advances in Alcohol and Drug Problems. New York: John Wiley and Sons, 1976, pp. l-47. RUSSELL, M.A.H., FEYERABEND, C. Cigarette smoking: A dependence on high- nicotine boli. Drug Metabolism Recieus 8(11:29-57. 1978. RUSSELL, M.A.H.. JARVIS, M.J, DEVI'TT, G., FEYERABEND, C. Nicotine intake by snuff users. British Medical Journal 283(6295):814-817, September 26, 1981. RUSSELL, M.A.H., RAW, M., JARVIS, M.J. Clinical use of nicotine chewing gum. British Medical Journal 280(6231):1599-1602, June 28, 1980. SAKMANN, B., PATLAK, J., NEHER. E. Single acetylcholine-activated channels show burst-kinetics in presence of desensitizing concentrations of agonist. Nature 286(3):71-73, July 1980. SASSON, I.M., HALEY, N.J., HOFFMANN, D., WYNDER, E.L., HELLBERG, D., NILSSON, S. Cigarette smoking and neoplasia of the uterine cervix: Smoke constituents in cervical mucus. (Letter.) New England Journal of Medicine 312(5):315-316, January 31, 1985. SAXENA, K., SCHEMAN, A. Suicide plan by nicotine poisoning: A review of nicotine toxicity. Veterinary and Human Toxicofogv 27(6):495-497, December 1985. SCHACHTER, S. Pharmacological and psychological determinants of smoking. In: Thornton, R.E. (ed.1 Smoking Behavior. Physiological and Psychological Influences. London and New York: Churchill Livingstone, 1978. SCHIEVELBEIN, H. Nicotine, resorption and fate. Pharmacology and Therapeutics l&2):233-247, 1982. SCHIEVELBEIN, H., EBERHARDT, R., LOESCHENKOHL, K., RAHLFS, V., BE- DALL, F.K. Absorption of nicotine through the oral mucosa. I. Measurement of nicotine concentration in the blood after application of nicotine and total particulate matter. Agents and Actions 3(4):254-258, November 1973. SCHIEVELBEIN, H., HEINEMANN, G., LOESCHENKOHL, K., TROLL, C., SCHLE- GEL, J. Metabolic aspects of smoking behavior. In: Thornton, R.E. Ced.) Smoking Behavior: Physiological and Psychological ZnfZuences. Edinburgh: Churchill Liv- ingstone, 1978. SCHLATTER, J., BATITG, K. Differential effects of nicotine and amphetamine on locomotor activity and maze exploration in two rat lines. Pqvchopharmacologv 64(2):155--161, 1979. SCHMELTZ, I., HOFFMANN, D. Nitrogen-containing compounds in tobacco and tobacco smoke. Chemical Reuiews 77(3):295-311, June 1977. SCHMITERLOW, C.G., HANSSON. E., ANDERSSON, G., APPLEGREN, L.-E., HOFFMANN, P.C. Distribution of nicotine in the central nervous system. Annals of the New York Academy of Science 142:2-14, 1967. SCHWARTZ, R.D.. KELLAR, K.J. In vivo regulation of [3H]acetycholine recognition sites in brain by nicotinic cholinergic drugs. Journal of Neurochemistry 45(2):427433, August 1985. SCHWARTZ, R.D., MCGEE, R., KELLAR, K.J. Nicotinic cholinergic receptors labeled by [3H]acetylcholine in rat brain. b1oleculnr Pharmacologv 22~ 11:5&62. July 1982. 71 SEPKOVIC. D.W.. HALEY. N.J., AXELRAD, C.M., LAVOIE, E.J. Thyroid hormone concentrations in rats after chronic nicotine metabolite administration. Proceed- ings of. the Society for Experimental Biology and Medicine 177(3):412-416, December 1984. SEPKOVIC, D.W., HALEY, N.J., AXELRAD, CM., SHIGEMATSU, A., LAVOIE, E.J. Short-term studies on the in vivo metabolism of N-oxides of nicotine in rats. Journal of Toxicology and Enc+onmental Health 18(2):205-214, 1986. SHARP. B.M., BEYER, H.S. Rapid desensitization of the acute stimulatory effects of mcotine on plasma adrenocorticotropin and proiactin. Journal of Pharmacology and E.rperimenttrl Therupeutzcs 238(2):486191, 1986. SHIBATA, S., HATTORI, K.. SANDERS, B. The relationship between external calcuim concentration and the recovery rate of aortic strips from nicotine tachyphylaxis. European Journal of Pharmacology 16(1):109-112, September 1971. SHIMAMOTO, K., OYAIZU, S., KAWAI, K.. KANAMITSU, 0. On the pharmacologi- cal action of nicotine methiodides. Foli Pharmacologia Juponica 54:55-5, 1958. SHULGIN, A.T.. JACOB, P. III, BENOWITZ, N.L., LAU, D. Identification and quantitative analysis of cotinine-N-oxide in human urine. Journal ofchromatogru- phy, 1987, in press. SLOAN, J.W., MARTIN, W.R., BOSTWICK, M., HOOK, R., WALA, E. The compara- ti\-e binding characteristics of nicotinic ligands and their pharmacology. Pharma- co101g.v Biochemist? and Behavior 26, 1987 SLOAN, J.W., MARTIN, W.R., HOOK, R., HERNANDEZ, J. Structure-activity relationships of some pyridine, piperidine and pyrrolidine analogues for enhancing and inhibiting the binding of (plus or minus)-[`HInicotine to rat brain P(,) preparation. Journal of Medicinal Chemistry 28(9):1245-1251, September 1985. SNOOK, ME.. CHORTYK. O.T. The rigid determination of harman and norharman in cigarette smoke. l'obucco Science 28:3-O, 1984. STALHANDSKE, T. Effects of increased liver metabolism of nicotine on its uptake, elimination and toxicity in mice. Actn Physiologica Scandinaoica 80(2):222-234, October 1970. STALHANDSKE, T.. SLANINA, P. Nicotyrine inhibits in vivo metabolism of nicotine without increasing its toxicity. Toxicology and Applied Pharmacology 65t31:366-372, September 30, 1982. STEWART, R.D., BARETTA, E.D., PLATTE, L.R., STEWART, E.B., KALBFLEISCH, J.H., VAN YSERLOO. B., RIMM, A.A. Carboxyhemoglobin levels in American blood donors. Journal of the American Medical -4ssocintion 229(9):1187-1195, August 26, 1974. STITZER, M.. MORRISON, J.. DOMINO. E.F. Effects of nicotine on fixed-interval behavior and their modification by cholinergic antagonists. Journal of Pharmacol- og>' urrd Experimental Thwapeutics 17112):166-177, February 1970. STOLERMAN, 1.P.. BUNKER, P., JARVIK, M.E. Nicotine tolerance in rats; Role of dose and dose interval. P.s~chopharnlocologia 34:317-324. 1974. PTOLERMAN. 1.P FINK, R., JARVIK. M.E. Acute and chronic tolerance to nicotine measured by activity in rats. Psvchopharmacologia 30(4):329-342, 1973. SI!. C Actions of nicotine and smoking on circulation. Pharmacology and Therupeu- tic,? 17,11:129-141, 1982. SUTTON. S.R., RUSSELL, M.A.H., IYER, I.. FEYERABEND, C., SALOOJEE, Y. Relationship between cigarette yields, puffing patterns, and smoke intake: Evidence for tar compensation? British Medical Journal 285(6342):6-03, August 2%September 4. 1982. TXKEUCHI. 31.. KUROGOCHI. Y.. YAMAOKA, M. Experiments on the repeated injection of nicotine Into albino rats. Folk Phnrmacologica Juponica 50:6f%39, 1954. 72 TEPPER, J.M., WILSON, J.R.. SCHLESINGER, K. Relations between nicotine- induced convulsive behavior and blood and brain levels of nicotine as a function of sex and age in two inbred strains of mice. Pharmuco/r:gF Bzuchemistp and Reha~ior l&349-353. 1959. THORNTON, R.E. Smukzng Behat,wr. Physrologwal and Pswhologlcal Influences. London and New York: Churchill Livingstone. 1978. TORREILLES, J., GUERIN, M.-C.. PREVIERO, A. Des structures simples aux potentialites pharmacologiques elevees: Les B-carbolinrs. Origines, syntheses, proprietis biologiques. Bioc.`limir 67:929-947, 1985. TRAVELL, J. Absorption of nicotine from various sites. Annals of the h'w York Academy of Sciences 9(X1):13-30. September 27, 1960. TURNER, D.M., ARMITAGE, AK., BRIANT. R.H.. DOLLERY, C.T. Metabolism of nicotine by the isolated perfused dog lung. Xenohiotrca 5(91:539-551. 1975. TURNER, J.A.M., SILLETT. R.W.. McNICOL. M.W. Effect of cigar smoking on carboxyhaemoglobin and plasma nicotine concentrations in primary pipe and cigar smokers and ex-cigarette smokers. British Med/cal Journal 216(1991:1387-1389, November 26, 1977. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Consr- puences of Smoking: Cardiocascular Disewe. A Report of the Surgeon General. U.S. Department of Health and Human Services, Public Health Service, Office on Smoking and Health. DHHS Publication No. tPHSi 8450204. 1983. VAN LOON, G.R., KIRITSY-ROY, J.A., BROWN. L.V., BOBBITT. FA. Nicotinic regulation of sympathoadrenal caterholamine secretion. In: Martin. W.R., Van Loon, G.R., Iwamoto. E.T., Davis, L. teds.) Tobacco Smoking and &`irotine. New York: Plenum Press, 1987, pp. 263-276. VAN VUNAKIS, H., LANGONE, J.J., MILUNSKY. A. Nicotine and cotinine in the amniotic fluid of smokers in the second trimester of pregnancy. American Jor~rnal of Obstetrics and GynecoZog> 120(11:64-66. September 1974. VEREBEY, K.G., DEPACE, A., MULE, S.J. A rapid, quantitative GLC method for the simultaneous determination of nicotine and cotinine. Journal of Analytical Toxicology 6:294-296, November-December 1982. WALD. N.J.. BOREHAM, J., BAILEY. A., RITCHIE, C.. HADDOW. J.E , KNIGHT, G. Urinary cotinine as marker of breathing other people's tobacco smoke. (Letter.1 Lancet 1(8370):23@231, January 28, 1984. WALD, N., HOWARD, S., SMITH, P.G., BAILEY, A. Use of carboxyhaemoglobin levels to predict the development of diseases associated with cigarette smoking. Thorax 30:133-140. 1975. WALD, N.J., IDLE, M., BOREHAM, J., BAILEY, A. Inhaling habits among smokers of different types of cigarette. Thorax 35(12):925-928, December 1980. WALD, N.J., IDLE, M., BOREHAM, J., BAILEY, A. Carbon monoxide in breath in relation to smoking and carboxyhemoglobin levels. Thorax 36(51:366-36. May 1981. WEILAND, G., GEORGIA, B., LAPPA, S., CHIGNELL, C.F., TAYLOR, P. Kinetics of agonist-mediated transitions in state of the cholinergic receptor. .Jourrral of Biological Chemistp 252(211:7648-7656, November 10. 1977. WENZEL, D.G., AZMEH. N.. CLARK, J.J. Studies on the acute and chronic depressor actions of nicotine in the rat. Archives Intcmationales de Pharmatndynamia et dc Therapie 193(1!23-36. September 1971. WEST, R.J., RUSSELL, M.A.H. Cardiovascular and subjective effects of smoking before and after 24 h of abstinence from cigarettes Ps,~~cho~~harmnco/~~~ 92:118-121, 1987. WESTFALL, T.C. Effect of nicotine and other drugs on the release of `H-norepineph- rine and `H-dopamine from rat brain slices. h'europharnlcfcolo~~~ 13t8):693-700, August 1974. 73 WESTFALL. T.C.. PERRY, H. The nicotinic-induced release of endogenous dopamine from rat striatal slices from animals chronically exposed to dimethylphenylpipera- zinium (DMPP). iVe(euroscience Letters 71(3):340-344, November 21, 1986. WOOD, J.D. Electrophysiological and pharmacological properties of the stomach of the squid loligo pealii (Lesueur). Comparative Biochemstry and Physiology 30(5):813-824, September 1, 1969. WRIGHT, G., RANDELL, P., SHEPHARD, R.J. Carbon monoxide and driving skills. Archives of Environmental Health 27(6):349-354, December 1973. ZEIDENBERG, P., JAFFE, J.H., KANZLER, M., LEVITT, M.D., LANGONE, J.J., VAN VUNAKIS, H. Nicotine: Cotinine levels in blood during cessation of smoking. Comprehensive Psychiatry 18(1):93-101, January-February 1977. 74 CHAPTER III NICOTINE: SITES AND MECHANISMS OF ACTIONS 75 CONTENTS Overview .............................................................. .79 Peripheral Effects of Nicotine ............................. .79 Central Sites of Nicotine Actions ........................ .80 Neuroendocrine Effects of Nicotine ...................... .81 Electrophysiological Effects of Nicotine ................ .81 D listribution and Cerebral Metabolic Effects of Nicotine.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .82 Distribution of Nicotine,. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .82 Tissue Distribution of Nicotine: Time Course and Other Considerations . . . . . . . . . . . . . . . . . . . . . . . . . .82 Heterogeneity of Nicotine Uptake: Microauto- radiographic and Subcellular Studies.. . . . . . . . . .85 Effects of Nicotine on Cerebral Metabolism . . . . . . . . . . .85 Nicotine Receptors ................................................. .88 Peripheral Nicotine Receptors ............................. .88 Radioligand Binding to Putative Nicotine Choliner- gic Receptors in Mammalian Brain ................... .89 Agonist Binding ......................................... .89 Radioligand Binding ................................... .91 Antagonist Binding .................................... .91 Functional Significance of Nicotinic Binding Sites .. .92 High-Affinity Agonist Binding Sites .............. .92 Alpha-Bungarotoxin Binding Sites ................. .92 Behavioral and Physiological Studies ............. .93 The Neuroanatomical Distribution of Nicotinic Binding Sites in the Brain .............................. .93 High-Affinity Agonist Binding Sites .............. .93 Rodent .................................................. .93 Monkey ................................................. -94 Human ................................................. .94 Alpha-Bungarotoxin Binding Sites ................. .94 Molecular Biology ...................................... .95 Central Nicotinic Cholinergic Receptors: Pre- or Postsynaptic?. ................................................ .95 Presynaptic Regulation of Neurotransmitter Release .................................................. -95 Somatodendritic Postsynaptic Actions ............ .95 77 Neuroendocrine and Endocrine Effects of Nicotine ....... .95 Cholinergic Effects ............................................ .96 Modulation of Catecholamine and Serotonin Activity ......................................................... 97 Effects on Serotonergic Neurons ................... .99 Effects on Catecholaminergic Neurons .......... 100 Stimulation of Pituitary Hormones ..................... 101 Arginine Vasopressin ................................. 102 The Pro-Opiomelanocorticotropin Group of Hormones ............................................. 103 Thyroid .......................................................... 104 Adrenal Cortex ............................................... 104 Androgens ...................................................... 106 Estrogens ....................................................... 106 Pancreas and Carbohydrate Metabolism .............. 107 Electrophysiological Actions of Nicotine .................... 107 Electrocortical Effects ....................................... 107 Spontaneous Electroencephalogram ..................... 108 Sensory Event-Related Potentials ........................ 112 Cognitive Ever&Related Potentials ...................... 114 Motor Potentials .............................................. 115 Other Peripheral Effects Relevant to Tobacco Use.. . , . .115 Psychophysiological Reactivity and Smoking.. . . . . . . . 116 Psychophysiological Reactivity, Smoking Cessation, and Relapse.................................................120 Summary and Conclusions.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 78 Overview Nicotine, in tobacco smoking concentrations, is a powerful psy- choactive drug (Domino 1973; Kumar and Lader 1981; Balfour 1984). A wide variety of stimulant and depressant effects is observed in animals and humans that involves the central and peripheral nervous, cardiovascular, endocrine, gastrointestinal, and skeletal motor systems. These heterogeneous effects, along with behavioral and psychological variables, result in self-administration of tobacco, tobacco dependence, and withdrawal phenomena with abrupt cessa- tion of tobacco smoking. This Chapter discusses sites and mechan- isms of nicotine actions that may help to explain why tobacco products are self-administered. The first Section of this Chapter provides general summaries of several major effects of nicotine in the body. Following this broad overview, the Chapter presents detailed discussions of sites and mechanisms of nicotine action that may be particularly important to understand tobacco use. Tissue distribution of nicotine, cerebral metabolic effects, and nicotine receptor binding are reviewed. Next, neuroendocrine and endocrine effects of nicotine are discussed. Then, electrophysiological effects of nicotine are presented. Finally, the effects of smoking on psychophysiological reactivity are discuss- ed. Peripheral Effects of Nicotine Nicotine exerts its action on the cardiovascular, respiratory, skeletal motor, and gastrointestinal systems through stimulation of peripheral cholinergic neurons via afferent chemoreceptors and ganglia of the autonomic nervous system (ANSI (Ginzel 1967b). Inasmuch as both sympathetic and parasympathetic ganglia are stimulated by levels of nicotine derived from tobacco smoking, the end result depends on the summation of the effects of autonomic ganglion stimulation and reflex effects. The resulting peripheral physiological changes generally resemble sympathetic nervous sys- tem (SNS) arousal, but there are also some effects of nicotine and smoking that lead to physiological relaxation. For example, there is usually an increase in heart rate and blood pressure immediately following cigarette smoking. In addition, there is cutaneous vasocon- striction of the distal extremities. In contrast, nicotine can relax skeletal muscles (e.g., reduce patellar reflex) in humans and animals via effects on Renshaw cells (Domino and Von Baumgarten 1969; Ginzel and Eldred 1972; Ginzel1987). But it also can enhance tension in some muscles (e.g., trapezius muscle) (Fagerstrom and Gotestam 1977). Nicotine in small doses can enhance respiration through stimulation of peripheral chemoreceptors. Yet, high nicotine doses can cause respiratory failure. (See Appendix B for a discussion of 79 nicotine toxicity.) The gastrointestinal effects of nicotine are com- plex, involving an increase in secretions and reduced motility for a short period of time. The peripheral actions of nicotine as a cholinergic agonist have made it a valuable pharmacologic tool for studying nicotinic cholinergic actions and functioning in many physiological systems. This Chapter focuses on the mechanisms of nicotine's actions relevant to tobacco use. Several peripheral actions of nicotine, for instance muscular relaxation, may contribute to the habitual use of tobacco products (see smoking and stress in Chapter VI). However, because the central nervous system (CNS) actions of nicotine and resulting neurochemical and electrical effects mediate subsequent biological and behavioral responses, a review of these actions contributes to an understanding of the reinforcing effects of nicotine. Central Sites of Nicotine Actions Nicotinic binding sites or receptors in the brain have been differentiated as very high, high, and low affinity types (Shimohama et al. 1985; Sloan, Todd, Martin 1984; Sloan et al. 1985). In the rat brain, when cholinergic muscarinic receptors are blocked, the autoradiographic distribution of 3H-acetylcholine (ACh) and "H- nicotine are essentially identical (Clarke and Kumar 1984; Clarke, Pert, Pert 1984). However, these brain binding sites differ from peripheral nicotinic receptors in ganglia and skeletal muscle. Chronic nicotine administration results in up-regulation in region- al rat brain 3H-ACh binding sites measured in the presence of atropine to block the muscarinic sites (Schwartz and Kellar 1985). Up-regulation of 3H-nicotine binding sites also has been reported after continuous nicotine infusions in mice (Marks, Burch, Collins 1983a). In contrast, most agonists that act on receptor sites in the body, when given chronically, produce a reduction (or down-regula- tion) in the number of receptors. Both Marks, Burch, and Collins (1983b) and Schwartz and Kellar (1983, 1985) have suggested that nicotinic cholinergic receptors undergo a functional blockade but that sufficient recovery would allow enhanced behavioral responses to low doses of nicotine to occur within 24 hr, as has been shown behaviorally by Clarke and Kumar (1983) and Ksir and coworkers (1985). This phenomenon may help to explain the tolerance to nicotine that develops with repeated exposure. However, the time course of changes in receptor number and other biological effects of nicotine must be carefully compared to determine mechanisms underlying tolerance. (See Chapter II for additional discussion.) Several investigators have used in vitro autoradiography to identify 3H-nicotine binding sites in the rat brain. These audioradio- graphic binding studies suggest where nicotine is acting. London, Waller, and Wamsley (1985) have found the most intense localization 80 of 3H-labeled nicotine in the interpeduncular nucleus and medial habenula. Cerebral metabolism studies also suggest key sites of action. London and colleagues (1985) have reported that nicotine stimulated local cerebral glucose utilization (LCGU) by 139 percent over that of the control in the medial habenula and by 50 to 100 percent in the superior colliculus and the anteroventral thalamic and interpedun- cular nuclei. Other areas of the brain showed moderate or no significant changes. These effects of nicotine were blocked by mecamylamine, a nicotinic recept,or antagonist, confirming that they acted via nicotinic receptors. Furthermore, they correlated well with the distribution of 3H-nicotine binding in the brain except in layer IV of the neocortex, which showed nicotine binding but no change in LCGU. Sites that show increased glucose utilization after nicotine administration are probably functionally important loci of nicotinic actions. When nicotine binding and increased energy utilization both occur at a given site, it is likely to be involved in nicotine's actions. Neuroendocrine Effects of Nicotine Some of the actions of nicotine result from the release of ACh and other neurotransmitters, including norepinephrine (NE). Nicotinic cholinergic agonists including nicotine, carbachol, and 1,1-dimethyl4- phenylpiperazinium (DMPP) release endogenous ACh from the presynaptic cholinergic nerve terminals in addition to stimulating postsynaptic nicotinic receptors (Chiou 1973; Chiou and Long 1969). Nicotinic agonists also release ACh from rat cerebral cortical synaptic vesicles and can release newly synthesized 3H-ACh from synaptosomes prepared from the myenteric plexus of guinea pig ileum and from mouse cortical synapses (Briggs and Cooper 1982; Rowe11 and Winkler 1984). These effects are Ca"+-dependent and are blocked by hexamethonium, a quarternary nicotinic receptor antago- nist. In addition, nicotine-induced release of ACh in the hippocampal synaptosomes is blocked by the ion channel blocker, histrionicotoxin (Rapier et al. 1987). There is good evidence that nicotine releases ACh by a presynaptic mechanism. In contrast, presynaptic musca- rinic receptors, mostly of the M,-subtype, inhibit ACh release. Nicotine administration increases the amounts of other chemicals in the blood and brain, including serotonin, endogenous opioid peptides, pituitary hormones, catecholamines, and vasopressin (Domino 1979; Gilman et al. 1985; Marty and colleagues 1985). These chemicals may be involved in reinforcing effects of nicotine (see Chapters IV, VI). Electrophysiological Effects of Nicotine Nicotine administration is accompanied by brain wave or electro- encephalogram (EEG) activation in animals (Domino 1967). The EEG- activating effects of small doses of nicotine occur in intact as well as 81 brainstem-transected animals. Nicotine acts primarily directly on brainstem neuronal circuits to produce these effects (Domino 1967). However, stimulation of peripheral afferents (Ginzel 1987) and release of catecholamines and possibly neurotransmitters and modu- lators, such as serotonin or histamine, may enhance the direct central effects of nicotine. The EEG-activating effects of nicotine result in behavioral arousal (Domino, Dren, Yamamoto 1967). In cigarette smokers, nicotine produces sedat.ive and stimulant effects (Kumar and Lader 1981). Aceto and Martin (1982) have reviewed the large variety of nicotine effects on behavior including facilitation of memory, the increase in spontaneous motor activity, nicotine's antinociceptive properties, and its suppression of irritability. These behavioral and psychologi- cal effects are discussed in Chapters IV and VI. Distribution and Cerebral Metabolic Effects of Nicotine Nicotine, administered by various routes, rapidly enters the brain and also distributes to specific, peripheral organs. Nicotine produces a distinct pattern of stimulation of cerebral metabolic activity that suggests where nicotine acts in the brain. This Section reviews studies on the distribution of nicotine after its administration to experimental animals, data on the relationship between tissue levels of nicotine and the drug's biological effects, and studies on mapping the cerebral metabolic effects of nicotine in the rat brain. Distribution of Nicotine Tissue Distribution of Nicotine: Time Course and Other Considerations The distribution in the body of exogenously administered nicotine has been a topic of interest for more than a century and has been reviewed several times (Larson, Haag, Silvette 1961; Larson and Silvette 1968, 1971). As early as 1851, Orfila described experiments in which he detected nicotine in various organs (e.g., liver, kidney, lungs) and in the blood of animals after nicotine administration. In the 1950s the development of radiotracer methods led to a reexami- nation of nicotine distribution in the body. Werle and Meyer (1950) found that the brain, compared with other organs, contained the highest nicotine levels immediately after injection of a lethal dose in guinea pigs. Tsujimoto and colleagues (1955) found a high concentration of nicotine in the brain after the drug was administered to rabbits and dogs. Yamamoto (1955) observed that 1 hr after a subcutaneous (s.c.) injection of 5 mg/kg in the rabbit, the nicotine content was highest in the kidney. The pancreas, ileum, ventricular muscle, skeletal muscle, lung, spleen, cerebral cortex, omental fat, and liver showed progressively lower 82 levels of nicotine at 3 hr. None of the tissues had detectable levels at 6 hr. In the dog, the highest level at 1 hr was in the kidney, followed by the pancreas, brain, ileum, liver and omental fat, spleen, heart, muscle, and lung. Schmiterlow and colleagues used radiolabeled nicotine and whole- body autoradiography to study the distribution of nicotine in several species (Hansson and Schmiterlow 1962; Appelgren, Hansson, Schmiterlow 1962, 1963; Hansson, Hoffman, Schmiterlow 1964; Schmiterlow et al. 1965; Schmiterlow et al. 1967). After radiolabeled nicotine was administered, radioactivity representing nicotine and its metabolites was concentrated in some organs, particularly the brain. Hansson and Schmiterlow (1962) injected (Sl-nicotine-methyl- `*C intramuscularly or intravenously (iv.) in mice. Within 5 min, high concentrations were found in the brain, adrenal medulla, stomach wall, and kidney. Lower concentrations were observed in the liver, skeletal muscle, and blood, but all concentrations were higher in tissue than in blood. Activity was high in the kidney from 5 min to 4 hr after the nicotine injection, with the highest activity occurring within the first hour. The adrenal medulla maintained a high concentration at 1 hr and 4 hr after injection, but little or no activity was observed at 24 hr. At 30 min, the levels were high in the walls of large blood vessels and in the bone marrow. Radioactivity disappeared rapidly from the brain. Appelgren, Hansson, and Schmiterlow (1962) prepared whole-body autoradiograms of mice and cats given i.v. injections of 14C-nicotine. An initial, heterogeneous accumulation of radioactivity occurred in the CNS. Fifteen minutes after the radiotracer injection, the cat brain showed distinctly more intense labeling of grey than of white matter. Also apparent was a regional distribution within grey matter areas, particularly in the hippocampus. By 30 min, radioac- tivity was reduced. Studies of mice demonstrated a high concentra- tion of label in the brain at 5 min. By 30 min, the concentration was high in salivary glands, stomach contents, liver, and kidneys, while the brain was almost devoid of radioactivity. The same group also showed the accumulation of 14C-nicotine in the retina of the eye after i.v. administration (Schmiterlow et al. 1965). Fishman (1963) reported that in rats given randomly labeled 14C- nicotine intraperitoneally (i.p.) and killed 3 hr later, the kidney contained the highest concentration of radioactivity, followed by the lung, liver, brain, skeletal muscle, spleen, and heart. In the dog, more `%-nicotine was present in the stomach wall than in any other tissue analyzed 3 hr after i.v. injection of radioactive nicotine. Yamamoto, Inoki, and Iwatsubo (1967) gave mice S.C. injections of 5 mg/kg methyl-`4C-nicotine. Five minutes later, they found 0.5 to 1 pg/g (wet weight) of nicotine in various brain regions, including the cerebral cortex, superior and inferior portions of the brain stem, and 83 the cerebellum. Highest levels were detected 5 to 10 min after injection. Maximum levels in liver and whole blood were observed 2 and 10 min, respectively, after the injection. Yamamoto, Inoki, and Iwatsubo (1968) studied penetration of 14C- nicotine in rat tissues in vivo and in vitro. They found that 5 mg/kg, i.p., in male Wistar rats produced the following maximum tissue-to- blood ratios of 14C-nicotine activity after 10 to 20 min: kidney, 8.7; liver, 6.7; submaxillary gland, 6.2; cerebral cortex, 3.5; brainstem, 2.4; and heart, 1.8. When they incubated tissue slices with 10e4 M 14C- nicotine for 30 min at 37"C, the relative uptake of the label was similar: kidney cortex, 2.6; liver, 2.1; submaxillary gland, 2.1; and cerebral cortex, 2.0. Penetration in slices was unaffected by uncou- pling oxidative phosphorylation or blocking metabolic pathways, indicating that the uptake was not by active transport. In vivo, tissue-to-blood ratios were greater than slice-to-medium ratios, indicating that a process other than passive diffusion was involved. Because the respiratory tract is a major route by which nicotine from tobacco smoke enters the body, Schmiterlow and coworkers (1965) sprayed 14C-nicotine solution directly onto the trachea of mice. Autoradiograms from mice killed at 2 min exhibited a high amount of radioactivity in the respiratory tract and lungs and showed that nicotine enters the CNS rapidly by this route as well. At 15 min, radioactivity still persisted in the lungs, was reduced in the brain, and appeared in large amounts in the kidneys and stomach. Uptake and distribution of nicotine from tobacco smoke have also been assessed. Harris and Negroni (1965) exposed mice to cigarette smoke and extracted nicotine from the lungs (5 to 25 pg). Mattila and Airaksinen (1966) exposed guinea pigs to the smoke of one 4-g cigar over a period of 40 min, with intermittent ventilation with fresh air, and found that the same tissues which concentrated nicotine administered by other routes also showed nicotine uptake from smoke. Organ-to-blood ratios were lung, 2.0; spleen, 3.0; intestine, 2.9; and brain, 1.1. The use of positron-emitting radiotracers permits in vivo estima- tion of nicotine uptake into the brain and other organs, offering the potential of eventually relating nicotine action in the living human brain to behavioral and disease states. Maziere and coworkers (1976) prepared (S)-nicotine-methyl-"C, which they administered by i.v. injection to mice and rabbits. The time course of the radiotracer confirmed earlier studies and showed a maximum concentration in the 5 min following injection, except in the liver and spleen. Highest radioactivity was in kidneys and brain, followed by liver and lungs. The brain activity dropped rapidly, whereas the kidney concentra- tion remained high (8 percent of injected dose) at 50 min after the injection. External imaging by a y camera showed considerable 84 radioactivity in the head, kidneys, and liver. Brain activity decreased sharply over 1 hr, while activity remained high in liver and kidneys. Maziere and coworkers (1979) used "C-nicotine and positron emission tomography (PET) in baboons and found that "C-nicotine readily penetrated into the brain and then dropped sharply with time. Radioactivity was high in the temporal lobe, cerebellum, occipital cortex, pons, and medulla oblongata. There was also a high, stable radioactivity level in the retina, consistent with the earlier observation that radioactivity from `V-nicotine is found in the retina after i.v. administration (Schmiterlow et al. 1965). Heterogeneity of Nicotine Uptake: Microautoradiographic and Subcellular Studies Appelgren, Hansson, and Schmiterlow (1963) used a microautora- diographic method to study the localization of nicotine within the superior cervical ganglion of the cat. Most of the radioactivity was localized in the ganglion cells, with little labeling of satellite cells and connective tissue. Schmiterlow and coworkers (19671, using microautoradiograms of mouse brains after injection of 14C-nicotine and 3H-nicotine, reported that nicotine is concentrated in nerve cells. Brain areas with a high density of nerve cells, such as the molecular and pyramidal cell layers of the hippocampus and the molecular layer of the cerebel- lum, contained high amounts of radioactivity. Yamamoto, Inoki, and Iwatsubo (1967) studied accumulation of 14C-nicotine into subcellular fractions (nuclear, mitochondrial, nerve ending, microsomal, soluble) of mouse brain after i.p. injection of 5 mg/kg (20 $X/kg). Most of the radioactivity was in the soluble fraction. Less than one-tenth of the radioactivity in the soluble fraction was found in microsomes and nerve endings; however, radioactivity levels in microsomes were somewhat higher than in nerve endings. Effects of Nicotine on Cerebral Metabolism Following the demonstration that 3H-nicotine binds stereoselec- tively and specifically in preparations of rat brain (Yoshida and Imura 1979; Martin and Aceto 1981; Marks and Collins 19821, brain binding sites were visualized (Clarke, Pert, Pert 1984) and quantified (London, Waller, Wamsley 1985) by light microscopic autoradiogra- phy. However, mapping nicotinic binding sites or identifying specific binding sites for any drug or neurotransmitter does not necessarily mean that receptors are coupled to pharmacologic actions. An example of nonfunctional, stereoselective, specific binding is that of 3H-naloxone to glass fiber filters (Hoffman, Altschuler, Fex 1981). In addition, because the brain is a highly interconnected organ, drugs 85 may produce effects in brain regions remote from their initial receptor interactions. Receptor maps would show primary binding sites but not sites where important secondary actions might occur. Functional mapping procedures, such as the use of autoradio- graphic techniques to measure rates of LCGU and regional cerebral blood flow, are another way to determine the sites of the in vivo effects of nicotine in the brain. The 2-deoxy-D-[1-`Y$$ucose (2-DG) method for measuring LCGU (Sokoloff et al. 19771 has been used to demonstrate a relationship between local cerebral function and glucose utilization under a wide variety of experimental conditions, including pharmacologic treatments (Sokoloff 1981; McCulloch 1982). The effects of acute, S.C. injections of nicotine on LCGU were examined by London and colleagues (1985, 1986) and by London, Szikszay, and Dam (1986), while Grunwald, Schrock, and Kuschinsky (1987) measured the effects on LCGU of constant plasma levels of nicotine produced by iv. infusion. Subcutaneous injections of nicotine stimulated LCGU in specific brain regions (Table 1, Figure 11, including portions of the visual, limbic, and motor systems. Effects of nicotine infusion generally paralleled those obtained with S.C. injections. The greatest increase in response to S.C. nicotine occurred in the medial habenula. Marked increases in LCGU were noted in the anteroventral thalamic nucleus, interpeduncular nucleus, and superior colliculus. Moderate increases were seen in the retrosplenial cortex, interanteromedial thalamic nucleus, lateral geniculate body, and ventral tegmental area. No significant effects were observed in the frontoparietal cortex, lateral habenula, or central grey matter. LCGU responses to S.C. injection of nicotine were completely blocked by mecamylamine, indicating the specificity of nicotine effects. The effects of nicotine on LCGU correlate well with the distribu- tions of 3H-nicotine binding sites (Clarke, Pert, Pert 1984; London, Waller, Wamsley 1985). Areas such as the thalamic nuclei, the interpeduncular nucleus, medial habenula, and the superior collicu- lus, where there is dense labeling with 3H-nicotine, show moderate to marked nicotine-induced LCGU increases. Areas with less specific binding show smaller LCGU responses to nicotine, and the central grey matter, which lacks specific 3H-nicotine binding, shows no LCGU response. Similarly, nicotine dramatically increases LCGU in the medial but not the lateral habenula, reflecting different densities of 3H-nicotine binding sites. In general, 3H-nicotine binding sites visualized autoradiographically in the rat brain are functional nicotine receptors. However, layer IV of the neocortex displays significant 3H-nicotine binding, but lacks an LCGU response. In most brain areas, significant LCGU stimulation was obtained with 0.3 mg/kg of nicotine S.C. (London et al. 19861, a dose similar to one used successfully in training rats to distinguish nicotine from 86 TABLE l.-R&Nicotine effects on glucose utilization in the rat brain Local cerebral glucose utilization (um01/100 g tissue!mmuteI Brarn region Saline control Nxotine 11.7j mg!kgr Prontopar1etal cortex. layer I\ 110 2 8.1 108 t 6.5 Retrosplenml cortex. law I 98 i 6.5 123 + 5.1' Thaiamlc nuclei .L\nteroventral Interantcromed~al Lateral gemculatP body Interpeduncular nucleus Medial habenula Supw7or colllculus 109 1 6.5 201 L 61' 125 i- 86 Ii5 t 12.3' 82 z 6.8 106 r 44' 99 -t 9.8 182 + 9.31 70 2 52 167 f 37' 72 i 52 142 f 4.6' Central grey matter 66 2 4.0 77 f 4.3 FIGURE l.-Effect of subcutaneous R,S-nicotine (1 mg/kg, 2 min before S-deoxyglucose) on autoradiographic grain densities, representing glucose utilization saline in a T-maze apparatus (0.4 mg/kg, s.c.) (Overton 1969). Nicotine-induced stimulation of LCGU in the ventral tegmental area 87 and the habenular complex (London et al. 1985, 1986) may relate to the reinforcing properties of the drug (see Chapter IV). These regions of the brain have been implicated in drug- and stimulation-induced reward systems, respectively (Wise 1980; Nakajima 1984). Additional studies, using specific conditions under which nicotine is reinforcing, are needed to elucidate the anatomical loci involved in nicotine- induced reward and to identify the neurophysiological mechanisms by which nicotine acts as a reinforcer. Nicotine Receptors Nicotine exerts diverse pharmacologic effects in both the peripher- al nervous system (PNS) and CNS. The peripheral actions of nicotine are important, and some may reinforce the self-administration of nicotine. For example, stimulation in the trachea (Rose et al. 1984) seems to be involved in some of the pleasurable effects of smoking. Skeletal muscle relaxation and electrocortical arousal, both stimu- lated by actions of nicotine in the lung (Ginzel 1967a,b, 1975, 1987), may contribute to habitual tobacco use (Chapter VI). However, it is generally believed that the central actions of nicotine are of primary importance in reinforcing tobacco use (Chapter IV). In animals, the neuropsychopharmacologic effects of this drug are, with few if any exceptions, mediated through central sites of action. These effects are likely to contribute to the drug's reinforcing properties in animals and humans (Clarke 1987b). In addition, the effects of nicotinic antagonists on tobacco smoking in humans (Stolerman et al. 1973) and in rhesus monkeys (Glick, Jarvik, Nakamura 1970) suggest a central site of reinforcement, but do not rule out a peripheral site. To understand these actions, it is important to know exactly where nicotine acts in the body. This Section discusses evidence for nicotine receptors. Peripheral Nicotine Receptors In the mammalian PNS, nicotine and muscarine mimic different actions of ACh by acting at different types of cholinergic receptors. Nicotinic cholinergic receptors (nAChRs) have been subdivided according to location and sensitivity to nicotinic antagonists. Recep- tors of the C6 or "ganglionic" type are found principally at autonomic ganglia, in the adrenal medulla, and at sensory nerve endings; nicotinic cholinergic transmission in autonomic ganglia is selectively blocked by hexamethonium and certain other compounds. Receptors of the "neuromuscular" type (sometimes referred to as Cl0 type) are located on the muscle endplate, where transmission is selectively blocked by compounds such as decamethonium and alpha- bungarotoxin (a-BTX). 88 Higher doses of nicotine are required to stimulate nAChRs in skeletal muscle than at autonomic ganglia. Ganglionic nAChRs appear to be more sensitive than their neuromuscular counterparts, not only to the stimulant but also to the desensitizing actions of nicotine (Paton and Savini 1968). Doses of nicotine obtained by smoking cigarettes do not appear to affect the muscle endplate direct,ly. Therefore, if the CNS were to possess both types of nAChR, doses of nicotine obtained by normal cigarette smoking might affect only the CG-receptor population. Accordingly, many of the central effects of nicotine in vivo and in vitro are reduced or blocked by nicotinic antagonists that are CG-selective in the periphery. The most widely used CG-selective antagonist is mecamylamine, which passes freely into the CNS after systemic administration. Mecamyia- mine ant.agonizes actions of nicotine in the brain and spinal cord, as revealed by behavioral (Collins et al. 1986; Goldberg, Spealman, Goldberg 1981) and electrophysiological experiments (Ueki, Koketsu, Domino 1961) and also by studies of neurotransmitter release (Hery et al. 1977; Chesselet 1984). There have been few attempts to determine whether these central nicotinic actions are also blocked by neuromuscular antagonists, while several studies support the existence of central C6 nAChRs (Aceto, Bentley, Dembinski 1969; Brown, Docherty, Halliwell 1983; Caulfield and Higgins 1983; Egan and North 1986). The search for putative central a-BTX nAChRs has been hindered by several factors, including the central convulsant actions of a-BTX antagonists (Cohen, Morley, Snead 1981) and the probable need to deliver locally high concentrations of nicotine. Nevertheless, several studies have demonstrated actions of nicotine or cholinergic agonists that can be reduced or blocked by a-BTX, which acts selectively at. neuromuscular nAChRs (Zatz and Brownstein 1981; Farley et al. 1983; de la Garza et al. 1987a). Radioligand Binding to Putative Nicotine Cholinergic Receptors in Mammalian Brain Many receptors for neurotransmitters in the brain have been identified through the use of radiolabeled probes (radioligands). Attempts to label putative brain nAChRs have used compounds with known potency at peripheral sites (see Table 2). Agonist Binding The stereospecific, saturable, and reversible binding of 3H-nicotine to rodent brain is well-described (Roman0 and Goldstein 1980; Marks and Collins 1982; Costa and Murphy 1983; Benwell and Balfour 1985a; Clarke, Pert, Pert 1984). Most studies have demonstrated the existence of a population of high-affinity binding sites (reflected by a dissociation constant in the low nanomolar range) that is potently 89 TABLE 2.-Radioligands for putative nicotinic cholinergic receptors in mammals Antagonists Functional Bmd antagonism Sites examned Agonists "`[.BTX Yes Yes Muscle endplate `H-nicotine Yes YE Autonomic ganglia, spinal cord Yes YCS Bram cc&am sites only, JH-methylcarbachol !"hZlJa tOXln Yes ses Muscle endplate `H-ACh iwith excess Yes ND1 BLWI muscarinic antagonist and AChE inhibitort `H-dTC ND Yes Muscle. spinal cord, ganglia Yes Yt?S Brain `H-DHBE ND Yes Muscle. autonomic ganglia Yes Yes Dram. spinal cord Neosurugat0x1n ND No Muscle endplate ND Yes Autonomic ganglia Yes Yes Brain lmhlbits `H-nxotinel ' ND-no data inhibited by nicotinic agonists including ACh. In contrast, most nicotinic antagonists have very low affinity for this site. Binding with similar characteristics has been reported in rat brain tissue with 3H-methyl-carbachol (Abood and Grassi 1986; Boksa and Quirion 1987) and with 3H-ACh in the presence of excess atropine to prevent binding to muscarinic receptor sites (Schwartz, McGee, Kellar 1982). In the presence of atropine, tritiated nicotine and 3H-ACh proba- bly bind to the same population of high-affinity sites in rat brain. Thus, the two radioligands share the same neuroanatomical distribu- tion of binding (Clarke, Schwartz et al. 1985; Marks et al. 1986; Martino-Barrows and Kellar 1987). Binding of both ligands is inhibited with similar potency by a range of nicotinic agents, is up- regulated by chronic nicotine treatment in vivo, is down-regulated by chronic treatment with acetylcholinesterase inhibitors, and is dimin- ished by disulfide reducing agents in vitro (Marks et al. 1986; Martino-Barrows and Kellar 1987; Schwartz and Kellar 1983). Although less well studied, it appears that sites labeled by 3H- methyl-carbachol are the same as those labeled by 3H-ACh and 3H- nicotine (Abood and Grassi 1986; Boksa and Quirion 1987). High- affinity nicotine binding sites have been found in brain tissue of mice (Marks and Collins 1982), rats (Roman0 and Goldstein 1980), monkeys (Friedman et al. 1985), and humans (Shimohama et al. 1985; Flynn and Mash 1986; Whitehouse et al. 1986). Some investigators have reported a second class of sites which are characterized by lower binding affinity and higher capacity for 3H- 90 nicotine. With no demonstrated differential anatomical distribution or stereoselectivity (Roman0 and Goldstein 1980; Marks and Collins 1982; Benwell and Balfour 1985b), these low-affinity sites are of questionable pharmacologic significance, but may be the result of post mortem proteolysis (Lippiello and Fernandes 1986). Careful analysis of 3H-nicotine binding conducted in the absence of protease inhibitors has revealed the existence of five affinity sites or states (Sloan, Todd, Martin 1984). Functional studies (Martin et al. 1986) suggest that some of these different sites may represent in vivo sites of action for nicotine, although it is not clear which if any would be activated by nicotine doses obtained from typical cigarette smoking. Radioligand Binding Many receptors of different nicotine binding affinities have been reported. It is unclear whether these reflect different conformational states or binding sites of a single type of receptor, distinct receptor populations, or a single type of high-affinity site which has under- gone proteolytic degradation. Preliminary evidence supports the existence of distinct receptor subtypes labeled by agonists. Two components of high-affinity 3H-nicctine binding, differing in their affinity for neosurugatoxin, can be distinguished in rat brain. The relative proportion of these two components differs in different regions of the rat brain, suggesting that they are physically distinct receptors (Yamada et al. 1985). Antagonist Binding Most studies of nicotine binding in mammalian brain have used radioiodinated a-BTX (lz51-BTX), which binds with high affinity and in a saturable manner to sites in mammalian brain (Schmidt, Hunt, Polz-Tejera 1980; Oswald and Freeman 1981). This binding is selectively inhibited by nicotinic agents, including nicotine and ACh. Cobra (naja) alpha-toxin, like a-BTX, is a selective neuromuscular blocker in the mammal, and appears to label the same sites as a-BTX in mammalian brain. Binding is potently inhibited by unlabeled a- BTX and has a regional distribution resembling that of iz51-BTX binding (Speth et al. 1977). The antagonist dihydro-beta-erythroidine (DHBE) binds to two sites in rat brain, but the regional distribution of binding differs from that of lz51-BTX (Williams and Robinson 1984). DHBE acts with similar potency at both types of peripheral nAChR in vivo. It is not clear whether 3H-d-tubocurarine binding is selectively inhibited by nicotinic agents. In rat brain, lz51-BTX binds to a distinct population of sites that are not labeled with high affinity (nanomolar kD) by tritiated nicotinic agonists. Radioiodinated a- BTX sites have a different neuroanatomical distribution (Marks and Collins 1982; Schwartz, McGee, Kellar 1982; Clarke, Schwartz et al. 91 1985) and can be physically separated from tritiated agonist binding sites by affinity chromatography (Schneider and Betz 1985; Wonna- cott 1986). This type of study helps to determine the location and numbers of nicotine binding sites. Functional Significance of Nicotinic Binding Sites High-Affinity Agonist Binding Sites Brain sites which bind 3H-ACh and 3H-nicotine with high affinity represent nAChRs that respond in some ways like the C6 type of receptor found in the periphery (Clarke 1987a). Studies using the 2- DG technique have revealed that the neuroanatomical pattern of cerebral activation following the systemic administration of nicotine in rats is strikingly similar to the distribution of high-affinity agonist binding demonstrated autoradiographically (London et al. 1985; Grunwald, Schrok, Kuschinsky 1987). Pretreatment with mecamyla- mine blocks the effects of nicotine on LCGU, suggesting that putative ganglionic (CG-type) receptors in the brain are associated with high-affinity agonist binding. Most of nicotine's actions on central receptors are blocked by the CG-selective antagonist mecamylamine. The relevant nAChRs are probably those which are labeled with high affinity by tritiated agonists. However, the absence of high-affinity agonist binding sites in PC12 cells (derived from a pheochromocytoma cell line) known to express CG-type receptors (Kemp and Morley 1986) indicates that although central and ganglionic nAChRs have pharmacologic simi- larities, they may not be identical at the molecular level. High-affinity agonist binding sites are relevant to long-term effects of human tobacco smoking. Recently, Benwell, Balfour, and Ander- son (in press) observed that the density of high-affinity 3H-nicotine binding in post mortem human brain is higher in smokers than in nonsmokers. The increased density of sites in smokers is consistent with studies in animals that show that chronic treatment with nicotine leads to an increased number of nicotinic receptors in the brain (Schwartz and Kellar 1983; Marks, Burch, Collins 1983b). Alpha-Bungarotoxin Binding Sites Although a-BTX does not block nicotinic actions in all areas of the CNS (Duggan, Hall, Lee 1976; Egan and North 1986), there are several reports of antagonism (Zatz and Brownstein 1981; Farley et al. 1983; de la Garza et al. 1987a). In the rat cerebellum, locally applied nicotine alters single-unit activity in a manner dependent on cell type: nicotine excites interneurons but inhibits Purkinje cells. Both actions are directly postsynaptic (de la Garza et al. 1987, in press(b)). The inhibitory effects of nicotine are blocked by hexame- thonium but not by a-BTX, which does block the excitatory effects (de la Garza et al., in press(a)). Strain differences exist in mice in the physiological and behavioral effects of nicotine, in the development of tolerance to these effects, and in the regional distribution of lz51-BTX binding density (Marks, Burch, Collins 1983a; Marks, Stitzel, Collins 19861. The genetically determined variation in response is not readily explained by differences in brain nicotinic receptors. However, a classical genetic analysis indicates that the density of `""I-BTX binding sites in mouse hippocampus correlates with susceptibility to seizures induced by high doses of nicotine (Miner, Marks, Collins 1984). These and other considerations (Clarke 1987a) suggest that lZ51-BTX may label a subtype of nAChR in the brain and that this receptor is pharmaco- logically akin to the nAChR found in muscle. Although ""I-BTX binding sites are found in human brain, the available evidence suggests that nicotine at doses obtained from cigarette smoking does not activate this population of brain nAChRs. Rather, the pattern of neuronal activation that follows the in vivo administration of nicotine in animal experiments, even in doses far greater than those likely to occur during smoking, resembles the neuroanatomical distribution of high-affinity agonist binding sites (London et al. 1985; Grunwald, Schrok, Kuschinsky 1987). However, this issue is not conclusively resolved, and a potential role for bungarotoxin binding receptors in mediating effects of smoking cannot be completely excluded. Behavioral and Physiological Studies The effects of mecamylamine on several responses elicited by nicotine in mice have been examined (Collins et al. 1986). The responses are of two major classes: those blocked by low doses of mecamylamine (inhibitory concentrations for 50 percent of mice tested (IC,,) thalamus > putamen > hippocampus, cerebellum, cerebral cortex, and caudate nucleus (Shimohama et al. 19851. Two affinity sites for 3H-nicotine have been detected, and the regional distribution observed reflects the presence of both sites. Alpha-Bungarotoxin Binding Sites Because "j1-BTX sites may not be relevant to tobacco smoking, they will be discussed only briefly here. There are clear differences of regional distribution not only between mice and rats, but also between different strains of mice (Marks et al. 19861. The autoradio- graphic distribution of lz51-BTX labeling in rat brain is strikingly different from the pattern of 3H-agonist labeling, with highest site density in hippocampus, hypothalamus, and superior and inferior colliculi (Clarke, Schwartz et al. 1985). An attempt to map lz51-BTX binding in human brain was hampered by a high degree of nonspecific binding, with diffuse specific labeling in the hippocam- pus and cerebral cortex (Lang and Henke 19831. 94 Molecular Biology Goldman and colleagues have mapped regions in the brain which contain cell bodies expressing RNA that codes for putative nAChRs. The RN.4 identified is homologous to cDNA clones encoding the alpha subunits of the muscle nAChR and a putative neuronal nAChR (Goldman et al. 1986; Goldman et al. 1987). These and related findings show that a family of genes exists that codes for proteins similar to, but not identical with, the muscle nAChR. The functional role of these putative nAChR subtypes in the CNS is not clear. Central Nicotinic Cholinergic Receptors: Pre- or Postsynaptic? Presynaptic Regulation of Neurotransmitter Release The release of ACh from some nerve terminals in the CNS (Rowe11 and Winkler 1984; Beani et al. 1985) and periphery (Briggs and Cooper 1982) is increased by activation of presynaptic nicotinic "autoreceptors." Preliminary evidence from lesion experiments suggests that some nicotinic autoreceptors in the brain may be high- affinity 3H-nicotine binding sites (Clarke et al. 1986). Nicotine also modulates the release of certain other neurotrans- mitters by acting at receptors located on nerve terminals. This form of regulation has been shown for dopaminergic, noradrenergic, and serotonergic terminals (Starke 1977; Chesselet 1984). Lesion studies suggest that these receptors are labeled by 3H-agonists (Schwartz, Lehmann, Kellar 1984; Clarke and Pert 1985; Prutsky, Shaw, Cynader 1987). Somatodendritic Postsynaptic Actions Much of 3H-agonist labeling probably represents nAChRs located on neuronal cell bodies or dendrites. For example, nicotine excites neurons postsynaptically in the medial habenula, locus coeruleus, and interpeduncular nucleus, all areas of moderate to dense 3H- agonist binding (Brown, Docherty, Halliwell 1983; Egan and North 1986; McCormick and Prince 19871. Neuroendocrine and Endocrine Effects of Nicotine Nicotine has direct and indirect effects on several neuroendocrine and endocrine systems (Balfour 1982; Clarke 1987a; Hall 1982). This Section reviews research on the effects of nicotine in animals and humans that are relevant to understanding cigarette smoking. Nicotine effects on cholinergic and noncholinergic nicotinic recep- tors, as well as on the release of catecholamines, monoamines, pituitary hormones, cortisol, and other neuroendocrine chemicals, 95 are discussed. Effects on single neuroregulators are emphasized, but it is important to recognize that there are extensive interrelation- ships among these substances (Tuomisto and Mtinnisto 1985). Nicotine has effects on peripheral endocrine as well as on central neuroendocrine functions. In the early 1900s researchers discovered that nicotine stimulated autonomic ganglia (ganglia were painted with tobacco solutions), inducing such effects as the release of adrenal catecholamines (Larson, Haag, Silvette 1961). As the health consequences of cigarette smoking have become clearer, many investigators have sought to determine tobacco's effects on the endocrine system, with the possibility that understanding such effects may help to explain smoking behavior. Nicotine is regarded as the major pharmacologic agent in tobacco and tobacco smoke responsible for alterations in endocrine function. However, there has not been a systematic evaluation of the effects of metabolites of nicotine or constituents of tobacco other than nicotine on the endocrine system. The functional significance of nicotine-induced perturbations in hormonal patterns and the role of neuroregulators in smoking are poorly understood. Extensive literature using nicotinic agonists and antagonists indicates relationships between cholinergic activity and particular behavioral effects (Henningfield et al. 1983; Kumar, Reavill, Stolerman, in press). Similar strategies have been employed to explore the contributions of catecholamines to smoking-related behavior. However, the exploration of the importance of neuroregu- lators in the reinforcement of cigarette smoking is still at an early stage. Cholinergic Effects Nicotine has cholinergic effects in the PNS and CNS. Nicotine is a cholinergic agonist. at peripheral autonomic ganglia and somatic neuromuscular junctions at low doses and becomes an antagonist at high doses (Voile and Koelle 1975). Nicotine also releases ACh in the cerebral cortex (Armitage, Hall, Morrison 1968; Rowe11 and Winkler 1984) and in the myenteric plexus of the peripheral ANS (Briggs and Cooper 1982). Balfour (1982) has suggested that cortical arousal (see Electrophysiological Actions of Nicotine for a detailed discussion) is mediated by ACh release but that behavioral stimulation (see Chapter IV) either is not mediated by ACh release or does not depend on the action of ACh at a muscarinic receptor. Studies involving intracerebral administration of nicotine have been used to determine the loci of nicotine's action (Kammerling et al. 1982; Wu and Martin 1983). The injection of nicotine into the cerebral ventricles of cats, dogs, and rats produces a variety of effects including changes in cardiovascular activity, body temperature, respiration, salivation, muscle reflex tone, and electrocortical indices 96 of sleep and arousal; the direction and duration of effects depend on dosage and on baseline response parameters (Ha!1 1982). Nicotine's cholinergic actions can affect other neuroregulators in the body (Andersson 1985). Nicotine stimulates NE release in the hypot,halamus by a Ca'- -dependent process that can be inhibited by prior administration of hexamethonium or ACh (Hall and Turner 1972; Westfail 1974). The mechanism resembles nicotine's effects on peripheral adrenergic nerve terminals (Westfall and Brasted 1972). At high dose levels. nicotine stimulates NE release by displacing it from vesicle stores at sites outside the hypothalamus (Balfour 1982). These actions are relevant to understanding the reinforcing effects of nicotine. For example, using drug discrimination procedures, Rosecrans (1.987) has demonstrated that intact central NE and dopamine IDA) function were required to elicit the cue properties of nicotine. Intravenous administration of nicotine modulates the release of both neurohypophyseal and adenohypophyseal hormones (Bisset et al. 1975; Hall, Francis, Morrison 1978). Hillhouse, Burden, and Jones (1975) found that the in vitro application of ACh to the hypophysio- tropic area of the rat caused a significant increase in the basal secretion of corticotropin-releasing hormone (as measured by bioas- say), which in t,urn controls, via the anterior pituitary, the release of the pro-opiomelanocortin (POMC) group of hormones-+-endorphin, @lipotropin, melanocyte-stimulating hormone-releasing factor, and adrenocorticotropic hormone (ACTH) (Meites and Sonntag 1981). The humoral mechanism for the release of vasopressin has been traced from the medulla to the paraventricular nuclei of the hypothalamus (Bisset et al. 1975; Castro de Souza and Rocha e Silva 1977). Similarly, Risch and colleagues (1980) have demonstrated a cholinergic mechanism for the release of 8-endorphin. Modulation of Catecholamine and Serotonin Activity Dale and Laidlaw (1912) found that the pressor response of the cat to nicot,ine was due in part to the release of epinephrine from the adrenal glands. Over the past 75 years, a large body of research has confirmed and further investigated this phenomenon. Stewart and Rogoff (1919) quantified the effect of nicotine on adrenal epinephrine release. Kottegoda (1953) observed that nicotine releases catechol- amines from extra-adrenal chromaffin tissues. Watt,s (1961) demon- strated the effect of smoking on adrenal secretion of epinephrine. Hill and Wynder (1974) reported that increasing the nicotine content in cigarette smoke progressively increased the serum concentration of epinephrine, but not NE. Winternitz and Quillen (1977) found that the excretion of urinary catecholamines tended to be higher on smoking days than on nonsmoking days. Several recent studies have focused on the role of nicotine and the mechanisms involved in the 97 release of catecholamines from cultured chromaffin cells (Forsberg, Rojas. Pollard 1986). Earlier experiments by Douglas and Rubin [1961), using denervated perfused cat adrenal glands, indicated that nicotine augments catecholamine release from chromaffin cells by promoting an influx of extracellular calcium. Forsberg, Rojas, and Pollard (1986) suggested that nicotine-induced catecholamine secre- tion may be mediated by phosphoinositide metabolism in bovine adrenal chromaffin cells. The anatomical localization and importance of biogenic mono- amines such as serotonin (5-HT [5-hydroxytryptamine]), DA, and NE have been the subject of intense research for the past 30 years. The classic studies of Dahlstrom and Fuxe (1966) revealed that neurons containing these amines were localized in specific ascending projec- tion systems; descending monoaminergic neurons have also been described. The physiological integrity of these systems was further demonstrated by Aghajanian, Rosecrans, and Sheard (1967J who observed that stimulation of 5-HT cell bodies localized in the midbrain raphe nucleus released 5-HT from nerve endings located in the more rostra1 forebrain. The recognition that these amine systems constitute a unique interneuronal communication system has played a central role in understanding underlying neurochemical and behavioral mechanisms. The cholinergic system has undergone a similar analysis (Fibiger 1982), but the delineation of specific cholinergic pathways has been more difficult because no histochemical method has been available for ACh. It does appear, however, that the cholinergic system is similarly organized and interacts with specific biogenic amine pathways. For example, Robinson (1983) has clearly shown that both 5-HT and DA systems exert tonic inhibitory control over ACh turnover in both the hippocampus and frontal cortex regions. Lesions of the medial raphe nuclei increase the ACh turnover rate in hippocampal sites, while lesions of the dorsal raphe elicit a similar effect in frontal cortical areas. Evidence of DA control comes from the observation that the catecholamine neurotoxin, 6-OHDA, when injected into the DA-rich septal area, facilitated hippocampal ACh turnover. The research of Kellar, Schwartz. and Martin0 (1987) and others also suggests that nicotinic receptors may occupy a presynap- tic site on select DA and 5-HT nerve endings. Westfall, Grant, and Perry (1983), using a tissue slice preparation, have shown that the DMPP-induced stimulation of nicotinic receptors in the striatum will facilitate the release of both 5-HT and DA. This preparation is devoid of cell bodies or 5-HT- and DA-containing axon terminals, suggesting that these nicotinic cholinergic receptors are primarily presynaptic. Further, hexamethonium, but not atropine, attenuated nicotine- induced amine release, confirming that these effects are nicotinic in nature. 98 Nicotine may have simultaneous actions on many types of neurons. Even though only one kind of receptor may be stimulated, either activation or inhibition of a particular SIIT, NE, or DA neuron may be the ultimate outcome. Conversely, the activity of specific cholinergic neurons may also be controlled by one of these biogenic-amine-containing projection systems. Nicotine appears to produce its discriminative stimulus effect in at least one major brain area, the hippocampus. This site is rendered insensitive if DA neurons innervating this area are destroyed (Rosecrans 1987). The interrelationships of these amine pathways are important to under- stand nicotine's effects on behavior and its effects on the neuroendoc- rine system because of the central role that these amine systems play in the hypothalamic control of the pituitary. Effects on Serotonergic Neurons Research evaluating the relationship between nicotine and 5-HT has involved several different approaches. Hendry and Rosecrans (1982) compared the effects of nicotine on conditioned and uncondi- tioned behaviors in rats selected for differences in physical activity and 5-HT turnover. Balfour, Khuller, and Longden (1975) observed that acute doses of nicotine were capable of attenuating hippocampal 5-HT turnover, an effect specific to the hippocampus. Fuxe and colleagues (19871 did not observe any acute changes in 5-HT function following acute nicotine dosing but did observe a significant reduc- tion of 5-HT turnover following repeated doses (3 x 2 mg/kg/hr). This effect, however, was suggested to be due to cotinine, the primary metabolite of nicotine. In addition to attempts to correlate 5-HT function with some pharmacologic effect of nicotine, investigators have evaluated poten- tial links between 5-HT and neuroendocrine function. Balfour, Khuller, and Longden (1975) showed a relationship between 5-HT and nicotine's ability to induce the release of plasma corticosterone, presumably by activation of the pituitary-adrenal axis. Following acute nicotine injections in the rat, a reduction in 5-HT turnover correlated with an increase in plasma corticosterone. Rats exhibited tolerance to pituitary activation following repeated nicot.ine doses, but not to the attenuation of hippocampal 5-HT turnover. Stress antagonized nicotine-induced reductions of hippocampal 5-HT. Also, nicotine was reported to inhibit the adaptive response to adrenocorti- cal stimulation following chronic stress (Balfour, Graham, Vale 1986). One interpretation of these data is that nicotine can modify how rats adapt to stress, which may be mediated by changes in hippocampal 5-HT function. At this point, however, it is difficult to draw firm conclusions concerning how nicotine affects 5-HT neurons and whether this neurotransmitter is involved in any of nicotine's 99 effects on neuroendocrine function. Hippocampal 5-HT turnover appears to be selectively attenuated by nicotine. Effects on Catecholaminergic Neurons Studies of the effects of nicotine on NE-containing neurons have produced mixed results. Earlier work suggested that nicotine may affect behavior via a NE component, but recent research has not supported such claims (Balfour 1982). It has been reported that nicotine releases DA from brain tissue (Westfall, Grant, Perry 1983). Lichtenst,eiger and colleagues (1982) observed that nicotine releases DA through an acceleration of the firing rate of DA cell bodies located in substantia nigra zona compacta when nicotine is adminis- tered via iontophoretic application or S.C. (0.4 to 1.0 mg/kg). This activation was marked by a significant increase in striatal DA turnover; DHBE, but not atropine, attenuated nigrostriatal activa- tion. Evidence that nicotine facilitates the firing of DA cell bodies by stimulating nicotinic cholinergic receptors has recently been report- ed by Clarke, Hommer, and coworkers (1985), who showed a specific effect of nicotine antagonized by mecamylamine on pars compacta cell bodies. Connelly and Littleton (1983) noted t.hat DA release from synaptosomes lacked stereoselectivity but was blocked by the ganglionic-blocking drug pempidine. Fuxe and coworkers (1986, 1987) have studied nicotine's effects on central catecholamine neurons in relation to neuroendocrine func- tion. These investigators use quantitative histofluorometric tech- niques that measure the disappearance of catecholamine stores by administering a tyrosine hydroxylase inhibitor (AMPT) to rats receiving various doses of nicotine or exposed to tobacco smoke. Tissues are then exposed to formaldehyde gas, and histofluorescence in AMPT-treated rats is evaluated in comparison to controls. Nicotine is a potent activator of both DA and NE neuron systems located primarily in the median eminence and in areas of the hypothalamus. These effects result from a stimulation of nicotinic cholinergic receptors, generally antagonized by mecamylamine. Intermittent nicotine dosing (4 x 2 mg/kg, S.C. every 30 min) or tobacco smoke exposure (rats were exposed to one to four cigarettes with a smoking machine-determined nicotine yield of 2.6 mg; rats received 8 puffs at lo-min intervals) results in a decrease of prolactin, thyroid-stimulating hormone (TSH), and luteinizing hor- mone (LH) and an increase of plasma corticosterone levels. Nicotine doses of 0.3 mg/kg administered iv. induce an overall activation of the hypothalamic-pituitary axis, causing an increase of both ACTH and prolactin that subsides within 60 min. Tolerance to the corticosterone response develops after repeated nicotine doses, and there is evidence that it develops after a single dose of nicotine (Sharp and Beyer 1986; Sharp et al. 1987). Restraint stress increases 100 ACTH, corticosterone, and prolactin levels and decreases DA and NE levels in hypothalamic regions. This stressor attenuates nicotine's activation of NE neurons but does not reverse its attenuating effects on prolactin. Nicotine appears to be associated with neuroendocrine activity by NE and DA activation (Fuxe et al. 1987). Immunohistochemical studies suggest that alterations in NE function are more important for the control of the pituitary-adrenal-axis, while DA turnover appears to be crucial for nicotine's effects on prolactin, LH, and follicle-stimulating hormone (FSH). Moreover, these studies indicate that similar nAChRs are located within both DA mesolimbic and neostriatal systems. Stimulation of Pituitary Hormones Nicotine administration and cigarette smoking stimulate the release of several anterior and posterior pituitary hormones. Seyler and coworkers (1986) had human subjects smoke two high-nicotine (2.87 mg) cigarettes in quick succession. Plasma levels of prolactin, ACTH, l3-endorphin/P-lipoprotein, growth hormone (GH), vasopres- sin, and neurophysin I increased. No change was seen in TSH, LH, or FSH. The rapid smoking paradigm used by Seyler and coworkers (1986) may have contributed to the effects of nicotine. Growth hormone levels exhibited a prolonged increase after subjects smoked three cigarettes in rapid succession (Sandberg et al. 1973). In experiments conducted by Winternitz and Quillen (1977) with male habitual smokers, GH began to rise after two cigarettes, peaked at 1 hr, and then returned to control levels while smoking continued. Wilkins and colleagues (1982) also found that smoking increases GH levels and presented evidence that the effect is nicotine mediated. Coiro and coworkers (1984) reported that the increase in GH produced by clonidine was greatly enhanced by cigarette smoking, suggesting that nicotinic cholinergic and adrenergic mechanisms might interact in the stimulation of GH secretion. The TSH plasma levels were not affected when nicotine was administered over a 60-min period to female rats (Blake 1974). In studies involving exposure to cigarette smoke, Andersen and col- leagues (1982) reported a lowering of TSH secretion in rats, but as noted, Seyler and coworkers (1986) found no change in human subjects. Thus, the data on the effects of nicotine on TSH release are inconclusive at this time. ACTH plasma levels increased after i.p. injection of nicotine in the rat (Conte-Devolx et al. 1981). In similar experiments, Cam and Bassett (1983b) found that elevated ACTH levels peaked and rapidly declined to a sustained plateau level. Sharp and Beyer (1986) reported that the effects of nicotine on ACTH in rats show a rapid and marked desensitization. Seyler and coworkers (1984) had male 101 subjects smoke cigarettes containing 0.48 or 2.87 mg of nicotine. No increases in ACTH or cortisol were detected after subjects smoked 0.48-mg-nicotine cigarettes. Cortisol levels rose significantly in 11 of 15 instances after smoking the high-nicotine cigarettes, but ACTH rose in only 5 of the 11 instances when cortisol increased. Each ACTH increase occurred in a subject who reported nausea and was observed to be pale, sweaty, and tachycardic. Seyler and coworkers (1984) studied smokers and concluded that ACTH release occurs only in smokers who become nauseated. LH levels were reduced in male rats exposed to unfiltered cigarette smoke, while FSH was unchanged (Andersen et al. 1982). In experiments by Winternitz and Quillen (1977), there were no differences in LH and FSH among male cigarette smokers while smoking as compared with not smoking. Seyler and colleagues (1986) found no change in human LH or FSH levels after smoking. There is no evidence of gonadotropin release stimulated by nicotine or smoking. Prolactin plasma levels were lowered considerably in lactating rats injected twice daily with nicotine (Terkel et al. 1973). It was suggested that failure of prolactin release following chronic nicotine administration was responsible for low milk production and starva- tion of pups. Blake and Sawyer (1972) found that, in lactating rats, the rapid suckling-induced release of prolactin into the blood is inhibited by S.C. injections of nicotine. Ferry, McLean, and Nikitito- vich-Winer (1974) reported that tobacco smoke inhalation in rats delays the suckling-induced release of prolactin. Andersen and coworkers (1982) found that prolactin secretion was reduced in male rats in a dose-dependent manner by exposure to unfiltered cigarette smoke. However, Sharp and Beyer (1986) reported that the effects of nicotine on prolactin in rats shows a biphasic effect, first increasing and then decreasing. Suppressed prolactin levels were found in female smokers who were breast feeding (Andersen et al. 1982). These researchers noted that smokers weaned their babies signifi- cantly earlier than nonsmokers. However, Wilkins and coworkers (1982) observed an increased level of prolactin in male chronic smokers. Arginim Va.sopressin In addition t.o its antidiuretic effects, arginine vasopressin acts as a vasoconstrictor (Munck, Guyre, Holbrook 1984; Waeber et al. 1984). Arginine vasopressin may also act as a neuromodulator in pathways that affect behavior. It has been shown to promote memory consolidation and retrieval in rats (Bohus, Kovacs, de Wied 1978) and there are reports of memory enhancement following intranasal administration of a vasopressin analog in both normal and memory- deficient humans (LeBoeuf, Lodge, Eames 1978; Legros et al. 1978; 102 Weingartner et al. 1981). Nicotinic cholinergic receptors in the medial basal hypothalamus and muscerinic cholinergic receptors in the neurohypophysis (posterior pituitary) have been implicated in the release of vasopressin (Gregg 19851. Nicotine has been found to stimulate vasopressin release in a dose-related manner in animals (Reaves et al. 1981; Siegel et al. 1983) and in humans (Dietz et al. 1984; Pomerleau et al. 1983; Seyler et al. 1986). These observations are consistent, with the effects of nicotine on cognitive performance (Chapter VI). The Pro-Opiomelanocorticotropin Group of Hormones The POMC hormones are released in response to stress and in response to corticotropin-releasing hormone (Munck, Guyre, Hol- brook 1984; Krieger and Martin 19811. ACTH has behavioral effects and stimulates the release of steroids such as cortisol from the adrenal cortex. ACTH produces rapid cycling between sleeping and waking as well as sexual stimulation, grooming/scratching, blocking of opiate effects such as analgesia, and the enhancement of attention and stimulus discrimination (Bertolini and Gessa 1981). Endogenous opioids, such as 8-endorphin, potentiate vagal reflexes, cause respira- tory depression, lower blood pressure, block the release of catechol- amines (Beaumont and Hughes 1979; Schwartz 19811, have antinoci- ceptive effects (van Ree and de Wied 19811, and modulate neuro- transmitter systems leading to amnesic effects (Izquierdo et al. 1980; Introini and Baratti 19841. It has been suggested that the primary function of the endogenous opioids is metabolic, serving to conserve body resources and energy (Amir, Brown, Amit 1980; Margules 1979; Millan and Emrich 1981). Nicotine appears to stimulate the release of corticotropin-releasing hormone from the hypothalamus through a nicotinic cholinergic mechanism (Hillhouse, Burden, Jones 1975; Weidenfeld et al. 1983). Using an isolated perfused mouse brain preparation, Marty and coworkers (1985) demonstrated that nicotine stimulates secretion of 8-endorphin and ACTH in a dose-related manner when applied directly to the hypothalamus but not when applied to t,he pituitary. The work of Sharp and Beyer (19861 supports this finding; they reported that the secretion of ACTH following nicotine was unaffect- ed by adrenalectomy. Nicotine administration to rats has also been shown to increase the plasma levels of corticosterone, ACTH, and /3- endorphin in a dose-related manner (Conte-Devolx et al. 1981). Termination of chronic nicotine administration reduced hypotha- lamic 8-endorphin levels (Rosecrans, Hendry, Hong 1985). Hurlick and Corrigal (1987) have also observed that the narcotic antagonist naltrexone inhibits some nicotine-modulated behavior in mice, providing a possible link between nicotine stimulation of endogenous opioid activity and behavioral responses. Acute administration of 103 nicotine increases levels of plasma ACTH and corticosterone sharply (Cam and Bassett 1983b), while chronic exposure results in complete adaptation (Cam and Bassett 1984). Melanocyte-stimulating hor- mone was decreased and &endorphin was increased by i.p. injections of nicotine in the rat (~Conte-Devolx et al. 1981). Risch and colleagues (1980. 198211 have accumulated evidence for cholinergic control of cortisol, prolactin, and 8-endorphin release in humans. Rapid smoking increases circulating cortisol, 8-endorphin, and neurophysin I !Pomerleau et al. 1983; Seyler et al. 1984; Novack and Allen-Rowlands 1985; Novack, Allen-Rowlands, Gann, in press). Moreover, in a study that examined the role of endogenous opioid mechanisms in smoking, Tobin, Jenouri, and Sackner (1982) ob- served that mean inspiratory flow rate increases during the smoking of a cigarette but is depressed shortly after smoking. Naloxone had no effect on the initial stimulation of respiration in response to smoking but did significantly blunt the subsequent depression of respiration. The significance of these findings for the control of cigarette smoking remains equivocal (Karras and Kane 1980; Nemeth-Coslett and Griffiths 1986; Chapter IV). Thyroid Most of the earlier work (1930s through 1950s) assessing the effects of nicotine on thyroid function involved histological studies of the thyroid glands from animals treated chronically with nicotine. The findings are inconsistent in that some studies suggest elevated thyroid activity and others do not (Cam and Bassett 1983a). In a more recent study of nicotine's action on the plasma levels of the thyroid hormones, thyroxine (T4) and triiodothyronine (T31, Cam and Bassett (1983a) found that a single i.p. injection of 200 pg/kg did not alter the level of either hormone, although it did produce an increase in plasma corticosterone. As mentioned earlier, nicotine does not consistently affect TSH in animals or humans (Blake 1974; Seyler et al. 19861. Adrenal Cortex Several studies in animals and human subject.s have reported that nicotine and cigarette smoking lead to elevated levels of corticoste- roids. Kershbaum and colleagues (1968) administered nicotine i.v. to anesthetized dogs and found a 64 percent rise in plasma corticoste- roids. In rat,s. corticosteroid concentrations increased 50 percent after i.p. administration of nicotine. Suzuki and coworkers (19731 also reported adrenal cortical secretion in response to nicotine in conscious and anesthetized dogs. The effects of nicotine on plasma corticosteroids in stressed and unstressed rats were studied by Balfour, Khuller, and Longden (1975). The administration of nicotine to unstressed rats caused a rise in corticosterone which persisted for 104 60 min. Nicotine did not affect plasma corticosterone concentration in rats stressed by being placed on an elevated platform. Ot.her studies showed increased plasma corticosteroid levels after nicotine administration (Turner 1975; Cam, Bassett, Cairncross 1979; Cam and Bassett 1983b). Andersen and colleagues (1982) exposed male rats to unfiltered cigarette smoke and found a dose-related increase in corticosterone secretion. Filtered cigarette smoke was inactive. Seifert and coworkers (i984) found that the chronic administration of 0.5 or 1.0 mg/kg of nicotine S.C. twice daily for 8 weeks to rats produced a marked decrease in plasma aldosterone levels. In this study, nicotine had no effect on plasma corticosterone concentration. Hokfelt (1961) report,ed increases in plasma cortisol and urinary 17-hydroxycorticosteroids following cigarette smoking in human subjects. Kershbaum and coworkers (1968) reported similar results involving elevations of 11-hydroxycorticosteroids. Hill and Wynder (1974) found that serum corticosteroids were markedly elevated after high-nicotine (2.73 mg) cigarettes were smoked. No increase was seen with cigarettes containing less nicotine. Cryer and colleagues (1976) also found an increase in circulating levels of corticosteroids after smoking. Winternitz and Quillen (1977) reported a sharp increase in circulating cortisol after two cigarettes. The levels were maintained through the smoking period and fell gradually to normal. Wilkins and coworkers (1982) also observed increased levels of cortisol after 2-mg-nicotine cigarettes were smoked. No increases in cortisol were detected after smoking 0.48-mg-nicotine cigarettes, but cortisol rose significantly in 11 of 15 cases smoking 2.87-mg-nicotine cigarettes (Seyler et al. 1984). Consistent with these results is the observation of Puddey and colleagues (1984) that cessation of smoking is associated with a significant fall in cortisol levels. In contrast to these findings, Tucci and Sode (1972) reported intact diurnal circadian variations of cortisol and unchanged 24-hr 17- hydroxycorticosteroids durin, u smoking. Benowitz, Kuyt, and Jacob (1984) studied 10 subjects who either smoked their usual brand of cigarettes, some of which contained 2.5 mg nicotine, or abstained. Plasma cortisol concentrations throughout the day did not differ during smoking or abstaining. Thus, while the majority of human and animal data indicates that nicotine or smoking elevates cortico- steroid levels, the effects appear to be influenced by dose, time, and perhaps other factors. Many investigators cited above have proposed that nicotine's effects on corticosteroids are mediated by the release of ACTH. Indeed, hypophysecbomy abolished the increase in adrenocortical secretion following nicotine administration (Suzuki et al. 1973; Cam, Bassett, Cairncross 1979) and nicotine-induced increase in plasma ACTH precedes the increase in cortisol (Conte-Devolx et al. 1981). However, Turner (1975) found that bilateral adrenal demedullation 105 abolished the rise in corticosterone in response to nicotine and suggested that the effect of nicotine is mediated via adrenal release of catecholamines and that centrally mediated stimulation is not significant. In contrast, the work of Matta and associates (1987) demonstrates that the effects of nicotine on ACTH secretion are centrally mediated. Rubin and Warner (1975) have also shown that nicotine directly stimulates isolated adrenocortical cells of the cat. The stimulant effect was dose-dependent and required the presence of calcium. These experiments also indicated that nicotine enhances the steroidogenic effect of ACTH. Androgens In male beagles, chronic smoking of high-nicotine/tar cigarettes was associated with decreased activity of 7a-hydroxylase active on testosterone (Mittler, Pogach, Ertel 1983). Testicular 66- and 16a- hydroxylases were not altered, while the hepatic androgen 6(3- hydroxylase activity in the testis was stimulated markedly by smoking. Serum testosterone levels were reduced to 54 percent of control levels by heavy smoking. It was concluded that chronic cigarette smoking increased hepatic metabolism of testosterone, resulting in lowered serum testosterone levels. However, it may be that total testosterone is lower while free testosterone is not. Estrogens Cigarette smoking is associated with antiestrogenic effects in women, including earlier menopause, lower incidence of breast and endometrial cancer, and increased osteoporosis. MacMahon and colleagues 11982) reported lower urinary estrogen levels in premeno- pausal smokers than in premenopausal nonsmokers and suggested that the low estrogen secretion reflected lower estrogen production, based on decreased estrone, estradiol, and estriol. However, 2- hydroxyestrogens, the major metabolites of estradiol in women, were not measured. Jensen, Christiansen, and Rodbro (1985) presented evidence for increased hepatic metabolism of estrogens as a result of smoking based on an observation of decreased serum estrogen levels in postmenopausal smokers receiving exogenous hormone therapy. This study examined 136 women treated for 1 year with different doses of estrogen. Reduction of serum estrogen was most pronounced in the highest estrogen-dose group. There was a significant inverse correlation between the number of cigarettes smoked daily and changes in serum estrogen. Michnovicz and colleagues (1986) found a significant increase in estradiol 2-hydroxylation in premenopausal women who smoked at least 15 cigarettes/day. They concluded that smoking exerts a powerful inducing effect on the 2-hydroxylation pathway of estradiol metabolism, which is likely to lead to decreased bioavailability of hormone at estrogen target tissues. 106 Pancreas and Carbohydrate Metabolism The body weight of smokers is consistently lower than that of nonsmokers, and smokers tend to gain weight after cessation of smoking (see Chapter VI for a detailed discussion of these relation- ships). These phenomena are thought to contribute to tobacco use. Glauser and coworkers (1970) and Hofstetter and coworkers (1986) suggested that a change in metabolic rate is partially responsible for these effects. Schechter and Cook (1976) and Grunberg, Bowen, and Morse (1984) showed that rats which were administered nicotine lost body weight without reducing food intake, although the body weight changes were not as great as when eating behavior declined as well (Grunberg 1982). Grunberg (1986) has pointed out that differences in body weight between smokers and nonsmokers result from changes in energy consumption (via changes in specific food consumption) and changes in energy utilization. Recently, Grunberg and cowork- ers (1988) have reported reductions of insulin levels accompanying nicotine administration in rats which could result in an increase in the utilization of fat, protein, and glycogen. This finding is consistent with work of Tjalve and Popov (1973), using rabbit pancreas pieces, and studies by Florey, Milner, and Miall (1977) of human smokers versus nonsmokers. Grunberg and coworkers (1988) have suggested that the effects of nicotine on insulin levels also may be involved in the nicotine-induced decrease of sweet food preferences. Electrophysiological Actions of Nicotine Electrocortical Effects The brain responds to electrical as well as to chemical stimuli. Therefore, measurements of the electrophysiological actions of nicotine complement studies of its chemical effects. In addition, electrophysiological activity reflects function that may relate to sensory and cognitive changes observed in humans after smoking (see Chapter VI). In animals, nicotine produces changes ranging from subtle latency decreases in the primary auditory pathway to seizures. The electrophysiological actions of nicotine may help to relate the anatomical and receptor data (discussed earlier in this Chapter) with sensory and cognitive data (discussed in greater detail in Chapter VI). The human studies on electrocortical effects of nicotine have some methodological limitations. Most of the human studies had subjects smoke cigarettes and did not measure blood levels of nicotine. Also, most studies were performed on smokers whose immediate and long- term smoking history was determined by questionnaires which may not accurately reflect tolerance and physical dependence (Chapter IV). In some studies the subjects were deprived of cigarettes, but no objective measures such as expired carbon monoxide or blood 107 nicotine levels were collected to verify compliance with the depriva- tion conditions. Spontaneous Electroencephalogram Historically, nicotine and ACh were used in animal experiments to study the cholinergic mechanisms in the midbrain and thalamus which produced EEG and behavioral activation (Longo, von Berger, Bovet 1954; Rinaldi and Himwich 1955a,b). The administration of nicotine produced EEG activation, consisting of desynchronized low- voltage, fast activity, and behavioral arousal or alerting. These EEG and behavioral responses resembled those produced by electrical stimulation of the midbrain reticulomesencephalic activating system (Moruzzi and Magoun 1949). With the discovery by Eccles, Eccles, and Fatt (1956) of nicotinic receptors in the Renshaw cell of the spinal cord, other investigators began to study the precise pharma- cology of the EEG and behavioral alerting produced by nicotine and electrical stimulation of the midbrain. Cigarette smoking in humans also produced EEG desynchronization (Hauser et al. 1958, Wechsler 1958; Bickford 1960) or EEG desynchronization with an increase in alpha frequency (Lambiase and Serra 1957). By the late 1950s and early 1960s it was generally known that nicotine or tobacco smoke caused EEG and behavioral arousal in animals and humans, but several important issues were unresolved. The central effects of nicotine were originally thought to result from its action on the cardiovascular system (Heymans, Bouckeart, Dautrebande 1931). Early studies found that EEG desynchronization occurred when the subjects smoked nicotine cigarettes, nicotine-free cigarettes, or sucked on glass tubes filled with cotton (Hauser et al. 1958; Wechsler 1958). Schaeppi (1968) injected nicotine into the vertebral artery, carotid artery, and third and fourth ventricles of a cat's brain and was able to dissociate the effects of nicotine on the EEG from those on the cardiovascular system. Kawamura and Domino (1969) demonstrated that the EEG changes induced by nicotine could be obtained in animals whose blood pressure increase was blocked. Prevention of release of catecholamines in reserpine- pretreated animals did not interfere with the EEG desynchroniza- tion produced by nicotine (Knapp and Domino 1962). Inhaled tobacco smoke (2-mL samples with about 2 pg/kg of nicotine) and 2 pg of nicotine injected every 30 set in a cat encephale isole preparation produced EEG desynchronization. EEG and behav- ioral activation after cigarette smoke inhalation was also observed in unanesthetized cats with implanted electrodes (Hudson 1979). Lukas and Jasinski (1983) found that i.v. doses (0.75 to 3.0 mg) in human smokers resulted in dose-dependent decreases in alpha (8 to 12 Hz EEG activity) power and EEG desynchronization. In an inpatient study where nicotine deprivation was carefully controlled and 108 monitored by measurement of expired carbon monoxide, the smok- ing of non-nicotine cigarettes did not change the EEG (Herning, Jones, Bachman 1983), but EEG changes did occur when subjects smoked nicotine-containing cigarettes. These studies confirm that nicotine has a direct action on the CNS separate from the cardiovas- cular effects and that the effects are produced primarily by the nicotine in inhaled tobacco smoke. As experimental physiological manipulations, EEG recording, and EEG quantification techniques improved, the specific nature of the nicotine-induced cortical EEG changes and their relationship to behavior were found to be more complex than originally thought. The desynchronization produced by nicotine (20 to 100 pg/kg) in the cat was blocked by anterior pontine transections, but not by midpontine transections (Knapp and Domino 1962). The midbrain reticular activating system was needed for the cortical EEG desyn- chronization produced by nicotine. However, larger doses of nicotine injections also produced synchronous slow high-voltage EEG activity in the hippocampus (hippocampal theta). Injections of the muscarin- ic agonist arecoline (20 to 40 mg/kg) in the anteriorly transected midbrain preparations still produced the hippocampal theta activity without the cortical desynchronization. Atropine (1 mg/kg) and mecamylamine (1 mg/kg), but not the ganglionic antagonist trimeth- idinium (1 mg/kg) block the nicotine induced EEG desynchroniza- tion in an intact animal. The convulsions observed after nicotine injections (1 to 5 mg/kg in cats; 0.05 to 0.25 pg/g in mice) (Laurence and Stacey 1952; Stone, Meckelnburg, Torchiana 1958; Stiimpf, Petsche, Gogolak 1962; Stumpf and Gogolak 1967) appear to be due to nicotine's ability in large doses to stimulate muscarinic choliner- gic receptors in the hippocampus. Because a high concentration of labeled nicotine binds to hippocampal cells of the cat (Schmiterlow et al. 1967) and areas adjacent to the hippocampus in the rat (Clarke, Pert, Pert 1984), the possibility that nicotine-induced limbic electri- cal activity contributes to its behavioral effects cannot be discounted. Nicotine's alerting effect on the brain may also involve a peripher- al component. Electrocortical and behavioral arousal occurs in the cat within 1 to 2 set after injection of 10 to 15 pg/kg into the right atrium of the heart, originating in vagal pulmonary C fiber afferents (Ginzel 1987). The human counterpart to this finding is the observation by Murphree, Pfeiffer, and Price (1967) that an initial EEG change occurred within 5 set after cigarette smoke inhalation, which is shorter than a chest-to-head circulation time. Another input from the periphery arises from nicotinic sites in the arterial tree. Injection of small amounts (2 to 4 pg/kg) of nicotine, even as far away from the brain as into the lower aorta or femoral artery, causes instantaneous arousal from all types of sleep (Ginzel and Lucas 1980). 109 The nicotine-induced release of ACh (Macintosh and Oborin 1953; Mitchell 19631 may be responsible for the EEG desynchronization in animals (Armitage, Hall, Sellers 1969). The effect does not appear to be due to the direct action of nicotine on the cortex because the cortical cholinergic receptors are largely muscarinic (Kuhar and Yamamura 1976; Rotter et al. 1979). Lower doses of nicotine (20 pg/kg/30 set for 20 min) induced EEG desynchronization and ACh release in the cat, whereas higher doses (40 pg/kg/30 set for 20 min) produced either an increase or decrease in EEG desynchronization with corresponding increase or decrease in ACh release (Armitage, Hall, Sellers 1969). The effect of nicotine on the EEG was short lived relative to the release of ACh. Two separate pathways have been proposed to explain these results: an ascending cholinergic pathway mediating the cortical desynchronization and a limbic pathway mediating the ACh release. In one strain of mice, C57BL, nicotine increased cortical high- voltage activity and decreased homovanillic acid (HVA) and 3- methoxy-4-hydroxyphenthyleneglycol (MHPG) production in a per- fused brain preparation (Erwin, Cornell, Towel1 1986). The decrease in HVA and MHPG levels reflects an increase in brain DA and NE levels. In intact C57BL mice, nicotine decreased locomotor activity (Marks, Burch, Collins 1983a). Thus, at least in one strain of mice, nicotine induces an increase in cortical EEG synchronization, a decrease in locomotor activity, and an increase in brain catechol- amines. Little evidence relates the cortical desynchronization ob- served in animals and humans to an increase in catecholamine changes in the brain. As trends in neuroscience research have shifted away from spontaneous EEG recording in animals to intracellular recording, receptor localization, and binding techniques, the precise quantifica- tion of the nicotine-induced EEG desynchronization and hippocam- pal synchronization has not been done. This type of quantification has been done in humans by power spectral analysis. This technique quantifies the EEG by the distribution and amplitude of brain waves at different frequencies. Alpha power includes EEG activity in the 8- to 12-Hz frequency range. Theta power includes EEG activity in the 4- to ~-HZ frequency range. Beta power includes EEG activity in the frequency range of 13 Hz and higher. The comparison of nicotine-induced EEG changes in animals and humans is complicated by an important methodological difference. Animals usually have not previously been given nicotine, while in studies of humans, the subjects always are experienced tobacco smokers. Moreover, in human studies that included a deprivation period, nicotine abstinence may have produced electrophysiological changes that are reversed by smoking or nicotine. 110 EEG desynchronization or increased beta power was observed in smokers after smoking a tobacco cigarette (Hauser et al. 1958; Wechsler 1958: Bickford 1960; Ulett and Itil 1969). These findings essentially replicated the animal studies of nicotine. Using power spectral analysis, Ulett and Itil (1969) also observed a decrease in theta power and an increase in alpha frequency. The increase in alpha frequency was previously noted with visual inspection by Lambriase. However, the increase in theta was not. The subjects in the study by Ulett and Itil had smoked one pack or more of cigarettes/day and had been deprived of tobacco cigarettes for 24 hr when the baseline EEG was recorded. Comparisons of the postsmok- ing EEG were made with this baseline period. Therefore, the decrease in alpha frequency and increase in theta power relative to the data from the postsmoking session may be the result of nicotine deprivation (Chapter IV). Knott and Venables (1978) compared the alpha frequencies of nonsmokers, 12-hr nicotine-deprived smokers. and nondeprived smokers. They observed a decrease of about 1 Hz in the dominant alpha frequency of the deprived smokers relative to the nonsmokers and nondeprived smokers in a passive eyes-closed situation. An active behavioral task and other frequencies of the EEG were not studied. Knott and Venables hypothesize that smokers were consti- tutionally different from nonsmokers. The slower alpha frequency was interpreted as an arousal deficit, and smoking as compensation to reduce the arousal deficit. Knott and Venables (1978) and Ulet and Itil (1969) both found an attentional deficit during tobacco deprivation. Herning and coworkers (1983) investigated the EEG changes related to cigarette smoking in a hospitalized group of healthy smokers who smoked at least a pack and a half of tobacco cigarettes with a machine nicotine delivery of 0.8 mg or more. A serial subtraction task was administered and EEGs were recorded from subjects in an eyes-open state. Alpha frequency was not affected by periods of smoking and deprivation. However, theta and alpha power increased during periods of deprivation and decreased after smoking tobacco but not placebo cigarettes. The effects were most pronounced on theta power. Increases in thet.a power occurred as early as 30 min after the last cigarette, and were of the same magnitude as those after 10 to 19 hr of nicotine deprivation. The increase in EEG theta was interpreted to be a sign of tobacco deprivation (Chapter IV). An indirect method of observing an increase in cortical activation was the measurement of alpha power changes after tobacco smoking. A number of investigators reported a decrease in alpha power or abundance with cigarette smoking (Murphree, Pfeiffer, Price 1967: Philips 1971; Caille and Bassano 1974, 1976; Murphree 1979: Herning, Jones, Bachman 1983; Cinciripini 1986). with nicotine 111 polacrilex gum (Pickworth, Herning, Henningfield 1986, in press), and with i.v. doses of nicotine (Lukas and Jasinski 1983). In spite of differences in the number of cigarettes regularly smoked by the subjects, the length of tobacco deprivation, the type of tobacco cigarette smoked during the experiment, and the route of adminis- tration, nicotine reduced alpha power. Brown (1968) measured the resting EEG for heavy smokers and nonsmokers. No cigarett.es were smoked. The EEG of the heavy smokers had less alpha and more beta activity. Twelve hours of nonconfirmed deprivation in the heavy smokers did not change the EEG patterns. The EEG of neonates of mothers who smoke is not different from that of neonates of control mothers (Chernick, Childiaeva, Ioffe 1983). Whether acute periods of smoking may affect the EEG of the child before birth is not known. In limited animal and human work, individual or species differ- ences in the effects of nicotine on the EEG have been observed. Nicotine produced a dose-dependent cortical EEG desynchronization in C3H mice and an increase in synchronized EEG similar to hippocampal theta activity in C57BL mice (Erwin, Cornell, Towel1 19861. Both effects have been observed at different doses in the same preparation (Kawamura and Domino 1969). Lower doses produce EEG desynchronization, and higher doses produce hippocampal theta. Tobacco cigarette smoking decreased EEG alpha power in Type A subjects and increased theta power in Type B subjects deprived of nicotine for about 4 hr (Cinciripini 1986). The relation- ship between hippocampal thet,a in animals and cortical theta in humans is not yet understood. In nondrugged animals cortical desynchronization and hippocampal theta activity often occur simul- taneously. Nicotine at low doses produces cortical desynchronization and at high doses produces both types of EEG activity. Animal data indicate that nicotine has effects on at least two systems in the brain: a midbrain area responsible for EEG desynchronization and a limbic system generating hippocampal theta activity. These findings are consistent with the observation that some smokers indicate that they smoke for nicotine's stimulating effects and others smoke for its sedating effect.s. Sensory Event-Related Potentials In animals and humans, the brainstem auditory-evoked potential technique provides a noninvasive method for studying the effects of nicotine on primary auditory sensory function. In the rat, nicotine reduced the amplitudes of Waves III and IV of the brainstem auditory-evoked response (BAER) iBhargava and McKean 1977; Bhargava, Salamy, McKean 1978; Bhargava, Salamy, Shah 1981). Serotoncrgic mechanisms may mediate the nicotine-induced reduc- 112 tion in latency. Lavernhe-Lemaire and Garand (1985) found essen- tially the opposite. Nicotine increased Waves I-III and did not decrease Waves IV and V of BAER. Auditory event-related potentials (AERPs) recorded directly from the cortex of rat have provided conflicting information about nicotine's effects on auditory transmission from the inferior collicu- lus to the cortical areas. Guha and Pradhan (1976), using pentobarbi- tal anesthesia, found a dose-dependent increase in PI (40 ms) and Nl (110 ms) of the AERP. Bhargava, Salamy, and McKean (1978), using chloralose anesthesia with atropine pretreatment, reported no nicotine-related change in Pl (11 ms), Nl (28 ms), P2 (75 ms), and N2 (121 ms) of the AERP. After smoking, the Pl (50 ms) of the human AERP is increased during passive tasks at all intensity levels and the Nl (110 ms) is increased in both passive and active tasks (Knott 1985). The N2 (about 215 ms) to P2 (about 260 ms) component of the AERP recorded during a passive task was reduced after cigarette smoking when compared with data from the baseline deprivation test (Friedman and Meares 1980). P2 was also reduced by nicotine in the study by Knott (1985). These components also increased in amplitude as the tobacco deprivation period was lengthened. Any attempt to relate this finding to results in the anesthetized rat would be speculative because AERPs recorded from the cortex of unanesthetized animals and humans are difficult to compare (Wood et al. 1984). Alterations in AERP components in the 75- to 150-ms latency range have been attributed to change in attention. The decrease in the later N2-P2 component is more likely to reflect reduced habituation to auditory stimuli. The effects of nicotine on visual event-related potentials (VERPs) are more complicated than those on the AERPs. In unaesthetized rabbits, iv. nicotine (0.025 to 0.500 mg/kg) produced a complex VERP change (Sabelli and Giardini 1972). At 2 min, nicotine depressed the Pl (100 ms) and the Nl (250 ms). At 5 min, these components were enhanced. At doses below 0.050 mg/kg, the Nl was again depressed from 10 to 20 min after the injection. Pretreatment with catecholamine inhibitors diminished the nicotine-induced VERP changes. The authors suggested that the effect of nicotine on VERPs was mediated in part by catecholaminergic mechanisms. The effects of nicotine on the human VERP using multiple flash intensities were the focus of four studies. The studies were designed to test Buchsbaum and Silverman's (1968) concept of stimulus intensity control and its modulation by nicotine. According to their theory, sensory processing in different individuals varies in at least two ways. Some persons, "augmenters," are more sensitive to higher intensities than to lower intensities, and others, "reducers," are more sensitive to lower than to higher intensities. Smokers might be 113 one particular type of stimulus processer and may smoke to alter or normalize stimulus intensity. In all studies the comparison was between results after 12 hr or more of unconfirmed tobacco deprivation and those after recent smoking. Components of the VERP increased after smoking in three studies (Hall et al. 1973; Friedman and Meares 1980; Woodson et al. 1982) but decreased in another study (Knott and Venables 1978). The increases and decreases occurred in components of the same latency range (75 to 250 ms) after flash onset. The fourth study differed only slightly from the others in that it used a between-subjects and not within- subject experimental design. Using a single flash intensity, Vasquez and Toman (19671 also observed a decrease in components IV (I*0 ms) and V (170 ms) of the VERP when compared with results after 36 hr of tobacco deprivation. Two studies found a nicotine-induced increase at earlier components (III-IV and IV-V) for the lower intensities only. The other study reported an increase in later components (V-VI and VI-VII) at the higher flash intensities. Knott and Venables (1978) observed the decrease after smoking in the middle components (IV-V and V-VI) for the lower intensities. Because of these divergent results, it is premature to conclude t,hat smokers are exclusively augmenters or reducers who are attempting to optimally adjust stimulus intensity by smoking. Cognitive Event-Related Potentials Cognitive event-related potentials reflect neural events which appear to be related to different aspects of cognition, such as attention and stimulus evaluation. They usually follow the sensory components of event-related potentials when human subjects are performing active behavioral tasks. They provide information not normally available from performance measures such as reaction time. Increases or decreases in these potentials after smoking can aid in our understanding the effects of nicotine on performance. When two task-relevant stimuli are separated by a short interval (1 to 3 set), a negative slow wave develops between them. In particular, this contingent negative variation (CNV) develops in warned or cued reaction times, successive discrimination, and some language processing tasks. The CNV appears to reflect brain preparation to process and respond to the second stimulus. Smoked tobacco and i.v. nicotine either increase or decrease the CNV (Ashton et al. 1973, 1974, 1980; Minnie and Comer 1978). Extraverted smokers took longer to smoke and nicotine increased the CNV. Introverted subjects smoked faster and nicotine decreased the CNV. Reaction time was inversely correlated with CNV amplitude; that is, shorter reaction time was associated with larger CNV. With iv. doses of nicotine (12.5 to 800.0 pg), larger doses produced a decrease and small doses produced an increase in the CNV in the same 114 subject. O'Connor (1982) studied the effects of smoking on the orienting (0 wave) and expectancy (E wave) components of the CNV in introverted and extraverted subjects. The 0 wave was not affected by smoking. The E wave, recorded in frontal areas, was increased in extraverted subjects after smoking. The E wave has been interpreted by some investigators as cortical preparation for a response. Smok- ing decreased a positive parietal E wave in introverts. Nicotine's effect on the E wave suggests the possible enhancement of motor preparation in the extraverted subjects. The decrease of parietal positivity indicates a possible enhancement of stimulus-processing capacities in the introverts. Poststimulus components PZ(O0) and P3(00) were affected by cigarette smoking and nicotine polacrilex gum. P2 is thought to be an index of habituation (Hillyard and Picton 1979), and P3 an index of stimulus evaluation (Johnson 1986). Both components were reduced in deprived smokers after smoking (Knott 1985; Herning and Jones 1979). Knott (1985) interprets the reduction in P2 as a more efficient habituation of sensory screening of relevant stimuli. The reduction in P3 amplitude after smoking indicates a poorer evaluation of task-relevant stimuli. The P3 latency and reaction time were reduced only by cigarettes with higher machine-tested nicotine yields (Edward et al. 1985). Such data indicate faster stimulus and response processing. These authors did not report any P3 amplitude changes. If none were present or P3 was reduced, the argument for enhanced stimulus processing would be weak. Herning and Pick- worth (1985) reported both dose-dependent increases and decreases in P3 amplitude as a function of background noise levels when deprived smokers chewed nicotine polacrilex gum (4 mg and 2 mg doses). The respective increase or decrease was blocked by mecamy- lamine pretreatment. Thus, the effect of nicotine on stimulus evaluation remains unclear and is perhaps confounded by cognitive deficits after periods of nicotine deprivation. Motor Potentials O'Connor (1986) investigated the effect of tobacco smoking on motor potential and motor performance. Smoking increased the motor readiness potential in extraverts, but not in introverts. These results are consistent with his earlier finding of an increased E wave in extraverts after smoking. For introverts, smoking improved task performance, but did not increase the motor readiness potential. Other Peripheral Effects Relevant to Tobacco Use In addition to vast central and peripheral effects, cigarette smoking and nicotine have other peripheral effects that may contribute to tobacco use. These additional factors have received less 115 research attention, mainly because they involve relatively new theory or methodological approaches. For example, there is evidence that direct stimulation of the trachea is important for cigarettes to satisfy smokers (Rose et al. 1984) (Chapter IV). There is also evidence that nicotine acts directly on the lung to stimulate afferent neurons that, in turn, result in skeletal muscle relaxation and electrocortical arousal (Ginzel 1987). These effects may contribute to the relation- ship between smoking and stress (Chapter VI). Other research indicates that smoking affects psychophysiological reactivity, an integrative mechanism that is different from the classic, physiologi- cal approach of examining individual systems or pathways. There- fore, psychophysiological reactivity and its relevance to smoking are discussed. Psychophysiological Reactivity and Smoking Psychophysiological reactivity is emerging as a useful construct in smoking research, linking basic biological processes (genetic vulnera- bility, central neurochemical factors) to behavioral coping and other psychosocial factors. Psychophysiological reactivity refers to a physiological response to a specific stimulus or as a result of the absence of stimulation. This response can, in some cases, act as a stressor. Within the broader conceptual framework of a stress-coping model of smoking addiction (Shiffman and Wills 19851, smoking behavior can be viewed both as a potential stimulus and as a coping response that modulates psychophysiological reactivity. Studies of psychophysiological reactivity illustrate the value of controlled laboratory procedures to study person-environment inter- actions. Psychophysiological reactivity reflects an interaction of the organism and the environment. It is affected by individual differ- ences in multiple response modes (physiological, cognitive, behavior- al) and takes into account the genetic and learning history and current state of the organism. This Section reviews two separate but interrelated lines of psychophysiological reactivity research with humans. The first is the effect of smoking on psychophysiological reactivity. Related issues include identification of mechanisms that may help to reveal why some individuals smoke and the relationship between smoking and coronary heart disease (CHD). The second research line addresses the relationship among situational events (general and drug-specif- ic), psychophysiological reactivity, and relapse. The effects of smoking on the cardiovascular aspects of physiologi- cal reactivity have been well documented and appear to be primarily due to effects of nicotine and carbon monoxide (Suter, Buzzi, Battig 1983; Koch et al. 1980; Rosenberg et al. 1980). In individuals with no cardiovascular disease, some of the typical effects of smoking and nicotine are elevated heart rate and blood pressure and a fall in 116 fingertip temperature and capillary blood flow (Richardson 1987; Ashton et al. 1982; Epstein and Jennings 1986; Henningfield et al. 1983). Accompanying cardiovascular reactions to smoking are cognitive reactions, including perceptions of relaxation, and anxiolytic, antino- ciceptive, euphoric, stimulative, and dysphoric effects (Kozlowski, Director, Harford 1981). Although there is consistency in the literature with regard to the self-reported emotional changes experi- enced as a result of smoking, there are clear differences in response and direction of effects between individuals and within individuals over time (Best and Hackstian 1978; Gilbert 1979; Gilbert and Welser, in press). Smoking can produce physiological changes that are concurrent with subjective tranquilizing effects (Nesbitt 1973; Shiffman and Jarvik 1984; Gilbert 1979). This phenomenon has led investigators to emphasize the importance of incorporating physio- logical, psychological, and environmental factors into more biobeha- vioral models to better understand the cognitive and physiological components of reactivity to smoking (Pomerleau and Pomerleau 1984; Baum, Grunberg, Singer 1982; Abrams et al. 1987; Grunberg and Baum 1985). For example, nicot,ine has direct and indirect actions on central neuroregulatory systems and has biphasic effects of both stimulation and blockade. These factors can help explain effects such as the anxiolytic and antinociceptive phenomena (Pomerleau 1986) at a cognitive and neurochemical level, while at the same time resulting in increased heart rate and blood pressure and decreased perception of muscle tension (Epstein et al. 1984). In addition to dosage, biphasic, and physiological factors, the influence of setting and expectancy set, the current state of the individual (smoking, deprived, stressed, not stressed), and individual differences in dependence, genetic, demographic, and learning history can all influence psychophysiological reactivity. For exam- ple, smoking a 1.3-mg-nicotine cigarette under conditions of mild sensory isolation produced consistent arousal effects (i.e., elevations in heart rate and skin conductance level with decreases in EEG alpha waves) in smokers compared with sham smoking or a situational control group. However, under conditions of stress, as induced by intermittent noise bursts, a mixed stimulant (heart rate) and depressant (EEG, skin conductance) response was observed (Golding and Mangan 1982). Woodson and coworkers (1986) also reported that during noise, smoking induced cardiovascular stimula- tion (i.e., heart rate acceleration, peripheral vasoconstriction) but electrodermal depression (i.e., lowered skin conductance response amplitude). These findings are consistent with the conclusions of Gilbert and Welser (in press) that unidimensional models are inadequate to explain the effects of smoking. 117 In addition to research on the impact of smoking on psychological and physiological processes, studies have also examined the com- bined cardiovascular effects of smoking and stress. In this context the concept of cardiovascular psychophysiological reactivity is used to help clarify the relationship among stress, smoking, and CHD (Epstein and Jennings 1986). MacDougall and colleagues (1983) randomly assigned 51 male smokers to smoking versus sham smoking and stress versus no stress conditions in a 2 x 2 factorial design. The stressor was a difficult video game performed under challenging conditions. Subjects who sham smoked under no stress showed minimal cardiovascular response. Subjects who smoked under no stress or who sham smoked under stress evidenced similar degrees of response of about a 15-bpm increase in heart rate, a 12- mmHg increase in systolic blood pressure, and a 9-mmHg increase in diastolic blood pressure. Subjects in the combined smoking and stress condition had larger increases in all cardiovascular measures. The combination of mild stress and smoking produced effects that were twice those of either condition alone. Smoking and stress combined to increase cardiovascular response in men. In a followup study of women, using the same 2 x 2 factorial design, Dembroski and colleagues (1985) found that the combined effect of stress and smoking produced blood pressure and heart rate increases that exceeded the sum of the individual effects. However, because modifications were made in dosage and psychological challenge, the two studies were not identical. The gender differences noted could therefore reflect methodological differences, uncon- trolled factors, or possibly differences between the sexes in response to the stress and smoking stimuli. Indeed, it has been noted that females may be more likely than males to smoke to regulate affect (Ikard and Tomkins 1973), are more likely to relapse after quitting (Gritz 1986), may differ in biological factors relating to stress reactivity/sensitivity (Abrams et al. 1987), and show greater changes in body weight and eating behavior in response to nicotine (Grun- berg, Bowen, Winders 1986; Grunberg, Winders, Popp 1987). (See Chapter VII for a discussion of treatment implications of these possible sex differences.) In a conceptually related study, the relationship between physio- logical responses to cognitive (mental arithmetic) and physical (cold pressor) stressors was examined in female smokers and nonsmokers who either used or did not use oral contraceptives (Emmons and Weidner, in press). All subjects showed some physiological response (heart rate and blood pressure responses) to the stressors, but in smokers oral contraceptive use significantly enhanced the systolic blood pressure response to cognitive stress. This finding may be related to the fact that smokers who use oral contraceptives are 5.6- times more likely to have a myocardial infarction than are smokers 118 who do not use oral contraceptives, 9.7-times more likely than nonsmoking users, and 39-times more likely than nonsmokers who do not use oral contraceptives (Shapiro et 21. 1979; Jain 1976; Ory 1977). In studies of psychophysiological reactivity, it is critical to identify, measure, and control for factors that might confound or alter the intended impact of the independent variables. For instance, time since last drink and beliefs, expectations, and setting are important variables to consider in the study of alcohol addiction (Abrams and Wilson 1979; Abrams 1983; Marlatt and Rohsenow 1980). The 2 x 2 balanced placebo design (Marlatt, Demming, Reid 19731, where expectancy set (told to expect the drug or told to expect no drug) and actual content (drug versus placebo) are fully controlled, has been used extensively in the alcohol addiction field t.o isolate the separate and interactive elements of cognitive and pharmacologic effects. With smoking, little is known about the separate and interactive impacts of expectations of cigarettes' effects versus their actual pharmacologic effects. This is partially because it is difficult to find a method of administration that closely resembles smoking but where the required manipulations to achieve a credible balanced placebo design can be accomplished. Another methodological concern is control over the dosage of nicotine absorbed by the smoker. Nicotine is thought to be the most important tobacco constituent responsible for the acute effects of smoking on reactivity, attention and task performance, mood, and withdrawal following cessation (Perkins et al., in press; Pomerleau, Turk, Fertig 1984; Hughes et al. 1984). However, in tobacco smoking, nicotine is accompanied by more than 4,000 other compounds (Dube and Green 1982) and smokers are known to smoke in individualized ways (Epstein et al. 1981) (Chapter IV). The coaching of puff frequency and other attempts to standardize intake of smoke are imperfect (Perkins et al., in press). An aerosol nasal spray appears to be a promising alternative to smoking in studies of behavioral and physiological effects. It allows for rapid uptake through inhalation, and a dose-response study indicates patterns of heart rate, blood pressure, and serum nicotine levels that are very similar to those obtained by smoking cigarettes of equivalent nicotine content (Perkins et al., in press). Perkins and coworkers (in press) studied the separate and interac- tive effects of nicotine administered by nasal aerosols and stress on psychophysiological reactivity. The authors note that the previous studies (MacDougall et al. 1983; Dembroski et al. 1985) could be confounded because smokers usually smoke more under stress and therefore they may inhale more nicotine or alter their smoking in other ways when stressed (Mangan and Golding 1978; Rose, Ananda, Jarvik 1983) (Chapter VI). In other words, the additive effects of 119 stress and smoking on physiological responses could have resulted from uncontrolled changes in smoking pattern between the smokers in the no-st.ress and stress conditions. Perkins and colleagues (in press) studied 12 male smokers in a repeated-measures design, where subjects received all 4 conditions (stress plus nicotine, stress plus placebo, rest and nicotine, and rest and placebo) on separate days with the order of condition counterbalanced within subjects. Follow- ing the methodology of previous studies of psychophysiological reactivity, the researchers used an active stressor consisting of a video game under conditions of competitive challenge. Nicotine was administered in measured l.O-mg doses by the aerosol nasal method (Perkins et al., in press). Consistent with observations of MacDougall and coworkers (1983), results were additive for heart rate reactivity. However, effects were less than additive for systolic and diastolic blood pressure. Taken together, the studies of the effects of smoking cigarettes and of nicotine aerosol stimuli on the physiological responses of adult males demonstrate a consistent effect for the stimuli alone, additive in combination with stress on heart rate, and additive or less than additive with stress on blood pressure. There is some suggestion that effects may be more than additive for women, but this finding requires replication. Psychophysiological Reactivity, Smoking Cessation, and Relapse Psychophysiological reactivity also serves as a conceptual frame- work to study relapse after cessation from smoking (Shiffman 1986b; Abrams 1986). Individual differences in psychophysiological reactivi- ty and associated coping responses, as a function of general and smoking-specific stressful stimuli, have been hypothesized to medi- ate relapse. For example, smokers who smoke more when stressed might be particularly vulnerable to relapse (Pomerleau, Adkins, Pertschuck 1978). This idea is consistent with the observation that relapse may be triggered by life stress events and other psychosocial demands (Ockene et al. 1982) and by high-risk situations including negative emotions, social conflicts and pressures, and the presence of alcohol or smoking cues (Marlatt and Gordon 1985; Shiffman 1979, 1982,1984. 1986a; Abrams et al. 1986). If certain psychophysiological reactivity responses distinguish potential abstainers from relapsers, cessation may be better maintained by identifying "relapse-prone" individuals (Chapter VII). Stressful environmental demands, sensitivity of the individual to these demands, and the repertoire of coping responses are important factors in relapse (Shiffman and Wills 1985; Abrams et al. 1987). These same factors also may contribute to initiation of smoking among adolescents. Wills (1985) provides evidence for the stress- 120 coping model of smoking in adolescence, relating both stress and coping patterns to substance use. Results are consistent wit.h other findings that, in addition to peer pressure to smoke, adolescents actively seek methods of coping with their perceptions of stress (Wills 1985; Friedman, Lichtenstein, Biglan 1985; Botvin and McAlister 1981). Although these survey studies are consistent with the notion of smoking as a means of coping with psychophysiological reactivity to environmental demands, research has not yet measured reactivity in adolescents prior to smoking onset. Observational and retrospective studies of relapse have identified other smoking-specific stressful stimuli and cogni- tive/psychophysiological measures of reactivity that are relevant to relapse. Situations or stimuli that cue smoking and are associated with relapse include pharmacologic dependence and withdrawal symptoms (Jarvik 1977; Pomerleau and Pomerleau, in press; Hughes et al. 19841, stimuli previously associated with smoking (e.g., coffee drinking, alcohol) (Shiffman 1984, 1986a; Best and Hakstian 19781, and urges to smoke (Myrsten, Elgerot, Edgren 1977). Situational stimuli may or may not have previously been paired with smoking and may or may not include smoking cues as a trigger for relapse. Substance use cues themselves (e.g., the sight and smell of cigarettes) also may precipitate relapse, perhaps in combination with other stressful stimuli or in a vulnerable individual (Shiffman 1986b; Abrams et al. 1987). Models of how substance use cues are related to relapse have been proposed on the basis of classical, operant, and social learning principles. Reactions may be conditioned to stimuli repeatedly paired with smoking, resulting in craving and physiologi- cal reactivity in their presence and moderated by dependence, tolerance, and nonpharmacologic withdrawal (Siegel 1983; Cooney, Baker, Pomerleau 1983; Gritz 1980). Psychophysiological reactivity to smoking cues could mimic the prior drug response (Wikler 19651, result in a drug-opposite (compensatory) response (Siegel 19831, or have other effects on psychological processes such as perceived anxiety, urges to smoke, and self-efficacy in resisting relapse according to a social learning model of relapse (Marlatt and Gordon 1985). Abrams and colleagues (1987) studied the psychophysiological reactivity and behavioral coping responses of male and female relapsers and quitters in four simulated situational contexts: general social situations, smoking-specific negative emotional and interper- sonal role-plays, high-demand social stress, and relaxation. Com- pared to abstainers, relapsers had higher heart rates and higher perceived anxiety and were rated as less skillful at coping in the smoking-specific intrapersonal (negative affect) situations. There were no differences on any measures in the high-performance- demand general-social-stress procedure. There were some differences 121 in heart rate and self-reported anxiety in the general social situations and in heart rate in the relaxation interval, with relapsers having higher levels than abstainers. Abstainers and relapsers did not differ in heart rate, perceived anxiety, or coping skills in the high-demand social anxiety procedure, but they did differ in the other situations. The results suggest that selected situational demands prompt situation-specific psychophysiological changes. Rickard-Figueroa and Zeichner (1985) used a within-subjects design to examine the responses of smokers to a confederate of the experimenter lighting and smoking the subject's preferred brand of cigarette behind a glass window. Cigarette paraphernalia were piaced adjacent to the subject but smoking was not permitted until after the session. The cue exposure manipulation resulted in higher urges to smoke, increased systolic and diastolic blood pressure, and increased heart rate variability compared with a no-cue condition. Urges were significantly positively correlated with diastolic blood pressure, the use of active mastery to cope with urges, and the more rapid smoking of a standard cigarette after the trial. In a study that shows some evidence for a conditioned response, Saumet and Dittmar (1985) measured finger-pulse amplitude, a measure of peripheral vasoconstrictive activity, while subjects placed an unlit cigarette into their mouths and waited for it to be lit. Heavy smokers showed an anticipatory vasoconstrictive response to the cigarette compared with light smokers and nonsmokers. Abrams and colleagues (in press) used smoking cues and a social st,ressor to simulate an interpersonal situation with high risk for relapse. Relapsers, abstainers, and never smokers were examined for psychophysiological reactivity. Compared with controls (never smok- ers), relapsers had significant heart rate reactivity, stronger urges to smoke, and subjective anxiety. Trained raters, unaware of subject smoking status, judged relapsers as having significantly less effec- tive coping skills to resist smoking. In a second study, the same assessment was used prospectively in a treatment outcome context to determine whether patt.erns of psychophysiological reactivity could discriminate between quitters who maintain abstinence from those who do not. Both heart rate reactivity and subjective anxiety were greater in quitters who relapsed at 6-month followup compared with those who continued to abstain. The groups did not differ with regard to urges to smoke or behavioral judgments of coping skill. Thus, the two studies were consistent, for heart rate and perceived anxiety but not for urges or objective ratings of coping effectiveness. In a reanalysis of the heart rate data from Abrams and coworkers (in pressj, Niaura and colleagues (in press) examined beat by beat event-related heart rate during the period immediately before and for the 10 set following the lighting of a cigarette by a confederate (subjects did not smoke throughout). Prospective relapsers showed a 122 strong decelerative trend at the point of lighting, whereas prospec- tive abstainers did not. The results may reflect a conditioned compensatory response (Siegel 1983) or some other information processing/attentional phenomenon (Sokolov 1963; Knott 1984). In another treatment, study, Emmons (1987) examined smokers' cardio- vascular reactivity to mental arithmetic or deep knee bends before and 6 months after smoking cessation. There was no change in reactivity (heart rate, systolic and diastolic blood pressure) to either stressor before and after quitting. Heightened pretreatment heart rate reactivity significantly discriminated relapse at g-month follow- UP. Individual differences in psychophysiological reactivity may influ- ence the likelihood of relapse. This possibility is discussed in Chapter VII. Summary and Conclusions 1. Nicotine is a powerful pharmacologic agent that acts in the brain and throughout the body. Actions include electrocortical activation, skeletal muscle relaxation, and cardiovascular and endocrine effects. The many biochemical and electrocortical effects of nicotine may act in concert to reinforce tobacco use. 2. Nicotine acts on specific binding sites or receptors throughout the nervous system. Nicotine readily crosses the blood-brain barrier and accumulates in the brain shortly after it enters the body. Once in the brain, it interacts with specific receptors and alters brain energy metabolism in a pattern consistent with the distribution of specific binding sites for the drug. 3. Nicotine and smoking exert effects on nearly all components of the endocrine and neuroendocrine systems (including catechol- amines, serotonin, corticosteroids, pituitary hormones). Some of these endocrine effects are mediated by actions of nicotine on brain neurotransmitter systems (e.g., hypothalamic-pitu- itary axis). In addition, nicotine has direct peripherally mediat- ed effects (e.g., on the adrenal medulla and the adrenal cortex). 123 References ABOOD. L.G , GRASSI, S. ["H]Methylcarbamylcholine, a new radioligand for studying brain nicotinic receptors. Biochemical Pharmacology 35(231:4199X202, December 1. 1986. ABRAMS, D B. Psychosocial assessment of alcohol-stress interactions: Bridging the gap between laboratory and treatment outcome research. In: Pohorecky, L., Brick, J. leds.1 Stress nnd Alcohol lise. Sew York: Elsevier, 1983. ABRAMS, D.B. Roles of psychosocial stress, smoking cues and coping in smoking- relapse prevention. Heulth Psyrhology S(Supplement):91-92, 1986. ABRAMS, D.B., MONTI, P.M.. CAREY, K.B., PINTO, R.P., JACOBUS, S.I. Reactivity to smoking cues and relapse: Two studies of discriminant validity. Behauiour Research and Therap?; in press. ABRAMS. D.B., MONTI, P.M., PINTO, R.P.. ELDER, J.P., BROWN, R.A., JACOBUS, S.I. Psychosocial stress and coping in smokers who relapse or quit. Health Ps,vchology 614):289-303, 1987. ABRAMS, D.B., NIAURA, R.S., CAREY, K.B., MONTI, P.M., BINKOFF, J.A. Understanding relapse and recovery in alcohol abuse. Annals of Behavioral Medicine 8(2!3):27-32, 1986. ABRAMS, D.B., WILSON, G.T. Effects of alcohol on social anxiety in women: Cognitive versus physiological processes. Journal of Abnormal Psychology 88161-173. 1979. ACETO, M.D., BENTLEY, H.C., DEMBINSKI, J.R. Effects of ganglion blocking agents on nicotine extensor convulsions and lethality in mice. British Journal of Pharmacology 37:104-111, September 1969. ACETO, M.D., MARTIN, B.R. Central actions of nicotine. Medicinal Research Reuieus 2( 11:43-62, January-March 1982. AGHAJANIAN, G.K., ROSECRANS, J.A., SHEARD, M.H. Serotonin release in the forebrain by stimulation of the midbrain raphe. Science 15:402-404, 1967. AMIR, S., BROWN, Z.W., AMIT. Z. The role of endorphins in stress: Evidence and speculations. Neuroscience and Biobehariorul Reviews 4:77-86, 1980. ANDERSEN, A.N.. LUND-ANDERSEN, C., LARSEN, J.F., CHRISTENSEN, N.J., LEGROS, J.J., LOUIS, F., ANGELO, H., MOLIN, J. Suppressed prolactin but normal neurophysin levels in cigarette smoking breast feeding women. Clinical Endocrinology 17(41:363-368, October 1982. ANDERSSON, K. Mecamylamine pretreatment counteracts cigarette smoke induced changes in hypothalamic catecholamine neuron systems and in anterior pituitary function. .4cta Ph.wiologica Scandina~ica 125445-452, 1985. APPELGREN, L.-E., HANSSON, E., SCHMITERLGW, C.G. The accumulation and metabolism of C'4-labelled nicotine in the brain of mice and cats. Acta Physiologica Scnndinucica 56:249-257. 1962. APPELGREN, L.-E., HANSSON, E., SCHMITERLGW, C.G. Localization of radioactiv- ity in the superior cervical ganglion of cats following injection of CL'-1abelled nicotine. Acta Physiologzca Scandinacica 59:330-336. 1963. ARMITAGE, A.K., HALL, G.H., MORRISON, C.F. Pharmacological basis for the tobacco smoking habit. Nature 217:331-334, 1968. ARMITAGE. A.K., HALL, G.H., SELLERS, C.M. Effects of nicotine on electrocortical activity and actylcholine release from the cat cerebral cortex. British Journal of Pharmaco/og.v 35(1~:152-160, 1969. ASHTON, H., MARSH, V.R., MILLMAN, J.E., RAWLINS, M.D., TELFORD, R., THOMPSON, J.W. Biphasic dose-related responses of the CNV (contingent negative variation) to I.V. nicotine in man. .Journal of Clinical Pharmacology 10161579-539, 1980. ASHTON, H., MILLMAN, J.E., TELFORD, R.. THOMPSON, J.W. Stimulant and depressant effects of cigarette smoking on brain activity in man. British Journal of Pharmacology 48141:715-717. August 1973. 124 ASHTON, H.. ~IILLMAN. J.E.. TELFORD, K., THOMPSON, J.W. The effect of caffeine, nitrazepam, and cigarette smoking on the contingent negative variation in man. Electroerlcephalo,gr.aph~ und Clinical Seuroph,vsiologv 37(11:59-71, 1974. ASHTON. H., STEPNEY. R.. TELFORD, R., THOMPSON, ,J.W. Cardiovascular and behavioural responses to smoking. In: Ashton, H.. Stepney, R. teds.1 Smoking, Psychology and Phnrmacolog~. London: Tavistock. 1982. BALFOUR, D.J.K. The effects of nicotine on brain neurotransmitter systems. Pharmacology and Therapeutics 16121:269-282. 1982. BALFOUR. D.J.K. ced.1 l\`?cotine clnd the Tohacw Smoking Hahrt. International Encyclopedia of Pharmacol and Therapwtics. Sertlon 114. New York: Pergamon Press, 1984 BALFOUR, D.J.K.. GRAHAM. C.A., VALE, A.L. Studies on the possible role of brain 5-HT systems and adrenocortical activity in behavioural responses to nicotine and diazepam in an elevated x-maze. Ps~c,hopl~r2rnlclf,of~~~~, 90141528-532, November 1986. BALFOUR, D.J.K., KHULLER, A.K LONGDEN. A. Effects of nicotine on plasma corticosterone and brain amlnes in stress and unstressed rats. Pharmacology Aiachemzstn; and Beha~~ior 3(2i:179-184. March-April 1975. BAUM, A.. GRUNBERG. N.E.. SINGER, J.E. The use of psychological and neuroendo- crinological measurements in the study of stress. Health Ps.vchology 1(3):217-236. Summer 1982. BEANI, L., BIANCHI, C.. XILSSON, L.. NORDBERG, A., ROMANELLI, L., SIVILOT- TI, L. The effect of nicotine and cytisine on "H-acetylcholine release from cortical slices of guinea-pig brain. Naun.w-Schmiedaherg:s Archives of Pharmacology 33112/31:293-296. November 1985. BEAUMONT. A., HUGHES, J. Biology of opioid peptides. Annual Retsiew of Pharmacology and Toxicology 19:245-267, 1979. BENOWITZ, N.L., KUYT, F., JACOB, P. Influence of nicotine on cardiovascular and hormonal effects of cigarette smoking. Clinical Pharmacology and Therapeutics 36(1):74-81, 1984. BENWELL, M.E.M., BALFOUR, D.J.K. Central nicotine binding sites: A study of post- mortem stability. Neuropharmacology 24(111:1135-1137. 1985a. BENWELL, M.E.M., BALFOUR, D.J.K. Nicot,ine binding to brain tissue from drug naive and nicotine-treated rats. Journal of Pharmac? and Pharmacology 37!6):405-409. June 1985b. BENWELL, M.E.M., BALFOUR. D.J.K., ANDERSON, J.M. Evidence that tobacco smoking increases the density of (-)-["HI-nicotine binding sites in human brain. +Journal of Neurochemistr?. probably in press but awaiting verification. BERTOLINI, A., GESSA, G.L. Behavioral effects of ACTH and MSH peptides. Journal of Endocrinological Znr,estigation 4(2j:241-251, April-June 1981. BEST, J.A., HACKSTIAN, A.R. A situation-specific model for smoking behavior. Addictille BehaLGors 3(2):79-92, 1978. BHARGAVA, V.K., McKEAN, CM. Role of 5-hydroxytryptamine in the modulation of acoustic brainstem (far-field) potentials. Neuropharmacologv 16:447-449, 1977. BHARGAVA, V.K., SALAMY, A., McKEAN, C.M. Effects of cholinergic drugs on auditory evoked responses (CERI of rat cortex. Neuropharmacology 17(12):1009-1013, December 1978. BHARGAVA. V., SALAMY, A., SHAH, S. Role of serotonin in the nicotine-induced depression of the brainstem auditory evoked response. Pharmacology Biochemistry and Behar,lor 15(4):587-589, October 1981. BICKFORD. R. Physiology and drug action: An electroencephalographic analysis. Federation Proceedings 19(2t:619-625, July 1960. BISSET, G.W., FELDBERG, W., GUERTZSTEIN. P.G., ROCHA e SILVA, M. Vasopressin release by nicotine: The site of action. British ?JooclrnaI of Pharmacolo- g.y 54(4):463-474. August lYi'5. 125 BLAKE, C.A. Stimulation of pituitary prolactin and TSH, release in lactating and proestrous rats. Endocrlnolo~~~ 94(21:503-508, February 1974. BLAKE, C.A., SAWYER, C.H. Nicotine blocks the suckling-induced rise in circulating prolactm in lactating rats. Science 177(4049):619-621, August 18, 1972. BOHUS B.. KOVACS, G.L., DE WIED, D. Oxytocin, vasopressin and memory: Opposite effects on consolidation and retrieval processes. Brain Research 157:414-417. 1978. BOKSA. P.. QUIRION. R. [3H;Methyl-carbachol, a new radioligand specific for nicotinic cholinergic receptors in brain. European Journal of Pharmacology 129:329--333, 1987. BOTVIN. G.. McALISTER, A. Cigarette smoking among children and adolescents: Causes and prevention. In: Arnold, C.B.. Kuller, L.H., Greenlick, M.R. (eds.1 Adrunces in Disease Precention. Volume 1. New York: Springer, 1981. BRIGGS, C.A., COOPER, J.R. Cholinergic modulation of the release of [3H]acetylcholine from synaptosomes of the myenteric plexus. Journal of Neuro- chemistry 3X(2):501-508, 1982. BROWN, B.B. Some characteristic EEG differences between heavy smoker and non- smoker subjects. h'europsychologia 6(4):381-388, December 1968. BROWN, D.A., DOCHERTY, R.J., HALLIWELL, J.V. Chemical transmission in the rat interpeduncular nucleus in vitro. Journal of Physiologv 341:655-670, August 1983. BUCHSBAUM, M., SILVERMAN, J. Stimulus intensity control and the cortical evoked response. Psychosomatic Medicine 30:12-22, January-February 1968. CAILLE, E.-J., BASSANO, J.-L. Effects electrophysiologiques de la privation chez le fumeur d'habitude. Psychologie Medicale 6(8):1571-1600, 1974. CAILLE, E.-J., BASSANO. J.-L. La cigarette dans le champ. Psychologic Medicale 8:893-908, 1976. CAM, G.R.. BASSETT, J.R. The effect of acute nicotine administration on plasma levels of the thyroid hormones and corticosterone in the rat. Pharmacology Biochemistr?; and Behavior 19:559-561, September 1983a. CAM, G.R., BASSETT, J.R. The plasma levels of ACTH following exposure to stress of nicotine. Znternatzonal Archives of Pharmacology 264:154-167, July 1983b. CAM. G.R., BASSETT, J.R. Effect of prolonged exposure to nicotine and stress on the pituitary-adrenocortical response; the possiblity of cross-adaptation. Pharmaco1og.v Biochemutn. and Behavior 20~221-226, 1984. CAM, G.R.. BASSETT. J.R., CAIRNCROSS, K.D. The action of nicotine on the pituitary-adrenal cortical axis. Archilles Znternationales de Pharmacodynamie et de Theraple 237(1):49-66, January 1979. CASTRO DE SOUZA, E.M.. ROCHA e SILVA, M. Jr. The release of vasopressin by nicotine: Further studies on its site of action. Journal ofPhysiology 265(2):297-311, February 1977. CAtJLFIELD, M.P., HIGGINS, G.A. Mediation of nicotine-induced convulsions by central nicotinic receptors of the X6" carbon type. Neuropharmacolog> 22(3Al:347-351, March 1983. CHERNICK, V., CHILDIAEVA. R., IOFFE, S. Effects of maternal alcohol intake and smoking on neonatal electroencephalogram and anthropometric measurements. American Journal of Obstetrics and C2ynecolog.v 146(1):41-47, May 1, 1983. CHESSELET. M.-F. Presynaptic regulation of neurotransmitter release in the brain: Facts and hypothesis. Neuroscience 12(2~:347-375, June 1984. CHIOU. C.Y. Mechanism of acetylcholine release by drugs and its blockade. ArchiLles Znternafmnules de Pharmacodwamie et de Therapie 201(1):170-181, 1973. CHIOU. C.Y., LONG, J.P. Acetylcholine-releasing effects of some nicotinic agents on chick biventer cervias muscle preparation. Proceedings of the S0ciet.v of Experimen- tal and Biological Medicine 13X:732-737, 1969. 126 CINCIRIPINI, P.M. The effects of smoking on electrocortical arousal in coronary prone (Type AI and non-coronary prone (Type BI subjects. Ps~,chopharmocolr~~~ 90(41:522-527. November 1986. CLARKE, P.B.S. Recent progress in identifymg nicotinic cholinoceptors in mamma- lian brain. Trends in PharnzacologiraI Sciences 811):32-35. January 1987a. CLARKE, P.B.S. Nicotine and smoking: .A perspective from animal studies. Ps,vcho- pharmacology 92(2):135-143, June 1987b. CLARKE. P.B.S., HAMILL. G.S., NADI. N.S.. JACOBOWITZ. D.M., PERT, A. "H- nicotine- and "`I-alpha-bungarotoxin-labeled nicotinic receptors in the interpe- duncular nucleus of rats. II. Effects of habenular deafferentation. &/r,urnal of Cornparut~t~c~ iVeurr,lt)gJ 251(3):407-413. September 1986. CLARKE. P.B.S., HOMMER, D.W., PERT, A., SKIRBOLL, L.R. Electrophysiological actions of nicotine on substantia nigra single units. British ,JwrnuI ofPhurmacoIo- 6' 8514r827-835. August 1985. CLARKE, P.B.S., KLJMAR. R. The effects of nicotine on locomotor activity in non- tolerant and tolerant rats. British ,Jorrrnal of Pharnzaco/oq+yv 78(21:329-337, 1983. CLARKE. P.B.S., KIJMAR. R. Effects of nicotine and d-amphetamine on intracranial self-stimulation in a shuttle box test in rats. Ps~ch(,phnrmactllofi." 8411 l:lO9-114, 1984. CLARKE. P.B.S.. PERT, A. Autoradiographic evidence for nicotine receptors on nigrostriatal and mesohmbic dopaminergic neurons. Bra z n Research 348(2):355-358, December 1985. CLARKE, P.B.S., PERT, C.B., PERT, A. Airtoradiographic distribution of nicotine receptors in rat brain. Brain Reseaxh 323(2):390-395, December 10, 1984. CLARKE, P.B.S., SCHWARTZ, R.D.. PAUL, SM., PERT, C.B.. PERT, A. Nicotinic binding in rat brain: Autoradiographic comparison of [,`H]acetylcholine, ["HInicotine, and [`251)-alpha-bungarotoxin. ~Jozzrnul of ~Veurosczence 515):1307-1315, May 1985. COHEN, S.L., MORLEY, B.J., SNEAD. O.C. An EEG analysis of convulsive activity produced by cholinergic agents. Progress in ,~ezrr~-ps~(.h~phar.mnroio%~ 514):383-388, 1981. COIRO, V., d'AMAT0, L., BORCIANI. E. ROSSI, G.. CAMELLINI. L.. MAFFEI. M.L., PIGNATTI, D., CHIODERA, P. Brztish Journal of Clinical Pharmat~olog~ 18(51:802-805, 1984. COLLINS, A.C., EVANS, C.B., MINER, L.L., MARKS, M.J. Mecamylamine blockade of nicotine responses: Evidence for two brain nicotinic receptors. Pharnzacolog~ Biochemistry and Behatsior 24(61:1767-1773, June 1986. CONNELLY, MS., LITTLETON, J.M. Lack of stereoslectivity in ability of nicotine to release dopamine from rat synaptosomal preparations. Journal ofh'eurochenzist~ 41(5):1297-1302, November 1983. CONTE-DEVOLX, B., OLIVER, C., GIRAUD, P.. GILLIOZ. P., CASTANAS, E., LISSITZKY. J.C., BOUDOURESQUE, F., MILLET, Y. Effect of nicotine on in viva secretion of melanocorticotropic hormones in the rat. Life Sciences 28(9):1067-1073, 1981. COONEY, N.L.. BAKER, L.H., POMERLEAU, O.F. Cue exposure for relapse prevention in alcohol treatment. In: Craig, K.D., McMahon, H.J. 1eds.1 Advances in Clinical Rchni,,or Therupy. New York: Brunner/Mazel Publishers, 1983, pp. 194-210. COSTA, L.G., MURPHY, S.D. [`HInicotine binding in rat brain: Alteration after chronic acetylcholinesterase inhibition. .Jwrnol of`Pliarmaco1c~g.1 and Espcrznzen- tul Therapeutits 2%6121:392-397, August 1983. CRYER, P.E.. HAYMOND. M.W., SANTIAGO, J.V., SIIAH, S.D. Norepinephrine and epinephrine release and adrenergic mediation of smoking-associated hemodynamic and metabolic events. .veu, England ,Joztrntri trf Mcdtciric 295(111:57:3-577. Septem- ber 9. 1976. 127 DAHLSTROM. A., FUXE, K. Evidence for the existence of monoamine-containing neurons in the central nervous system. I. Demonstration of monoamines in the cell bodies on brain stem neurons. Acta Physiologica Scandinauico 62 (Suppl 132). 1966. DALE, H.H.. LAIDLAW. P.P. The significance of the supra-renal capsules in the action of certain alkaloids. Journal of Physiology 45(1/2):1-26, August 2, 1912. DE LA GARZA, R., BICKFORD-WIMER, P.C., HOFFER, B.J., FREEDMAN, R. Heterogeneity of nicotine actions in the rat cerebellum: An in vivo electrophysio- logic study. .Jollrnal of Pharmacology and Experimental Therapeutics 240(2):689-695. February 1987. DE LA GARZA, R., McGUIRE, T.J., FREEDMAN, R., HOFFER, B.J. Selective antagonism of nicotine actions in the rat cerebellum with alpha-bungarotoxin. Neuroscience, in press(a). DE LA GARZA. R., McGUIRE, T.J., FREEDMAN, R., HOFFER, B.J. The electrophysi- ological effects of nicotine in the rat cerebellum: Evidence for direct p&synaptic effects. Neuroscience Letters 80:303-308, in press(b). DEMBROSKI, T.M., MACDOUGALL, J.M., CARDOZO, S.R., IRELAND, SK., KRUG- FITE, J. Selective cardiovascular effects of stress and cigarette smoking in young women. Health Psychology 4(2):153-167, 1985. DIETZ, R., SCHOMIG, A., KUSTERER, K., DART, A.M., KUBLER, W. Vasopressor systems during smoking in humans. Klinische Wochenschrift 62(Supplement II):ll-17. 1984. DOMINO, E.F. Electroencephalographic and behavioral arousal effects of small doses of nicotine: A neuropsychopharmacological study. Annuls of the New York Acadent of Sciences 142(1):216-244, March 15, 1967. DOMINO, E.F. Neuropsychopharmacology of nicotine and tobacco smoking. In: Dunn, W.L. (ed.) Smoking Behavior: Motives and IncentivesWashington, D.C.: V.H. Winston and Sons, 1973, pp. 5-31. DOMINO, E.F. Behavioral, electrophysiological, endocrine, and skeletal muscle actions of nicotine and tobacco smoking. In: Remond, A., Izard, C. (eds.) HectrophTsiologica1 Effects of Nicotine. Amsterdam: Elsevier/North-Holland Biomedical Press, 1979. pp. 133-146. DOMINO, E.F.. DREN, A.T., YAMAMOTO, K. Pharmacologic evidence for cholinergic mechanisms in neocortical and limbic activating systems. In: Adey, W.R., Tokizane, T. ieds.) Structure and Fzlnction of the Limbic System. Amsterdam: Elsevier. 1967, pp. 337-364. DOMINO. E.F.. VON BAUMGARTEN, A.M. Tobacco cigarette smoking and patellar reflex depression. Clinical Pharmacology and Therapeutics 10:72-79, 1969. DOUGLAS. W.W.. RUBIN, R.P. Mechanism of nicotine action at the adrenal medulla: Calcium as a link in stimulus-secretion coupling. Nature 192:1087-1089, 1961. DUBE. hl., GREEN, C.R. Methods of collection of smoke for analytical purposes. Recent Advances in Tobacco Science 8:42-102, 1982. DUGGAN. A.W.. HALL. J.G.. LEE, C.Y. Alpha-bungarotoxin, cobra neurotoxin and excitation of Renshaw cells by acetylcholine. Brain Research 107(1):166-170, April 30, 1976. ECCLES, J.C.. ECCLES, R.M., FATT, P. Pharmacological investigations on a central synapse operated by acetylcholine. -Journal of Physiology 131(1):154-169, January 1956. EDWARD. J.A., WESNES, K.. WARBURTON, D.M., GALE, A. Evidence of more rapid stimulus evaluation following cigarette smoking. Addictilje Behatliors 10121:113-126, 1985. EGAN, T.M.. NORTH, R.A. Actions of acetylcholine and nicotine on rat locus corruleus neurons in vitro. Neuroscience 19(2):565-571, October 1986. EMMONS, K.M. Smoking cessation and change in physiologic function. Doctoral Dissertation. State University of New York, 1987. 128 EMMONS, K.M., WEIDNER, G. The effects of cognitive and physical stress on cardiovascular reactivity among smokers and oral contraceptive users. Psychophy- siology, in press. EPSTEIN, L.H., DICKSON, B.E., MCKENZIE, S., RUSSELL, P.O. The effect of smoking on perception of muscle tension. Psychopharmacology 83(1):107-113, 1984. EPSTEIN, L.H., JENNINGS, J.R. Smoking, stress, cardiovascular reactivity, and coronary heart disease. In: Matthews, K.A.. Weiss, SM.. Detre. T., Dembroski, T.M., Falkner, B., Munuck, S.B., Williams, R.B. Jr. (eds.) Handbook of Stress, Reactivity, and Cardiovascular Disease. New York: John Wiley and Sons, 1986. EPSTEIN, L.H., OSSIP, D.J., COLEMAN, D., HUGHES, J., WIIST, W. Measurement of smoking topography during withdrawal or deprivation. Behavior Therapy 12(4):507-519, September 1981. ERWIN, V.G., CORNELL, K., TOWELL, J.F. Nicotine alters catecholamines and electrocortical activity in perfused mouse brain. Pharmacology Biochemistry and Behavior 24(1):99-105, January 1986. FAGERSTRGM, K.O., GOTESTAM, K.G. Increase in muscle tonus after tobacco smoking. Addictive Behaviors 2(4):203-206, 1977. FARLEY, G.R., MORLEY, B.J., JAVEL, E., GORGA, M.P. Single-unit responses to cholinergic agents in the rat inferior colliculus. Hearing Research 11(1):73-91, July 1983. FERRY, J.D., MCLEAN, B.K., NIKITITOVICH-WINER, M.B. Tobacco smoke inhala- tion delays suckling-induced prolactin release in the rat. Proceedings of the Society for Experimental Biology and Medicine 47(1):11C-113, October 1974. FIBIGER, H.C. The organization and some projections of cholinergic neurons of the mammalian forebrain. Brain Research Reviews 4(1):327-388. March 1982. FISHMAN, S.S. Studies on the excretion and distribution of radioactive nicotine and some evidence on the urinary metabolites. Archives Znternationales de Pharmaco- dynamie et de Therapie 145(1/2):123-136, 1963. FLOREY, C., MILNER, R.D.G., MIALL, W.E. Serum insulin and blood sugar levels in a rural population of Jamaican adults. Journal of Chronic Diseases 30(1):49-W 1977. FLYNN, D.D., MASH, DC. Characterization of L-[3H]nicotine binding in human cerebral cortex: Comparison between Alzheimer's disease and the normal. Journal of Neurochemistry 47(6):1948-1954, December 1986. FORSBERG, E.J., ROJAS, E., POLLARD, H.B. Muscarinic receptor enhancement of nicotine-induced catecholamine secretion may be mediated by phosphoinositide metabolism in bovine adrenal chromaffin cells, 1986. FRIEDMAN, D.P., CLARKE, P.B.S., O'NEILL, J.B., PERT, A. Distributions of nicotinic and muscarinic cholinergic receptors in monkey thalamus. Society for Neuroscience Abstracts 11:307.4, 1985. FRIEDMAN, J., MEARES, R. Tobacco smoking and cortical evoked potentials: An opposite effect on auditory and visual systems. Clinical and Experimental Pharmacology and Physiology 7t6k609-615, 1980. FRIEDMAN, L.S., LICHTENSTEIN, E., BIGLAN, A. Smoking onset among teens: An empirical analysis of initial situations. Addictive Behaviors lO:l-13, 1985. FUXE, K., ANDERSSON, K., ENEROTH, P., HARFSTRAND, A., NORDBERG, A., AGNATI, L.F. Effects of nicotine and exposure to ciagrette smoke on discrete dopamine and noradrenaline nerve terminal systems of the telencephalon and diencephalon of the rat. Relationship to reward mechanisms and distribution of nicotine binding sites in brain. In: Martin, W.R., Van Loon, G.R., Iwamoto, E.T., Davis, L. (eds.) Tobacco Smoking and Nicotine. A Neurobiological Approach. New York: Plenum Press, 1987, pp. 225-262. 129 FUXE, K., ANDERSSON, K., HARFSTRAND, A., AGNATI, L.F. Increases in dopamine utilization in certain limbic dopamine populations after a short period of intermittent exposure of male rats to cigarette smoke. Journal of Neuml Transmission 67:15-29, 1986. GILBERT, D.G. Paradoxical tranquilizing and emotion-reducing effects of nicotine. Psychological Bulletin 86(4):643-661, July 1979. GILBERT, D.G., WELSER, R. Emotion, anxiety, and smoking. In: Ney, T., Gale, A. (eds.) Smoking and Human Behauiour. Chichester: John Wiley, in press. GILMAN, A.G., GOODMAN, L.S., RALL, T.W., MURAD, F. (eds.) Guodman and Gilman's The Pharmacological Rasis of Therapeutics 7th Edition. New York: MacMillan Publishing Co., 1985. GINZEL, K.H. The action of nicotine and smoking on reflex pathways. Australasian Journal of Pharmacy 48(569, Supplement 52): S30533, May 30, 1967a. GINZEL, K.H. Introduction to the effects of nicotine on the central nervous system. Annals of the New York Academy of Sciences 142:101-120, 1967b. GINZEL, K.H. The importance of sensory nerve endings as sites of drug action. Naunyn-Schmiedeberg's Archives of Pharmacology 288(1):29-56, 1975. GINZEL, K.H. The lungs as sites of origin of nicotine-induced skeletomotor relaxation and behavioral and electrocortical arousal in the cat. Proc. Znt. Symp. on Nicotine. Goldcoast, Australia: ICSU Press, 1987. GINZEL, K.H., ELDRED, E. Inhibition of y- and a-motor activity caused reflexly by drug-induced excitation of sensory endings. Pharmacology and the Future of Man, Proceedings of the 5th International Congress of Pharmacology, Volume 4,1972, pp. 167-179. GINZEL, K.H., LUCAS, E.A. Electrocortical and behavioral arousal from various regions of the arterial tree. Sleep Research 9:29, 1980. GLAUSER, SC., GLAUSER, E.M., MARCUS, M.D., REIDENBERG, M., RUSY, B.F., TALLARIDA, R.J. Metabolic changes associated with the cessation of cigarette smoking. Archives of Environmental Health 20:377-381, 1970. GLICK, SD., JARVIK, M.E., NAKAMURA, R.K. Inhibition by drugs of smoking behaviour in monkeys. Nature 227(5261):969-971, August 29, 1970. GOLDBERG, S.R., SPEALMAN, R.D., GOLDBERG, D.M. Persistent behavior at high rates maintained by intravenous self-administration of nicotine. Science 214:573-575, 1981. GOLDING, J., MANGAN, G.L. Arousing and de-arousing effects of cigarette smoking under conditions of stress and mild sensory isolation. Psychophysiology 19(4):449456, July 1982. GOLDMAN, D., DENERIS, E., LUYTEN. W., KOCHHAR, A., PATRICK, J., HEINE- MANN, S. Members of a nicotinic acetylcholine gene family are expressed in different regions of the mammalian central nervous system. Cell 48(6)%X35-973, March 27, 1987. GOLDMAN, D., SIMMONS, D., SWANSON, L.W., PATRICK, J.. HEINEMANN, S. Mapping of brain areas expressing RNA homologous to two different acetylcholine receptor a-subunit cDNAs. Proceedings of the National Academy of Sciences 83(11):4076-4080, June 1986. GREGG, C.M. The compartmentalized hypothalamo-neurohypophyseal system: Evi- dence for a neurohypophyseal action of acetylcholine on vasopressin release. Neuroendocrinology 40:423-429, 1985. GRITZ, E.R. Smoking behavior and tobacco abuse. In: Mello, N.K. (ed.1 Advances in Substance Abuse, Volume 1. Greenwich, Connecticut: JAI Press, 1980, pp. 91-158. GRITZ, E. Gender and the teenage smoker. In: Ray, B.A., Braude, M.C. (eds.) Women and Drugs: A New Era for Research, NIDA Research Monograph 65. U.S. Department of Health and Human Services, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration. DHHS Publication No. (ADM) 86-1447, 1986. 130 GRUNBERG, N.E. The effects of nicotine and cigarette smoking on food consumption and taste preferences, Addirtit>e Behaviors 7(41:317-331, 1982. GRUNBERG, N.E. Behavioral and biological factors in the relationship between tobacco use and body weight. In: Katkin. E.S., Manuck, S.B. feds.1 Adrances in Behactioral Medicine, Volume 2. Greenwich, Connecticut: JAI Press. Inc., 1986. pp. 97-129. GRUNBERG, N.E.. BAUM, A. Biological commonalities of stress and substance abuse. In: Shiffman, S., Wills, T.A. (eds I Coping and Strbslance Use. Orlando, Florida: Academic Press, 1985, pp. 25-62. GRUNBERG, N.E., BOWEN, D.J.. MORSE, D.E. Effects of nicotine on body weight and food consumption in rats. Psl?c/topharma~r,I~,r(~ 83(1):93-98, April 1984. GRUNBERG, N.E., BOWEN. D.J.. WINDERS S.E. Effects of nicotine on body weight and food consumption in female rats. ~s~chophumlacolo)~~ 90(11:101-105, August 1986. GRUNBERG, N.E.. POPP. K.A.. BOWEN, D.J., NESPOR, SM.. WINDERS, SE., EURY, S.E. Effects of chronic nicotine administration on insulin, glucose, epinephrine. and norepinephrine. Life Sciences 42:161-170, 1988. GRUNBERG, N.E.. WINDERS, SE., POPP, K.A. Sex differences in nicotine's effects on consummatory behavior and body weight in rats, Psychopharmacology 91:221-225, 1987. GRUNWALD, F., SCHRGCK, H., KUSCHINSKY, W. The effect of an acute nicotine infusion on the local cerebral glucose utilization of the awake rat. Rroin Research 400(2):232-238. January 6, 1987. GUHA, D., PRADHAN, SN;. Effects of nicotine on EEG and evoked potentials and their interactions with autonomic drugs. i~`el~ropharnzacol(~gs 15(4~:225-232, April 1976. HALL, G.H. Pharmacological responses to the intracerebral administration of nicotine. Pharmacological Therapeutics 15(21:223-238. 1982. HALL, G.H., FRANCIS, R.L.. MORRISON, CF. Nicotine dependence, avoidance behavior and pituitary-adrenocortical function. In: Bdttig. K. (ed.1 Behavioral Effects of Nicotine. Basel: Karger, 1978, pp. 94-107. HALL, G.H., TURNER, D.M. Effects of nicotine on the release of `H-noradrenaline from the hypothalamus. Biochemical Pharmacolog~v 21:1829-1839, 1972. HALL, R.A., RAPPAPORT, M., HOPKINS, H.K., GRIFFIN, R. Tobacco and evoked potentials. Science 180:212-214, 1973. HANSSON, E., HOFFMAN, P., SCHMITERLGW, C.G. Metabolism of nicotine of mouse tissue slices. Acta Physiologica ScandinaLlwa 61:38&392, 1964. HANSSON, E., SCHMITERLGW, C.G. Physiological disposition and fate of C14- labelled nicotine in mice and rats. Journal of Pharmacolog>, and Experimental Therapeutics 137(11:91-102, July 1962. HARRIS, R.J.C., NEGRONI, G. Lung cancer and smoking. hperial Cancer Research Fund, 62nd Annual Report, 1963-64, April 6, 1965, p. 53. HAUSER, H., SCHWARTZ, B.E., ROTH, G., BICKFORD, R.G. Electroencephalo- graphic changes related to smoking. Electroencepha1ograph.v and Clinical Neuro- physiology 10(3):576, August 1958. HENDRY, J.S., ROSECRANS, J.A. Effects of nicotine on conditioned and uncondi- tioned behavior in experimental animals. Pharmacological Therapeutics 17(3):431-454, 1982. HENNINGFIELD, J.E., MIYASATO, K., JOHNSON, R.E.. JASINSKI, D.R. Rapid physiologic effects of nicotine in humans and selective blockade of behavioral effects by macamylamine. In: Harris. L.S. (ed.) Problems (f Drug Dependence, NIDA Research Monograph 43. U.S. Department of Health and Human Services, Public Health Service, Alcohol. Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse. DHHS Publication No. IADM) 83-1264. April 1983, pp. 259-265. 131 HERNING, RI., JONES, R.T. Application of ERPs in the study of drug use and abuse in man: A close look with more sensitive task and measurement techniques. In: Lehmann, D.. Calfaway, E. (eds.) Human Evoked Potentials: Applications and Problems. New York: Plenum, 1979. HERNING, RI., JONES, R.T., BACHMAN, J. EEG changes during tobacco withdraw- al. Psychophysiology 20(5):507-512, September 1983. HERNING, RI., JONES, R.T., BENOWITZ, N.L., MINES, A.H. How a cigarette is smoked determines blood nicotine levels. Clinical Pharmacology and Therapeutics 33(1):84-90, January 1983. HERNING, RI., PICKWORTH, W.B. Nicotine gum improved stimulus processing during tobacco withdrawal. Psychophysiology 22:594, 1985. HERY. F., BOURGOIN, S., HAMON, M., TERNAUX, J.P., GLOWINSKI, J. Control of the release of newly synthesized 3H-5-hydroxytryptamine by nicotinic and muscarinic receptors in rat hypothalamic slices. Naunyn-Schmiedeberg's Archioes of Pharmacology 296(2):91-97, January 1977. HEYMANS, C., BOUCKEART, J.J., DAUTREBANDE, L. Au sujet du mecanisme de la brudycandie provoquee par la nicotine, la lobeline, le cyranure, le sulfure de sodium, les nitrites et la morphine et de a bradycardie asphyxique. Archives of International Pharmacology 41:261-289, 1931. HILL, P., WYNDER, E.L. Smoking and cardiovascular disease. Effect of nicotine on the serum epinephrine and corticoids. American Heart Journal 87(4):491496, April 1974. HILLHOUSE, E.W., BURDEN, J., JONES, M.T. The effect of various putative neurotransmitters on the release of corticotrophin releasing hormone from the hypothalamus of the rat in vitro. Neuroendocrinology 17(1):1-11, 1975. HILLYARD, S., PICTON, T. Event-related potentials and selective information processing in man in Desmodt, cognitive components in cerebra1 event-related potential and selective attention. Progress in Clinical Neurophysiology 6:1-52, 1979. HOFFMAN, D.W., ALTSCHULER, R.A., FEX, J. Enkephalinergic mechanisms in the cochlea. Society for Neuroscience Abstracts 7:95, October 1981. HOFSTETTER, A., SCHUTZ, Y., JEQUIER, E., WAHREN, J. Increased 24-hour energy expenditure in cigarette smokers. New England Journal of Medicine 314:79-82, 1986. HOKFELT, B. The effect of smoking on the production of adrenocorticoid hormones. Acta Medica Scandinavica Supplement 170(369):123-124, 1961. HUDSON, R.D. Central nervous system responses to cigarette smoke inhalation in the cat. Archiues Znternationales de Pharmacodynamie et de Therapie 237(2):191-212, February 1979. HUGHES, J.R., HATSUKAMI, D.K., PICKENS, R.W., KRAHN, D., MALIN, S., LUKNIC, A. Effect of nicotine on the tobacco withdrawal syndrome. Psychophar- macology 83(1):82-87, April 1984. HURLICK, S., CORRIGAL, W.A. Role of Opioid Mechanisms in the Behavioral Effects of Nicotine. Paper presented at the Annual Meeting, Committee on Problems of Drug Dependence, Philadelphia, 1987. IKARD, F.F., TOMKINS, S. The experience of affect as a determinant of smoking behavior: A series of validity studies. ~lournal of Abnormal Psychology 81(2):172-181, 1973. INTROINI, I.B., BARA'MI, CM. The impairment of retention induced by 8-endorphin in mice may be mediated by a reduction of central cholinergic activity. Behavioral and Neural Bio1og.v 41:152-163, 1984. IZQUIERDO, I., DIAS, R.D., SOUZA, SO., CARRASCO, M.A., ELISABETSKY, E., PERRY, M.L. The role of opioid peptides in memory and learning. Behavioral Brain Research 1:451-468, 1980. 132 JAIN, A.K. Cigarette smoking, use of oral contraceptives, and myocardial infarction. American Journal of Obstetrics and Gynecology 126(3):301-307, October 1, 1976. JARVIK, M. Biological factors underlying the smoking habit. In: Jarvik. M.E., Cullen, J.W., Gritz, E.R., Vogt, T.M.. West, L.I. (eds.)Research on SmokingBehauior, NIDA Research Monograph 17. U.S. Department of Health and Human Services, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, Nation- al Institute on Drug Abuse. DHEW Publication No. (ADMl 78-581, 1977. pp. 122-146. JENSEN, J., CHRISTIANSEN, C., RODBRO, P. Cigarette smoking, serum estrogens, and bone loss during hormone-replacement therapy early after menopause. New England Journal of Medzcine 313(16):973-975, October 1985. JOHNSON, R. Jr. A triarchic model of P300 amplitude. Psychophysiology 23(4):367-384, July 1986. KAMERLING, S.G., WE'ITSTEIN, J.G., SLOAN. J.W., SU, T.-P.. MARTIN, W.R. Interaction between nicotine and endogenous opioid mechanisms in the una- nasthetized dog. Pharmacology Biochemistry and Behavior 17(4):733-740, October 1982. KARRAS, A., KANE, J. Naloxone reduces cigarette smoking. Life Sciences 27(17):1541-1545, 1980. KAWAMURA, H., DOMINO, E.F. Differential actions of m and n cholinergic agonists on the brainstem activating system. International Journal of Neuropharmacology 8(2):105-115, March 1969. KELLAR, K.J., SCHWARTZ, R.D., MARTINO, A.M. Nicotinic cholinergic receptor recognition sites in brain. In: Martin, W.R., Van Loon, G.R., Iwamoto, E.T., Davis, L.T. (eds.) Tobacco Smoking and Nicotine. A Neurobiologicul Approach. New York: Plenum Press, 1987, pp. 467480. KEMP, G., MORLEY, B.J. Ganglionic nAChRs and high-affinity nicotinic binding sites are not equivalent. Federation of European Biochemical Societies Letters 20X2):265-268, September 1986. KERSHBAUM, A., PAPPAJOHN, D.J., BELET, S., HIRABAYASHI, M., SHAFIIHA, H. Effects of smoking and nicotine on adrenocortical secretion. Journal of the American Medical Association 203:275278, 1968. KNAPP, D.E., DOMINO, E.F. Action of nicotine on the ascending reticular activating system. International Journal of Neuropharmacology 1(4!:333-351, 1962. KNOTT, V.J. Noise and task induced distraction effects on information processing: Sex differences in smokers and non-smokers. Addictive Behaviors 9(1):79-84, 1984. KNOTT, V.J. Tobacco effects on cortical evoked potentials to distracting stimuli. Neuropsychobiology 13(1/2):74-80, 1985. KNOTT, V.J., VENABLES, P.H. Stimulus intensity control and the cortical evoked response in smokers and non-smokers. Psychophysiology 15(3):186-192, May 1978. KOCH, A., HOFFMAN, K., STECK, W., HORSCH, A., HENGER, N., MOERL, H. Acute cardiovascular reactions after cigarette smoking. Atherosclerosis 3X1):67-75, January 1980. KO?TEGODA, S.R. Stimulation of isolated rabbit auricles by substances which stimulate ganglia. British Journal of Pharmacology 883-86, 1953. KOZLOWSKI, L.T., DIRECTOR, J., HARFORD, M.A. Tobacco dependence, restraint and time to the first cigarette of the day. Addictive Behaviors 6(4):307X312, 1981. KRIEGER, D.T., MARTIN, J.B. Brain peptides (Part II). New England Journal of Medicine 304:944-951. 1981. KSIR, C., HAKAN, R., HALL, D.P. Jr., KELLAR, K.J. Exposure to nicotine enhances the behavioral stimulant effect of nicotine and increases binding of [SHlacetylcholine to nicotine receptors. Neuropharmacology 24(6):527-532, 1985. KUHAR, M., YAMAMURA, H.I. Localization of cholinergic muscarinic receptors in rat brain by light microscopic radioautography. Brain Research 110(2):229-243, July 9, 1976. 133 KUMAR. R. LADER. M. Nicotine and smoking. In: Essmac, W.B., Valzelli, L. (eds.) Current Decelopments in Psychopharmacology. Volume 6. New York: Spectrum Publication, 1981, pp. 127-164. KUMAR. R., REAVILL, C., STOLERMAN, I.P. Nicotine cue in rats: Effects of central administration of ganglion-blocking drugs. British Journal of Pharmacology, in press. LAMBIASE. M., SERRA, C. Fume e sistema nervoso. I. Modificazioni dell'attivita elettric/corticale da fumo. ilcta Neurologica 12(4):475493, 1957. LANG, W.. HENKE, H. Cholinergic receptor binding and autoradiography in brains of non-neurological and senile dementia of Alzheimer-type patients. Brain Research 267(2):271-280, May 16, 1983. LARSON, P.S., HAAG, H.B., SILVETTE, H. T b o acco. Experimental and Clinical Studies. A Comprehensicte Account of the World Literature. Baltimore, Maryland: Williams and Wilkins Co., 1961. LARSON, P.S., SILVETTE, H. Tobacco. Experimental and Clinical Studies, A Comprehensive Account of the World Literature. Supplement I. Baltimore, Mary- land: Williams and Wilkins Co., 1968. LARSON, P.S., SILVETTE, H. Tobacco. Experimental and Clinical Studies. A Comprehensice Account of the World Literature. Supplement II Baltimore, Maryland: Williams and Wilkins Co., 1971. LAURENCE, D.R., STACEY, R.S. The effect of methonium compounds on nicotine convulsions. British Journal of Pharmacology and Chemotherapy 7:80-84, March 1952. LAVERNHE-LEMAIRE, M.C, GARAND, G. Effet de la nicotine sur les fonctions auditives du rat, explore par Clectrocochleographie et potentiels evoques auditifs du tronc cerebral. Travail preliminaire. Archives Znternationales de Physiologie et de Biochimie 93:253-261, 1985. LEBOEUF, A., LODGE, J., EAMES, P.G. Vasopressin and memory in Korsakoff syndrome. Lancet 2(8104/51:1370-1372, December 23-30, 1978. LEGROS, J.J., GILOT, P., SERON, X., CLAESSENS, J., ADAM, A., MOEGLEN, J.M., AUDIBERT, A., BERCHIER, P. Influence of vasopressin on learning and memory. Lancet 14-42, 1978. LICHTENSTEIGER, W.. HEFTI, F., FELIX, D., HUWYLER, T., MELAMED, E., SCHLUMPF, M. Stimulation of nigrostriate dopamine neurones by nicotine. Neuropharmacology 21(101:963-968, October 1982. LIPPIELLO. P.M., FERNANDES, K.G. The binding of Lj3H]nicotine to a single class of high affinity sites in rat brain membranes. Molecular Pharmacology 29(5):448-454, May 1986. LONDON: ED.. CONNOLLY, R.J., SZIKSZAY, M., WAMSLEY, J.K. Distribution of cerebral metabolic effects of nicotine in the rat. European Journal of Pharmacology 110(3):391-392. April 16, 1985. LONDON. E.D.. SZIKSZAY, M.. DAM, M. Metabolic Mapping of the Cerebral Effects of Abused Drugs. In: Harris, L.S. (ed.1 Problems of Drug Dependence, 1985. Proceedings of the 47th Annual Scientific Meeting, NIDA Monograph 67. U.S. Department of Health and Human Services, Public Health Service, The Commit- tee on Problems of Drug Dependence, Inc., 1986. LONDON, E.D., WALLER, S.B., WAMSLEY, J.K. Autoradiographic localization of [`HInicotine binding sites in the rat brain. Neuroscience Letters 53(2):179-l&34, January 21, 1985. LONDON, E.D., WEISSMAN, A.D., FANELLI, R.J., WILKERSON, G., BROUS- SOLLE. E.P., JAFFE, J.H. Mapping the cerebral distributions of action of euphoriant drugs. Clinical Neuropharmacology 9Supplement 4):208-210, 1986. LONGO, V.G.. VON BERGER, G.P., BOVET, D. Action of nicotine and of the "ganglioplegiques centraux" on electrical activity of the brain. Journal of Pharmacology and Experimental Therapapeutics 111:349-359, May-August 1954. 134 LUKAS, S.E., JASINSKI, D.R. EEG power spectral effects of intravenous nicotine administration in humans. (Abstract). Federal Proceedings 42:1018, 1983. MACDOUGALL, J.M., DEMBROSKI, T.M., SLAATS, S., HERD, J.A., ELIOT, R.S. Selective cardiovascular effects of stress and cigarette smoking. Journal of Human Stress Research and Management 9(3):13-21, September 1983. MACINTOSH, F.C., OBORIN, P.E. Release of acetycholine from intact cerebral cortex. Abstr. XIX Znt. Physiol. Congress :5SO-591. 1953. MACMAHON, B., TRICHOPOULOS, D., COLE, P., BROWN, J. Cigarette smoking and urinary estrogens. New England Journal of Medicine 307(171:1062-106.5, October 21, 1982. MANGAN, G.L., GOLDING, J. An ' enhancement * model of smoking maintenance? In: Thornton, R.E. (ed., Smoking Behoviour. Physiological and Psychological Influences. Edinburgh: Churchill Livingstone. 1978, pp. 87-114. MARGULES, D.L. Beta-endorphin and endoloxone: Hormones of the autonomic nervous system for the conservation or expenditure of bodily resources and energy in anticipation of famine or fast. -Neuroscience and Biobehavioral Reviews 3(31:155-162, Fall 1979. MARKS, M.J., BURCH, J.B., COLLINS, A.C. Genetics of nicotine response in four inbred strains of mice. Journal of Pharmacology and Experimental Therapeutics 226(1):291-302, 1983a. MARKS, M.J., BURCH, J.B., COLLINS, A.C. Effects of chronic nicotine infusion on tolerance development and cholinergic receptors. Journal of Pharmacology and Experimental Therapeutics 226(3):80&816, September 1983b. MARKS, M.J., COLLINS, A.C. Characterization of nicotine binding in mouse brain and comparison with the binding of a-bungarotoxin and quinuclidinyl benzilate. Molecular Pharmacology 22(3):554-564, November 1982. MARKS, M.J., STITZEL. J.A., COLLINS, A.C. Dose-response analysis of nicotine tolerance and receptor changes in two inbred mouse strains. Journal of Pharmacol- ogy and Experimental Therapeutics 239(2):358-364, November 1986. MARKS, M.J., STITZEL, J.A., ROMM, E., WEHNER, J.M., COLLINS, A.C. Nicotinic binding sites in rat and mouse brain: Comparison of acetylcholine, nicotine, and Q- bungarotoxin. Molecular Pharmacology 30(5):427-136, November 1986. MARLA'M', G.A., DEMMING, B., REID, J.B. Loss of control drinking in alcoholics: An experimental analogue. Journal of Abnormal Psychology 81(31:233-241, 1973. MARLATI', G.A., GORDON, J.R. (eds.) Relapse Prevention. Maintenance Strategies in the Treatment of Addictive Behaviors. New York: Guilford, 1985. MARLATI', G.A., ROHSENOW, D.J. Cognitive process in alcohol use: Expectancy and the balanced placebo design. In: Mello, N.K. (ed.) Advances in Substance Abuse. Volume 1. Greenwich, Connecticut: JAI Press, 1980, pp. 159-199. MARTIN, B.R., ACETO, M.D. Nicotine binding sites and their localization in the central nervous system. Neuroscience and Biobehavioral Reviews 5(4):473-478, 1981. MARTIN, W.R., SLOAN, J.W., HOOK, R., KAPLAN, E., WASH, C. Fourth ventricle effects of nicotine, 2-methylpiperidine and cytisine in dogs. Pharmacology Bio- chemistry and Behavior 25(4):843-848, October 1986. MARTINO-BARROWS, A.M., KELLAR, K.J. [3H]Acetylcholine and [3H](-fnicotine label the same recognition site in rat brain. Molecular Pharmacology 31:169-174, February 1987. MARTY, M.A., ERWIN, V.G., CORNELL, K., ZGOMBICK, J.M. Effects of nicotine on B-endorphin, aMSH, and ACTH secretion by isolated perfused mouse brains and pituitary glands, in vitro. Pharmacolog-y Biochemistp and Behavior 22(2):317-325, February 1985. MATTA, S.G., BEYER, H.S., McALLEN, K.M., SHARP, B.M. Nicotine elevates rat plasma ACTH by a central mechanism. Journal of Pharmacology and Therapeutics 243:217-226. 1987. 135 MA'R'ILA, M., AIRAKSINEN, M.M Effect of cigar smoke and nicotine on the 5- hydroxytryptamine content in guinea-pig tissues. Annales Medicinae Experimenta- lis et Biologiae Fenniae 44(3):384-387, 1966. MAZIERE, M., BERGER, G., MASSE, R., PLUMMER, D., COMAR, D. The "in vivo" distribution of carbon 11 labeled (-jnicotine in animals. A method suitable for use in man. In: Remond, A., Izard, C. (eds.) Electrophysiologicul Effects of Nicotine. Amsterdam: Elsevier/North-Holland Biomedical Press, 1979, pp. 31-47. MAZIERE, M., COMAR, D., MARAZANO, C., BERGER, G. Nicotine-"C: Synthesis and distribution kineics in animals. European Journal of Nuclear Medicine 1(4):255-258, 1976. MCCORMICK, D.A., PR!NCE, D.A. Ace;.ylcholine causes rapid nicotinic excitation in the medial habenular nucleus of guinea pig, in vitro. Journal of Neuroscience 7(3):742-752, March 1987. McCULLOCH, J. Mapping functional alterations in the CNS with ["Cl deoxyglucose. In: Iversen, L.L., Iversen, SD., Snyder, S.H. (ads.) New Techniques in Psychaphar- macology, Volume 15. New York: Plenum Press, 1982, pp. 321-410. MEITES, J., SONNTAG, W.E. Hypothalamic hypophysiotropic hormones and neuro- transmitter regulation: Current views. Annual Review of Pharmacology and Toxicology 21:295-322, 1981. MICHNOVICZ, J.J., HERSHCOPF, R.J., NAGANUMA, H., BRADLOW, H.L., FISH- MAN, J. Increased 2-hydroxylation of estradiol as a possible mechanism for the anti-estrogenic effect of cigarette smoking. New England Journal of Medicine 315(21):1305-1309, November 20, 1986. MILLAN, M.J., EMRICH, H.M. Endorphinergic systems and the response to stress. Psychotherapy and Psychosomatics 36(1):43-56, 1981. MINNIE, C.D, COMER, A.K. The effect of cigarette smoking on the contingent negative variation (CNV) and eye movement. In: Thornton, R.E. (ed.) Smoking Behaviour, Physiological and Psychological Influences. Churchill Livingstone: Edinburgh, 1978. MINER, L.L., MARKS, M.J., COLLINS, A.C. Classical genetic analysis of nicotine- induced seizures and nicotinic receptors. Journal of Pharmacology and Experimen- tal Therapeutics 231(3):545-554, December 1984. MITCHELL, J.F. The spontaneous and evoked release of acetylcholine from the cerebral cortex. Journal of Physiology 165:9%116, January 1963. MITI'LER, J.C., POGACH, L., ERTEL, N.H. Effects of chronic smoking on testoster- one metabolism in dogs. Journal of Steroid Biochemistry l&61:759-763, June 1983. MORUZZI, G., MAGOUN, H.W. Brain stem reticular formation and activation of the EEG. Electroencephalography and Clinical Neurophysiology 1(1):455-473, Febru- ary 1949. MUNCK, A., GUYRE, P.M., HOLBROOK, N.K. Physiological functions of glucocorti- coids in stress and their relation to pharmacological actions. Endocrine Reviews 5(1):25-44, Winter 1984. MURPHREE, H.B. EEG effects in humans of nicotine, tobacco smoking, withdrawal from smoking and possible surrogates. In: Remond, A., Izard, C. (eds.) Electrophysi- olos'cal Effects of Nicotine. i\msterdam: Elsevier/North-Holland Biomedical Press, 1979, pp. 227-247. MURPHREE, H.B., PFEIFFER, C.C., PRICE, L.M. Electroencephalographic changes in man following smoking. Annals of the New York Academy of Sciences 142(1):245-260, 1967. MYRSTEN, A.-L., ELGEROT, A., EDGREN, B. Effects of abstinence from tobacco smoking on physiological and psychological arousal levels in habitual smokers. Psychosomatic Medtcine 39(1):25-38, January-February 1977. NAKAJIMA, S. Serotonergic mediation of habenular self-stimulation in the rat. Pharmacology Biochemistry and Behavior 20(6):859-862, 1984. 136 NEMETH-COSLETT, R. GRIFFITHS, R.R. Naloxone does not affect cigarette smoking. Psychopharmacology 89(3):261-264. July 1986. NESBITT, P.D. Smoking, physiological arousal, and emotional response. Journal of Personality and Social Psychology 25(1~:137-144, January 1973. NIAURA. R., ABRAMS, D.B., DEMUTH, B.. MONTIP.. PINTO, R. Cue exposure to cigarettes as a predictor of relapse in smokers, in press. NOVACK, D.H., ALLEN-ROWLANDS, C.F. Pituitary-adrenal response to cigarette smoking. (Abstract). Psychosomatic Medicine 47(1,:78, January-February 1985. NOVACK, D.H., ALLEN-ROWLANDS, C.F., GASN, D.S. Some hormonal, metabolic, and cardiovascular responses to cigarette smoking in normal males. Psyrhophar- macology, in press. OCKENE, J.K., BENFARI, R.C., NUTTALL, R.L., HURWITZ, I., OCKENE, I.S. Relationship of psychosocial factors to smoking behavior change in an intervention program. Precentice Medicine llt1~:13-28, January 1982. O'CONNOR, K. Individual differences in the effect of smoking on frontal-central distribution of the CNV: Some observations on smokers' control of attentional behaviour. Personality and Individual Dtfferences 3:271-285, 1982. O'CONNOR, K. Motor potentials and motor performance associated with introverted anu extraverted smokers. Neurops~vchobiology 16:109-116, 1986. ORY, H.W. Association between oral contraceptives and myocardial infarction: A review. Journal of the American Medical Association 237(241:2619-2622, June 13, 1977. OSWALD, R.E., FREEMAN, 5.4. Alpha-bungarotoxin binding and central nervous system nicotinic acetylcholine receptors. h'euroscience 6(11:1-14, 1981. OVERTON, D.A. Control of T-maze choice by nicotinic, antmicotinic, and antimusca- rinic drugs. Proceedings of the 77th Annual American Psychological Association Conuention, 1969, pp. 869-870. PATON, W.D.M., SAVINI, E.C. The action of nicotim on the motor endplate in the cat. Rritish Journal of Pharmarology and Chenzotl.~:rap~ 32(2):360-380, February 1968. PERKINS, K.A., EPSTEIN, L.H., STILLER, R., JENNINGS, J.R., CHRISTIANSEN, C., MCCARTHY, T. An aerosol spray method of delivering measured doses of nicotine via inhalation. Behavioral Research Method Instrumentation, in press. PHILIPS, C. The EEG changes associated with smoking. Psvchophvsiology 8tli:64-74, January 1971. PICKWORTH, W.B., HERNING, R.I., HENNINGFIELD, J.E. Electroencephalograph- ic effects of nicotine chewing gum in humans. Pharmacology Biochemistry and Behacior 25(4):879-882, October 1986. PICKWORTH, W.B., HERNING, RI., HENNINGFIELD, J.E. Mecamylamine reduces some EEG effects of nicotine chewing gum in humans. Pharmacology Chemistry and Behatlior, in press. POMERLEAU, O.F. The "why" of tobacco dependence: Underlying reinforcing mechanisms in nicotine self-administration. In: Ockene, J.K. (ed.) The Pharmaco- logic Treatment of Tobacco Dependence: Proceedings of the World Congress November 4-5. 1985. Cambridge, Massachusetts: Institute for the Study of Smoking Behavior and Policy, 1986. pp. 36-47. POMERLEAU, O.F., ADKINS, D.M., PERTSCHUK, M. Predictors of outcome and recidivism in smoking cessation treatment. Addictice Behac'iors 3(2):65-70, 1978. POMERLEAU, O.F., FERTIG, J.B.. SEYLER. L.E., JAFFE. J. Neuroendocrine reactivity to nicotine in smokers. Psychopharmocolog.v 81111:61-67, August 1983. POMERLEAU, O.F., POMERLEAU, C.S. Neuroregulators and the reinforcement of smoking: Towards a biobehavioral explanation. Neuroscience and RiobehaLGoraZ ReLGercs 8(4):503-513, Winter 1984. 137 POMERLEAU, O.F.. POMERLEAU, C.S. A biobehavioral perspective on smoking. In: Ney, T., Gale, A. teds.) Smoking and Human Behauiour. Chichester, England: John Wiley 82 Sons, in press. POMERLEAU, O.F., TURK. D.C., FERTIG, J.B. The effects of cigarette smoking on pain and anxiety. Addictive Behaviors 9:265-2'71, 1984. PRUTSKY. G.T., SHAW, C., CYNADER, MS. Nicotine receptors are located on lateral geniculate nucleus terminals in cat visual cortex. Brain Research 412(1):131-138, May 26, 1987. PUDDEY, LB., VANDONGEN, R., BEILIN, L.J., ENGLISH, D. Haemodynamic and neuroendocrine consequences of stopping smoking-a controlled study. Clinical and Experimental Pharmacology and Physiology lL423-426, 1984. RAPIER, C., WONNACO'M', S., LUNT, G.G., ALBUQUERQUE, E.X. The neurotoxin histrionicotoxin interacts with the putative ion channel of the nicotinic acetylcho- line receptors in the central nervous system. FEBS Letters 212(2):292-296, February 1987. REAVES, T.A., LIU, H.M., QASIM, M., HAYWARD, J.N. Vasopressin release by nicotine in the cat. Peptides 2(1):13-17, 1981. RICHARDSON, D. Effects of tobacco smoke inhalation on capillary blood flow in human skin. Archbtes of Environmental Health 42(1):19-25, January-February 1987. RICKARD-FIGUEROA, K., ZEICHNER, A. Assessment of smoking urge and its concomitants under an environmental smoking cue manipulation. Addictive Behaviors 10:249-256, 1985. RINALDI, F., HIMWICH, H.E. Alerting responses in actions of atropine and cholinergic drugs. Archives of Neurology and Psychiatry 73:387-395, 1955a. RINALDI, F., HIMWICH, H.E. Choline& mechanism involved in function of mesodiencephalic activating system. Archives of Neurology and Psychiatry 73(4):396402, April 1955b. RISCH, SC., COHEN, R.M., JANOWSKY, D.S., KALIN, N.H., MURPHY, D.L. Mood and behavioral effects of physostigmine on humans are accompanied by elevations of plasma B-endorphin and cortisol. Science 209(4464):1545-1546, September 26, 1980. RISCH, SC., JANOWSKY, D.S., SIEVER, L.J., JUDD, L.J., RAUSCH, J.L., HUEY, L.Y., BECKMAN, K.A., COHEN, R.M., MURPHY, D.L. Correlated cholinomimet- ic-stimulated Beta-endorphin and prolactin release in humans. Peptides 3(3):319-322, May-June 1982. ROBINSON, S.E. Effect of specific serotonergic lesions on choline@ neurons in the hippocampus, cortex and striatum. Life Sciences 32(4):345-353, January 24, 1983. ROMANO, C., GOLDSTEIN, A. Stereospecific nicotine receptors on rat brain membranes. Scwnce 210:647-649, November 7, 1980. ROSE, J.E.. ANANDA, S., JARVIK, M.E. Cigarette smoking during anxiety-provok- ing and monotonous tasks. Addictive Behauiors 8(4):353-359, 1983. ROSE, J.E., ZINSER, MC., TASHKIN, D.P., NEWCOMB, R., ERTLE, A. Subjective response to cigarette smoking following airway anesthetization. Addictive Behau- iors 9:211-215, 1984. ROSECRANS, J.A. Noncholinergic mechanisms involved in the behavioral and stimulus effects of nicotine, and relationships to the process of nicotine depen- dence. In: Martin, W.R., Van Loon, G.R., Iwamoto, E.T., Davis, L. (eds.) Tobacco and Smoking and Nicotine. A `Veurobiological Approach. New York: Plenum Press, 1987, pp. 125-139. ROSECRANS, J.A., HENDRY, J.S., HONG, J.-S. Biphasic effects of chronic nicotine treatment of hypothalamic immunoreactive beta-endorphin in the mouse. Phar- macology Biochcmistp and Behacior 23(1):141-143, July 1985. 138 ROSENBERG, J., BENOWITZ, N.L., JACOB, P.. WILSON, KM. Disposition kinetics and effects of intravenous nicotine. Clinical Pharmacolog) and Therapeutics 28(4):517-522, October 1980. ROTTER, A., BIRDSALL, N.J.M., BURGEN, A.S.V., FIELD, P.M., HULME, E.C. RAISMAN, G. Muscarinic receptors in the central nervous system of the rat. Technique for autoradiographic localization of the binding of [3H]propylbenzilycholine mustard and its distribution in the forebrain. Bruin Research Reviews 1:141-165, October 1979. ROWELL, P., WINKLER, D.L. Nicotine stimulation of `H-acetylcholine release from mouse cerebral cortical synaptosomes. Journal of Keurochemist? 43(6):1593-1598, December 1984. RUBIN, R.P., WARNER, W. Nicotine-induced stimulation of steroidogenesis in adrenocortical cells of the cat. British Journal of Pharmacology 53:357-362, 1975. SABELLI, H.C., GIARDINI, W.J. Tranquilizing and electrophysiological effects of nicotine. Bio[ogicaZ Psychiatry 4(2):105-130, 1972. SANDBERG, H., ROMAN, L., ZAVODNICK, J., KYPERS, N. The effect of smoking on serum somatropin, immunoreactive insulin and blood pressure glucose levels of young adult males. Journal of Pharmaco1og.y and Experimental Therapeutics 184(3):787-791, 1973. SAUMET, J.L., DITTMAR, A. Heat loss and anticipatory finger vasoconstriction induced by the smoking of a single cigarette. Phystology and Rehaoior 35(2):229-232, August 1985. SCHAEPPI, U. Nicotine treatment of selected areas of the cat brain: Effects upon EEG and autonomic system. International Journal of Neuropharmncology 71207-220, 1968. SCHECHTER. M.D., COOK, P.G. Nicotine-induced weight loss in rats without an effect on appetite. European Journal of Pharmacology 38!1):63-69, July 1976. SCHMIDT, J., HUNT, S., POLZ-TEJERA, G. Nicotinic receptors of the central and autonomic nervous system. In: Essman, W.B. (ed.) Neurotransmifters, Receptors, and Drug Action. New York: Spectrum Publications, Inc., 1980, pp. l-45. SCHMITERLGW, C.G., HANSSON, E., APPELGREN, L.-E., HOFFMAN, P.C. Physio- logical disposition and biotransformation of C14-labeled nicotine. In: Roth, L.J. (ed.) Isotopes in Experimental PharmacoZog,v. Chicago: University of Chicago Press, 1965, pp. 7590. SCHMITERLBW. C.G., HANSSON, E., ANDERSSON, G., APPELGREN, L.-E., HOFFMANN, P.C. Distribution of nicotine in the central nervous system. Annals of the New York Academy of Sciences 142:2-14, March 15, 1967. SCHMITERLOW, C.G., HANSSON, E., APPELGREN, L.-E., HOFFMAN, P.C. Physio- logical disposition and biotransformation of C "-labeled nicotine. In: Roth, L.J. fed.) Isotopes in Experimental Pharmacolog,y. Chicago: University of Chicago, 1965, pp. 75-89. SCHNEIDER, M., ADEE, C., BETZ, H., SCHMIDT, J. Biochemical characterization of two nicotinic receptors from the optic lobe of the chick. Journal of Biological Chemistry 260:14505-14512, 1985. SCHWARTZ, J.H. Chemical basis of synaptic transmission. In: Kandel, E.R., Schwartz, J.H. (eds.) Principles of Neural Science. New York: Elsevier/North- Holland Biomedical Press, 1981, pp. 106120. SCHWARTZ, R.D., KELLAR, K.J. In vivo regulation of [3H]acetylchoIine recognition sites in brain by nicotinic cholinergic drugs. Journal of LVeurochemistrv 45!2):427433, August 1985. SCHWARTZ, R.D., LEHMANN, J., KELLAR, K.J. Presynaptic nicotinic cholinergic receptors labeled by [3H]acetylcholine on catecholamine and serotonin axons in brain. Journal of Neurochemistry 42(5):1495-1498, May 1984. SCHWARTZ, R.D., MCGEE, R., KELLAR, K.J. Nicotinic cholinergic receptors labeled by [3H]acetylcholine in rat brain. Molecular Pharmacology 22( 1):56-62, July 1982. 139 SEIFERT, J., SEIFERT, E., BRECHTELSBAUER, H., KURZ, C., THURAU, K. The influence of chronic subcutaneous nicotine administration on aldosterone and corticosterone plasma concentration and the plasma renin activity. Klinische Wochenschrift 62(Supplement 11):81-85, 1984. SEYLER, L.E., FERTIG, J.B., POMERLEAU, O.F., HUNT, D., PARKER, K. The effects of smoking on ACTH and cortisol secretion. Life Science 34(1):57-65, 1984. SEYLER. L.E., POMERLEAU, O.F., FERTIG, J.B., HUNT, D., PARKER, K. Pituitary hormone response to cigarette smoking. Pharmacology Biochemistry and Behavior 24(1):159-162, January 1986. SHAPIRO, S., ROSENBERG, L., SLONE, D., KAUFMAN, D.W., STOLLEY, P.D., MIETTINEN, O.S. Oral contraceptive use in relation to myocardial infarction. Lancet 1(8119):743-747, 1979. SHARP, B.M., BEYER, H.S. Rapid desensitization of the acute stimulatory effects of nicotine on rat plasma adrenocorticotropin and prolactin. Journal of Pharmacolo- gy and Experimental Therapeutics 238:486-491, 1986. SHARP, B.M., BEYER, H.S., LEVINE, AS., MORLEY, J.E., McALLEN, K.M., Attenuation of the plasma prolactin response to restraint stress after acute and chronic administration of nicotine to rats. Journal of Pharmacology and Experi- mental Therapeutics 24112):438442, 1987. SHIFFMAN, S.M. The tobacco withdrawal syndrome. In: Krasnegor, N.A. (ed.) Cigarette Smoking as a Dependence Process, NIDA Research Monograph 23. U.S. Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse. 1979, pp. 158-1840. SHIFFMAN, S. Relapse following smoking cessation: A situational analysis. Journal of Consulting and Clinical Psychology 50(11:71-86, February 1982. SHIFFMAN, S. Coping with temptations to smoke. Journal of Consulting and Clinical Psychology 52(2):261-267, April 1984. SHIFFMAN, S. A cluster-analytic classification of smoking relapse episodes. Addic- tive Behaviors 11(3):295-307, 1986a. SHIFFMAN, S. Task Force 2: Models of smoking relapse. Health Psychology S(Supplement):13-27, 1986b. SHIFFMAN, S., JARVIK, M.E. Cigarette smoking, physiological arousal, and emotional response: Nesbitt's paradox reexamined. Addictive Behaviors 9(1):95-98, 1984. SHIFFMAN, S., WILLS, T.A. Coping and Substance Use. Orlando, Florida: Academic Press, 1985. SHIMOHAMA, S., TANIGUCHI, T., FUJIWARA, M., KAMEYAMA, M. Biochemical characterization of the nicotinic cholinergic receptors in human brain: Binding of (-)-[3H]nicotine. Journal of Neurochemistry 45(2):604610, August 1985. SIEGEL, S. Classical conditioning, drug tolerance, and drug dependence. In: Smart, R.G.. Glaser, F.B., Israel, Y., Kalent, H., Popham, R.E., Schmidt, W. (eds.) Research Advances In Alcohol and Drug Problems, Volume 7. New York: Plenum Press, 1983, pp. 207-246. SIEGEL, R.A., ANDERSSON, K., FUXE, K., ENEROTH, P., LINDBOM, L.-O., AGNATI, L.F. Rapid and discrete changes in hypothalamic catecholamine nerve terminal systems induced by audiogenic stress, and their modulation of nicotine- relationship to neuroendocrine function. European Journal of Pharmacology 91(1):49-56, July 15, 1983. SLOAN, J.W., MARTIN, W.R., HERNANDEZ, J., HOOK, R. Binding characteristics of (-t and (+ tnicotine to the rat brain P, fraction. Pharmacology Biochemistry and Behavior 23:987-993, 1985. SLOAN, J.W., TODD, G.D., MARTIN, W.R. Nature of nicotine binding to rat brain P, fraction. Pharmacology Biochemistry and Behavior 20:899-909, 1984. 140 SOKOLOFF, L. Localization of functional activity in the central nervous system by measurement of glucose utilization with radioactive deoxyglucose. Journal of Cerebral Blood Flou, and Metabolism l(l):i-36 1981. SOKOLOFF, L., REIVICH, M., KENNEDY, C.. DES ROSIERS, M.H., PATLAK, C.S., PETTIGREW, K.D., SAKURADA, 0.. SHINOHARA, M. The "Cdeoxyglucose method for the measurement of local cerebral glucose utilization: Theory. procedure, and normal values in the conscious and anesthetized albino rat. Journal of Neurochemistr;\ 28:897-916, 1977. SOKOLOV, Y.N. Perception and the Conditional Reflex. (Translated by S.W. Waydenfeldl. Oxford: Pergamon Press, 1963. SPETH, R.C., CHEN, F.M., LINDSTROM, J.M., KOBAYASHI, R.M., YAMAMURA, HI. Nicotinic cholinergic receptors in rat brain identified by (`zJI] Naja naja siamensis a-toxin binding. Brain Research 131(21:350-355, August 12. 1977. STARKE, K. Regulation of noradrenaline release by presynaptic receptor systems. Rev. Physiol. Biochem. Pharmacoi. 77:1-24, 1977. STEWART, G.N., ROGOFF, J.M. The action of drugs on the output of epinephrine from the adrenals: III. Nicotine. Journal of Pharmarmacology and Experimental Therapeutics 13:183-241, 1919. STOLERMAN, I.P., GOLDFARB, T., FINK, R.. JARVIK. M.E. Influencing cigarette smoking with nicotinic antagonists. Psychopharmacology 28(3):247-259, 1973. STONE, CA.. MECKELNBURG, K.L, TORCHIANA, M.L. Antagonism of nicotine- induced convulsions ganglionic blocking agents. Archicles Intenationationales de Pharmacodynamie et de Z'herupie 117:419434, 1958. STUMPF, C., PETSCHE, H.. GOGOLAK, G. The signifcance of the rabbit's septum as a relay station between the midbrain and the hippocampus. II. The differential influence of drugs upon both the septal cell firing pattern and the hippocampus theta activity. Electroencephalography and Clinical Neurophysiology 14:212-219, 1962. STUMPF, C., GOGOLAK, G. Actions of nicotine upon limbic system. Annals of the -Velieu? York Academy of Sciences 142:143-158, 1967. SUTER, T.W., BUZZI, R., BA'ITIG, K. Cardiovascular effects of smoking cigarettes with different nicotine deliveries. A study using multilead plethysmography. Psychopharmorolog.y 80(2):106-112, May 1983. SUZUKI, T., IKEDA, N.. NARITA, S., SHIBATA, O., WAKI, S., EGASHIRA, K. Adrenal cortical secretion in response to nicotine in conscious and anesthetized dogs. Quarterly Journal of Experimental Physiology 58(2):139-142, 1973. TERKEL, J., BLAKE, C.A., HOOVER, V., SAWYER, C.H. Pup survival and prolactin levels in nicotine treated rats. Proceedings of the Society for Experimental Bioliology and Medicine 143:1131-1135, September 1973. TJALVE, H., POPOV, D. Effect of nicotine and nicotine metabolites on insulin secretion from rabbit pancreas pieces. Endocrinology 92:1343-1348, 1973. TOBIN, M.J., JENOURI, G., SACKNER, M..4. Effect of naloxone on change in breathing pattern with smoking. A hypothesis on the addictive nature of cigarette smoking. Chest 82(51:530-537, November 1982. TSUJIMOTO, A., TSUJIMURA, Y., YOSHIMOTO, S., KOMURA, I. Nicotine distribu- tion in dog and rabbit. Folia Pharmacoligica Japonica 53(3):553-565, 1955. TUCCI, J.R., SODE, J. Chronic cigarette smoking. Effect on adrenocortical and sympathoadrenal activity in man. Journal of the American Medical Association 221(3):282-285, July 17, 1972. TUOMISTO, J., MANNISTG, P. Neurotransmitter regulation of anterior pituitary hormones. Pharmacological Reviews 37(3):249-332. 1985. TURNER, D.M. The role of adrenal catecholamines in the release of corticosterone and fatty acids by nicotine in the rat. Research Communications in Chemical Pathology and Pharmacology 12(4):645-655, 1975. 141 UEKl, S., KOKETSU, K.. DOMINO. E.F. Effects of mecamylamine on the Golgi recurrent collateral-Renshaw cell synapse in the spinal cord. Experimental h'eumlog.v 3121:141-148, February 1961. ULETT. J.A.. ITIL, T.M. Quantitative electroencephalogram in smoking and smoking deprivation. Science 164(38821:969-970, May 1969. VAN REE, J.M., DE WIED. D. Brain peptides and psychoactive drug effects. In: Israel, Y., Glaser F.B., Kalant H., Popham, R.E., Schmidt, W., Smart, R. (eds.) Research Advances in Alcohol and Drug Problems, Volume 6. New York: Plenum Press, 1981, pp. 6'7-105. VAZQUEZ, A.J., TOMAN, J.E.P. Some interactions of nicotine with other drugs upon central nervous function. Annals of the New York Academy of Science 142(1):201-215, March 15, 1967. VOLLE. R.L.. KOELLE, G.B. Ganglionic stimulating and blocking agents. In: Goodman, L.S., Gilman, A. (eds.1 The Pharmacological Basis of Therapeutics. 5th Edition. New York: Macmillan Publishing Company, 1975, pp. 565-574. WAEBER, B., SCHALLER, M.-D., NLJSSBERGER, J., BUSSIEN, J.-P., HOFBAUER, K.G.. BRUNNER, H.R. Skin blood flow reduction induced by cigarette smoking: Role of vasopressin. American Journal of Physiology 247(6, Part 2):H895-H901, December 1984. WAITS, D.T. The effect of nicotine and smoking on the secretion of adrenaline. Annals of the New York Academy of Sciences 90:74-80, 1961. WECHSLER, R.L. Effects of cigarette smoking and intravenous nicotine on the human brain. (Abstract). Federation Proceedings 17(11:169, March 1958. WEIDENFELD, J., SIEGEL, R., CONFORTI, N., MIZRACHI, R., BRENNER, T. Effect of intracerebroventricular injection of nicotine acetycholine receptor antibodies on ACTH, corticosterone and prolactin secretion in the male rat. Brain Research 265(11:152-156, April 11, 1983. WEINGARTNER, H., GOLD, P., BALLENGER. J.C., SMALLBERG, S.A., SUMMERS, R., RUBINOW, D.R., POST, R.M., GOODWIN, F.K. Effects of vasopressin on human memory functions. Science 211(4482):601-603, February 1981. WERLE, E., MEYER, A. Uber den Abbau van Tabakalkaloiden durch tierisches Gewebe. Biochemischc Zeitschrift 321(31:221-235, November 24, 1950. WESTFALL, T.C. Effect of nicotine and other drugs on the release of `H-norepineph- rine and `H-dopamine from rat brain slices. Neuropharmacology 13(81:693-700, August 1974. WESTFALL, T.C., BRASTED, M. The mechanism of action of nicotine on adrenergic neurons in the perfused guinea-pig heart. Journal of Pharmacology and Experi- mental Therapeutms 182(31:409-418, 1972. WESTFALL. T.C., GRANT, H., PERRY, H. Release of dopamine and 5-hydroxytrypta- mine from rat striatal slices following activation of nicotinic cholinergic receptors. General Pharmacology 14(3):321-325, 1983. WHITEHOUSE, P.J.. MARTINO, A.M., ANTUONO, P.G., LOWENSTEIN, P.R., COYLE, J.T., PRICE. D.L., KELLAR, K.J. Nicotinic acetylcholine binding sites in Alzheimer's disease. Brain Research 371:146-151, 1986. WIKLER, A. Conditioning factors in opiate addiction and relapse. In: Wilner, D., Kassenbaum, D. reds.1 Narcotics. New York: McGraw-Hill. 1965, pp. 85-100. WILKINS, J.N., CARLSON, H.E., VAN VUNAKIS, H., HILL, M.A., GRITZ, E., JARVIK, M.E. Nicotine from cigarette smoking increases circulating levels of cortisol, growth hormone, and prolactin in male chronic smokers. Psychopharma- cology 78(41:305-308, December 1982. WILLIAMS, M., ROBINSON, J.L. Binding of the nicotinic cholinergic antagonist dihydro-6-erythroidine. to rat brain tissue. Journal of Neuroscience 41121:2906-2911, December 1984. 142 WILLS, T.A. Stress, coping, and tobacco and alcohol use in early adolescence. In: Shiffman. S.. Wills. T.A. teds.1 Coprng and Substarlce Use. Orlando, Florida: Academic Press, 1985. pp. 67-94. WINTERNITZ, W.W.. QUILLEN. D. Acute hormonal response to cigarette smoking. Journal of Clinical Pharmacologic 17(71:389-397, July 1977. WISE. R.A. Action of drugs of abuse on brain reward systems. Pharmacolog) Biochemial~ and BehaIxier 13tSupplement 1):213-223. 1980. WONNACOTT, S. Alpha-bungarotoxin binds to low-affinity nicotine binding sites in rat brain. rJournal of Neurachemist~ 47.1706-1712, 1986. WOOD, CC., MCCARTHY, G., SQUIRES, N.K., VAUGHAN, H.G., WOODS, D.L.. McCALLUM, W.C. Anatomical and physiological substrates of event-related potentials. In: Karrer, R., Cohen, J., Tueting, P. teds.1 Rrnrn and Information: Event-Related Potentials. Annals of fhe Neic, Iirh Alademr ofScienrv 425:681-721. 1984. WOODSON, P.P.. BATTIG, Ii.. ETKIN. ?v1.W., HARRY, G.J., KALLMAN. !V.M.. KALLMAN, M.J., ROSECRANS, J.A. Effects of nicotine on the visual evoked response. Pharmacology Biochemists: and Rehac,ror 17151:915-920. 1982. WOODSON, P.P.. BUZZI, R., NIL. R. BATTIG. K. Effects of smoking on vegetative reactivity to noise in women Ps,vchopb.wiolo~. Z3:272-282. 1986. WU, K.M., MARTIN, W.R. An analysis of nicotinic and opioid processes in the medulla oblongata and nucleus ambiguus of the dog. Jo~1r~io1 ofPhar:~1aw/ogy and Experimental Z'herapeutzcs 227(2):302-307, November 1983. YAMADA, S., ISOGAI. M., KAGAWA, Y , TXKAYANAGI. N., HAYASHl. E.. TSUJI, K., KOSUGE, T. Brain nicotinic acetylcholine receptors. Biochemicai characteriza- tion by neosurugatoxin. MolecrrInr Pharmacolog>~ 28(2):120-127. August 1985. YAMAMOTO, I. Nicotine metabolism. Seitni rro Kagaka 6!4):154-159, 1955. YAMAMOTO, I., INOKI. R., IWATSUBO. K. Antagonistic effect of phenothiazine derivatives on nicotine-induced death in mice. .?apanese .Journnl of Pharmaco1og.v 17(11:133-134, March 1967. YAMAMOTO, I., INOKI, R., IWATSUBO, K. Penetration of nicotine-14C into several rat tissues in viva and in vitro. Toxicology and -4ppfied Pharmacology 12(31:560-567, May 1968. YOSHIDA, K., IMURA, H. Nicotinic cholinergic receptors in brain synaptosomes. Brain Research 172(3):453-459. August 31. 1979. ZATZ, M., BROWNSTEIN, M.J. Injection of cl-bungarotoxin near the suprachiasmatic nucleus blocks the effects of light on nocturnal pineal enzyme activity. Brain Research 21312):438-442, June 1, 1981. 143 CHAPTER IV TOBACCO USE AS DRUG DEPENDENCE 145 CONTENTS Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149 Cigarette Smoking: Controlled Drug Self- Administration ................................................... 149 Measurement of Cigarette Smoking .................... 150 Characterization of Cigarette Smoking Behavior ... 153 Patterns of Puffing and Inhaling ....................... 155 Dose-Related Determinants of Tobacco Intake ....... 158 Control of Nicotine Intake ................................ 158 Smoke Concentration ................................. 159 Cigarette Length ....................................... 161 Cigarette Brand ........................................ 161 Cigarette Yield of Nicotine ......................... 162 Urine pH ................................................ 163 Tobacco Administration and Deprivation ....... 164 Nicotine Pretreatments .............................. 165 Nicotine Antagonist Pretreatments .............. 166 Effects of Nonnicotinic Drugs on Cigarette Smoking ...................................................... 166 Effects of Nonnicotine Constituents of Tobacco Smoke and Citric Acid Aerosol ....................... 168 Nicotine: Psychoactivity, Reinforcing and Related Behavioral Mechanisms of Nicotine Dependence . . . . . . 169 Interoceptive, Discriminative, and Subjective Effects of Nicotine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170 Drug Discrimination Testing in Animals . . . . . . . . . . . . . 171 Specificity of the Nicotine Stimulus.. . . . . . . . . . . . 171 Peripheral Versus Central Discriminative Stimulus Effects of Nicotine . . . . . . . . . . . . . . . . . . . . 173 Interactions with Noncholinergic Neurons.. . . .175 Subjective Effects of Nicotine in Humans . . . . . . . . . . . . 175 Psychoactivity of Nicotine . . . . . . . . . . . . . . . . . . . . . . . . . . 176 Sensory Effects of Nicotine.. . . . . . . . . . . . . . . . . . . . . . . . 178 State-Dependent Learning . . . . , . . , . . . . . . . . . . . . . . . . . . . . . . . . . 180 Nicotine as a Positive Reinforcer . . . . . . . . . . . . . . . . . . . . . . . 181 Animal Studies of Nicotine as a Reinforcer . . 182 Human Studies of Nicotine as a Reinforcer . . 192 Nicotine as an Aversive Stimulus . . . . . . . . . . . . . . . . . . . . . . 192 147 Nicotine as an Unconditioned Stimulus.. . . . . . . . . . . . . . 194 Conditioned Place Preference and Aversion.. . 194 Conditioned Taste Aversion and Rapid Smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . 195 Nicotine: Withdrawal Reactions (Physical Dependence) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197 Criteria for Physical Dependence on Nicotine and Clinical Characteristics of the Withdrawal Syn- drome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198 Retrospective Survey Data . . . . . . . . . . , ,. . . . . . . . . . . . . . . . . . . . 199 Prospective Data From Laboratory and Nonlabora- tory Studies . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .201 Time Course of Responses to Nicotine Abstinence. 204 Alleviation of Withdrawal Symptoms by Cigarette Smoking.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205 Relationship Between Preabstinence Nicotine In- take and Magnitude of Withdrawal Syndrome . . .206 Smokeless Tobacco Withdrawal Syndrome.. . . . . . . . . . . 207 Nicotine Polacrilex Gum: Treatment and Physical Dependence.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207 Treatment of Withdrawal Symptoms.. . . . . . . . . . . 208 Maintenance of Physical Dependence . . . . . . . . . . .209 Tobacco Craving.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . , . . . . . . . . . . . . 210 Alternate Nicotine Delivery Systems . . . . . . . . . . . . . . . . . . . . . . . .212 Kinds of Nicotine Delivery Systems. . . . . . . . . . . . . . . . . . . . 212 Safety of Alternate Nicotine Delivery Systems . . . . .213 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215 References . . . . . . . . . . . . . . . . . . . . . . . . . ..,...... . . . . . . . . . . . . . . . . . . . . . . . . . 217 148 Introduction This Chapter reviews the evidence that tobacco is a pharmacologi- cally addicting substance and that tobacco use can be considered a form of drug addiction. Specific criteria to identify a substance as pharmacologically addicting are discussed in Chapters I and V. In brief, the criteria are: (1) that highly controlled or compulsive patterns of drug taking occur, (2) that a psychoactive or mood- altering drug is ingested by use of the substance and is involved in the resulting patterns of behavior, and (3) that the drug is capable of functioning as a reinforcer that can directly strengthen behavior leading to further drug ingestion. Addicting drugs can be character- ized by other properties that include the following: they can produce pleasurable effects in users, they can cause tolerance and physical dependence, and they can have adverse or toxic effects. Drawing upon data from studies of tobacco and nicotine, involving both humans and animals, the present Chapter reviews the evidence that tobacco meets the criteria as a pharmacologically addicting sub- stance. A specific comparison of tobacco to other pharmacologically addicting substances is provided in Chapter V. Cigarette Smoking: Controlled Drug Self-Administration Highly controlled or compulsive drug use refers to drug-seeking and drug-taking behavior that is driven by strong, often irresistible urges. It can persist despite a desire to quit or even repeated attempts to quit. Basic observations and experimental research indicate that ciga- rette smoking is not a random or capricious behavior that simply occurs at the will or pleasure of those who smoke. Rather, smoking is the result of behavioral and pharmacologic factors that lead to highly controlled or compulsive use of cigarettes. The highly consistent patterns of cigarette smoking illustrate the controlled nature of the behavior. For example, following initiation of smoking the individual gradually increases cigarette intake over time until he or she achieves a level that remains stable, day after day, during the smoker's lifetime (Schuman 1977; US DHHS 1987a). The dependent smoker tends to adopt a pattern in which the initial cigarette of the day is smoked soon after waking (Fagerstrbm 1978) and in which smoking throughout the day is regular from day to day (Griffiths and Henningfield 1982; Griffiths, Henningfield, Bigelow 1982). "Occasional" cigarette smoking (or "chipping") occurs just as does occasional use of other addicting drugs (see Chapter V); however, the 1985 National Health Interview Survey showed that only 10.6 percent of current smokers smoke 5 or fewer cigarettes/day (unpublished data, Office on Smoking and Health; see also Russell 1976 and US DHHS 1987a). 149 Strong evidence that cigarett,e smoking is a highly controlled or compulsive behavior is provided by survey data showing that a majority of smokers have tried to quit or at, least would like to quit. For example, several Gallup surveys have shown that a large majority of smokers report a desire to quit smoking; in fact, the proportion of smokers who would like to quit increased from 66 percent in 1977 to 77 percent in 1987 (Gallup 1987), perhaps because of a declining social acceptability of smoking and the growing awareness of the health hazards of smoking. In addition, the 1986 Adult Use of Tobacco Survey (US DHHS 1987b) showed that 65 percent of cigarette smokers had made at least one serious attempt to quit; another 21 percent said that they would try to quit "if there were an easy way to do so" (Fiore et al., in press; US DHHS 1986). The compulsive nature of cigarette smoking is most apparent in extreme cases: for example, the laryngectomized patient who, having already suffered severe consequences of smoking, continues to smoke through a tracheostomy hole. Similarly, 50 percent or more of patients recovering from surgery for a smoking-related disease (e.g., cancer, cardiovascular disease) resume smoking while in the hospital or shortly after discharge (Burling, Singleton et al. 1986; West and Evans 1986). In this Section, the behavioral process of cigarette smoking and the factors which determine the course of the behavior are described. Evidence that cigarette smoking is repetitious and stereotypic, common features of compulsive drug use, is reviewed in this Section, as well as evidence that actions of nicotine are responsible for patterns of smoking behavior. Initially, however, it is necessary to briefly review the methods by which the behavioral process of cigarette smoking is studied, as well as the main findings from such studies. Measurement of Cigarette Smoking Cigarette smoking behavior may be analyzed at different levels ranging from epidemiological surveys to the analysis of cigarette puffing. In fact, many thousands of scientific articles have been published in which some aspect of cigarette smoking is described. Much of this research has been reviewed in the tobacco research compendia of Larson and his colleagues (Larson, Haag, Silvette 1961; Larson and Silvette 1968, 1971, 1975), a previous report of the Surgeon General (US DHEW 1979), several monographs of the National Institute on Drug Abuse (NIDA) (Jarvik et al. 1977; Krasnegor 1978,1979a,b,c; Grabowski and Bell 1983; Grabowski and Hall 1985) and in articles by others (Russell 1971, 1976; Gritz 1980; Henningfield 1984). It is characteristic of drug dependence that the drug-seeking and self-administration behaviors become stereotypical and automatic in 150 Tobacco campuses: 1 Cigarette constituents o ??????? matter o Nlwtfnic alkyloids o Addltlves 2 Pyrolysis products o Carbon dioxide o Carbon monoxide Filter 1_^_. -- AIM dilution / and coolrng ua porous paper \ To lungs, where absorption occurs Absorption factors: o Inhalation amount o Inhalation depth o lnhalatlon duration o pH of smoke o Absorption characteristics of indlvtdual constituents FIGURE l.-Production and fate of cigarette smoke constituents NOTE Descnpl~on of complexity of process by whxh n~cot~nr is extracted from c+we+te. Amount of nwotme ultimately absorbed 1s as much a function of smoker beha\lor as of cigarette charactenstlcs SOURCE: Henningfield (lY841 appearance; cigarette smoking is no exception. The behavior of lighting, smoking, and extinguishing cigarettes, including puffing and inhaling, also becomes regular in smokers over time. The measurement techniques that permit such conclusions, however, must address a complex behavior. There are many variables (e.g., number of puffs, depth of inhalations) that might change and thereby affect the intake of tobacco smoke and its various constitu- ents (e.g., nicotine, tar, carbon monoxide (CO)). As shown in Figure 1, the process of producing cigarette smoke constituents itself is complex (see US DHEW 1979; US DHHS 1981, for a more thorough discussion of these factors). This complexity emphasizes the impor- tance of the use of careful measurement and multiple measures to ensure accurate characterization of cigarette smoking. Quantification of cigarette smoking behavior has improved with the development of automated measurement techniques. These techniques permit the measurement of puffing and inhalation both in the laboratory (Gust, Pickens, Pechacek 1983; Epstein, Dickson, Stiller et al. 1982; Creighton, Noble, Whewell 1978; Herning, Hunt, 151 Jones 1983; Henningfield and Griffiths 1979; Puustinen et al. 1987) and outside the laboratory (Henningfield et al. 1980; Grabowski and Bell 1983). Puffing behavior is generally measured by having subjects smoke through cigarette holders that measure air flow by use of either temperature-sensitive thermistors (Gritz, Rose, Jarvik 1983; Fagerstrom and Bates 1981) or pressure-sensing transducers (Henningfield and Griffiths 1979; Gust, Pickens, Pechacek 1983a; Rawbone et al. 1978). Inhalation behavior has been measured by a variety of techniques, including mercury strain gauge pneumogra- phy (Rawbone et al. 1978; Herning et al. 1983), head- and arms-out whole-body plethysmography (Adams et al. 1983), and impedance (Nil, Buzzi, Battig 1986) and inductive plethysmography (Herning, Hunt, Jones 1983; Tobin and Sackner 1982; Tobin, Jenouri, Sackner 1982). Other methods include the use of inert gas radiotracers to determine the amount of smoke inhaled (Sheahan et al. 1980; Woodman et al. 1986) and a sensor for directly measuring the concentration of smoke particles in the holder before puffing (Jenkins and Gayle 1984). These procedures have proved to be valuable and reliable methods of measuring smoking behavior (Woodman et a!. 1984; Herning, Hunt, Jones 1983). Comparisons of data obtained when simply observing smokers to data obtained when using the mechanical devices indicate that such automated measuring techniques are valid. Such comparisons reveal consistent findings on measures such as number and duration of puffs and even of patterns of puffing within cigarettes (Henningfield and Griffiths 1979; Griffiths and Henningfield 1982). However, other research suggests that the devices may alter certain characteristics of smoking such as intensi- ty of puffing (Tobin and Sackner 1982; Ashton, Stepney, Thompson 1978; Ossip-Klein, Martin et al. 1983). In addition, some smoking behaviors, such as blocking the ventilation holes of filters of low- yieid cigarettes (which can markedly influence nicotine and tar intake from the cigarette) are thwarted by the use of a cigarette holder. Nonetheless, such measurements are useful and appear to provide valid means of evaluating the effects of specific experimental manipulations. Measurement of the intake of cigarette smoke constituents may also be obtained by analysis of various biological fluids (saliva, urine, or blood) and expired air. Chapter II reviewed the methods and practical issues of using such specimens to assess resulting levels of nicotine, cotinine (a nicotine metabolite), CO, and other tobacco- associated compounds (see also Jarvis et al. 1987; Benowitz 1983). Use of the methods described above has led to a much better understanding of how cigarettes are smoked and factors that affect intake of smoke constituents such as CO and nicotine. In addition, these methods permit conclusions regarding which aspects of smok- 152 ing are most robust across individuals, which aspects are strongly influenced by pharmacologic factors, and which aspects appear to be determined by other factors. Some of these findings are reviewed in subsequent sections. Characterization of Cigarette Smoking Behavior Although the process of smoking a cigarette may appear to be a simple behavior, it is actually a complex series of events; a full characterization requires the measurement of a variety of interde- pendent indices of frequency, duration, and volume. Even the act of taking a single puff is complex. Typically, a smoker puffs a volume of smoke into the mouth, where it is held for a short period of time (Guillerm and Radziszewski 1978; Medici, Unger, Riiegger 1985). The puff itself can occur at any point during inhalation, although most commonly it occurs toward the beginning of an inhalation (McBride et al. 1984; Guillerm and Radziszewski 1978). During inhalation, the puff is diluted with ambient air which may be inhaled through the nose, the mouth, or both (Rodenstein and Stanescu 1985; McBride et al. 1984; Adams et al. 1983). The postpuff inhalation is generally longer and larger in volume than normal inspirations (Rodenstein and Stanescu 1985; McBride et al. 1984). After a variable period of breath holding, the smoker exhales, usually through the mouth (Rodenstein and Stdnescu 1985). All of the above-mentioned behavioral factors can alter nicotine absorption. The likely impact of some factors is obvious (e.g., number of puffs taken) (Kozlowski 1981); others are much more subtle (e.g., puff shape, which is a function of the air flow rate over time) (Creighton and Lewis 197813). Analogous but distinct from puffing factors are inhalation factors (e.g., depth and duration, dilution of the puff with ambient air) which can also determine the amount of tobacco smoke constituents which are absorbed. Table 1 lists several measures of cigarette smoking that have been objectively defined and measured. The relationships among these behavioral measures have been studied. For insta.nce, duration and volume of puffing are generally highly correlated although they vary somewhat from smoker to smoker (Gust and Pickens 1982; Epstein et al. 1982; Adams et al. 1983; Nemeth-Coslett and Griffiths 1985; Gust, Pickens, Pechacek 198313; Gritz, Rose, Jarvik 1983). Peak smoke flow rate has been reported to be moderately correlated with puff volume and weakly correlated with puff duration (Gritz, Rose, Jarvik 1983). The relationship between puff volume and interpuff interval is much more variable (Adams et al. 1983; Gust, Pickens, Pechacek 1983b), and puffs per cigarette and puff duration have been found to be inversely related (Lichtenstein and Antonuccio 1981). 153 TABLE l.-Behavioral measures of cigarette smoking Puffing behavior Inhalation behavmr Puffsicigarette Inhalation volume Interpuff interval Inhalation duration Puff duration Breathhold duration Butt length we~ghti Lung exposure duration Puff volunle Percent of puff inhaled Puff shape Puff flow rate (puff intensity1 Peak flow rate ~pressure) Latency to peak flow rate \pressure, Percent puffing time When the smoking of individual cigarettes is studied, the mea- sures of cigarette smoking behavior and the resulting levels of biochemical markers have also been found to be highly correlated. For example, four studies found positive correlations between one or more of the behavioral measures and plasma nicotine levels (Pomer- leau, Pomerleau, Majchrzak 1987; Sutton et al. 1982; Bridges et al. 1986; Herning et al. 1983). Using another approach, Zacny and associates (1987) independently varied three aspects of smoking- puff volume, inhalation volume, and lung exposure duration. They found that increases in puff volume (from 15 to 60 mL) produced proportional increases in plasma nicotine level, whereas increases in inhalation volume (from 10 or 20 to 60 percent of vital capacity) or lung exposure duration (from 5 to 21 set) had no such effect. CO intake (measured either from expired air or blood samples) also tends to be positively related to measures of smoking behavior, including total puff volume (Gust and Pickens 1982; Guillerm and Radziszewski 1978; Xl, Buzzi, Battig 1984; Woodman et al. 1986) and mean puff volume (Zacny et al. 1987; Zacny and Stitzer 1986). McBride and coworkers (1984) found moderate correlations (r = 0.36 to 0.45) between CO boost and other measures of ventilation (tidal volume, minute ventilation, and prepuff expiratory volume). These studies illustrate some of the ways that specific aspects of cigarette smoking can affect absorption of smoke constituents. These mea- sures have been used to scientifically describe many features of cigarette smoking. A summary of findings that have emerged from such studies is presented in the next Section. 154 Patterns of Puffing and Inhaling Several studies have characterized the behavior of cigarette smoking in and outside the laboratory. The values of the most frequently measured variables are shown in Table 2. Despite a wide range of variations among studies, including differences in subject population (age, gender, smoking hist,ory, type of cigarette smoked), experimental setting, method used to collect the measurements, apparatus calibration procedures, and operational definitions of the measured variables, the findings among studies are strikingly consistent. Over the course of smoking each cigarette there are striking consistencies from cigarette to cigarette, both within and between individuals. For example, during the smoking of a single cigarette, the duration of each puff tends to decrease and/or the time between each puff (interpuff interval) tends to increase (Graham et al. 1963; Griffiths and Henningfield 1982; Nemeth-Coslett and Griffiths 1985; Herning et al. 1981; Gust, Pickens, Pechacek 1983b; Woodman et al. 1986; Buzzi, Nil, Battig 1985; Adams et al. 1983; McBride et al. 1984; Chait and Griffiths 1982a). These trends were also found in nonlaboratory observations by Schulz and Seehofer (1978). Although these observations reflect a tendency to decrease overall intensity of smoking over the course of the cigarette, the specific factors which produce such effects remain to be fully elucidated. The pattern has been hypothesized to be related to the nicotine dose per puff (Rickert et al. 1983; Russell et al. 1975; Chamberlain and Higenbot,tam 1985), because the nicotine concentration of smoke increases as the cigarette is smoked (Kozlowski 1981). However, experimental studies suggest that within-cigaret,te changes in puff intensity are not a simple function of the nicotine dose per puff (Nemeth-Coslett and Griffiths 1984a,b, 1985). Furthermore, puff volume may not be controlled by the same factors as puff duration (Nemeth-Coslett and Griffiths 1985). Thus, the orderliness of the behavior may be due to a variety of factors. Various other aspects of puffing and inhaling during the smoking of single cigarettes have been studied and provide further informa- tion that helps to characterize this complex behavioral process. For example, puff shape (puff intensity over time) (McBride et al. 1984), latency to peak puff pressure (Buzzi, Nil, BBttig 1985), and inhala- tion volume and duration (Adams et al. 1983) did not change over the course of smoking single cigarettes. The volume expired from puff to puff during and immediately after puffing (before inhalation) was lower for early puffs than for later puffs (Adams et al. 1983). Woodman and colleagues (1986) reported that the amount of smoke actually inhaled (range, 46 to 88 percent of puff volume) decreased proportionately with puff volume as cigarettes were smoked. Finally, significant changes from cigarette to cigarette in puff volume and 155 TABLE 2.-Published values of common measures of smoking Study Number Puffs/ of subjects cigarette Interpuff mterva1 b32) Cigarette duration kc) Puff duration isec) Puff volume (mLt Peak flow imL/swI Rawbone et al (1978) 12 10 41 1.8 Rawbone et al. (1978~ 9 10 35 2.1 43 Woodman et al. (1986) 9 13 18 254 1.9 49 413 Nemeth-Coslett et al. (1986~ 8 8 64 414 18 Nemeth-Coslett et al 11986b) 8 8 47 362 1.4 Nil, Wwdson, Battig (19861 132 13 28 2.2 30 28 560 Jarvik et al. (1978) 9 10 Russell et al. (198Ob) 10 11 35 Ashton. Stepney. Thompson (1978) 14 24 1.5 Schulz and Seehofer 11978) 100 11 50 1.4 Schulz and Seehofer (19781 218 12 42 1.3 Henningfield and Grifliths (19811 8 10 39 351 1.0 stepney (1981) 19 13 400 38 Battig, Buzzi, Nil (1982) 110 13 26 2.1 40 Epstein et al. (1982) 63 13 2.4 21 Russell et al. (1982) 12 15 26 324 2.3 40 Gritz. Rose, Jarvik (1983) 8 9 47 2.2 66 48 OsipKlein, Martin et al. (1983) 9 8 1.4 OssipKlein. Martin et al. (1983) 9 12 1.9 Guillerm and Radziszewski (1978) 8 12 41 1.9 39 35 918 Gust, Pickens. Pechacek (1983b) 8 9 40 1.6 44 351 339 390 393 Study Adams et al. (1983) Moody (1984) Nil, Buzzi, Battig (19841 Number of subjects 10 517 20 Puffs.1 cigarette 9 15 Interpuff interval bed 26 26 26 Cigarette duration bec) 232 Puff duration b32) 1.9 2.1 1.6 Puff volume (mL1 44 44 40 Peak flow (mL/sec) 40 Inhalation volume (mL) 614 McBride et al. (1984) 9 16 25 352 2.1 42 Medici, Unger. Ruegger (1985) 17 14 19 2.2 43 31 Burlmg et al. (1985) , 24 12 28 330 1.7 Nil, Buzzi, BBttig (1986) 117 13 22 2.1 42 36 Hughes et al. (1986bl 46 11 1.6 Bridges et al. (1986) 108 11 56 Puustinen et al. (1986) 11 13 22 2.3 44 Hildmg (19561 27 10 4.5a Mean 11 34 346 1.8 43 36 591 Median 11 28 351 1.9 42.5 35.5 560 Range 8-16 l&64 232-414 I.&24 21-66 2MR 413-918 NOTE. Data were taken from the baselme phase (or placebo treatment) of studies Involving an experimental manipulation, with at least eight SubJects Values are rounded off to the nearest unit. and in some cases. were calculated from other variables or estimated from data presented in figures; m&ng values indicate that the vnnable was not measured or was not presented in the publlshrd study inhalation volume, as well as their ratio, were reported for individu- al subjects over the course of a 4-hr smoking session (Herning, Hunt, Jones 1983). Dose-Related Determinants of Tobacco Intake As the preceding material shows, cigarette smoking is a complex but orderly behavior; it may be qualitatively and quantitatively described. Furthermore, the behavioral process of tobacco smoke self-administration substantially determines the amount of smoke that is actually consumed. Similarly, the behavior of smoking may change in response to factors related to the delivered smoke and/or nicotine dose. These interactions are described in the present section. Much of this research has addressed issues concerning the manipula- tion of some aspect of cigarette and/or nicotine dose level. Such data are relevant to comparing this form of drug self-administration with other forms of drug self-administration, because one of the basic findings in studies of drug-seeking behavior is that the dose may affect the behavior. For example, when the dose (quantity) of a psychoactive drug is high, fewer doses are generally taken compared to when the dose is very low (Griffiths, Bigelow, Henningfield 1980; Chapter V). With regard to cigarette smoking, the control and measurement of cigarette dose level is more complex than is the case with most other forms of drug delivery. For example, in opioid and alcohol studies, the amount of the morphine injected and volume of alcohol consumed can be precisely measured, but cigarette smoke can vary in levels of CO, tar, nicotine, and many other potentially important constituents (see Figure 2). The total smoke dose is positively related to the number of puffs taken per cigarette. However, total smoke dose might be changed by diluting the smoke with air or changing the number of available cigarettes. Alternatively, the smoke concen- trations can be kept constant while changes are made in the concentration of nicotine delivered. This Section reviews these and several other strategies used to investigate some form of tobac- co/nicotine dose manipulation and the resultant effects on cigarette smoking. Control of Nicotine Intake Among the most robust findings in research on cigarette smoking is the stability of nicotine intake that occurs from day to day within cigarette smokers. Several studies have collected blood samples from cigarette smokers while they are smoking their own cigarettes (Russell, Jarvis et al. 1980; Benowitz et al. 1983; Gori and Lynch 1985). This research has shown that blood levels of nicotine and cotinine among different cigarette smokers are stable and are relatively independent of the machine-estimated nicotine yield of the 158 cigarettes. Similarly, there are generally only modest correlations between the number of cigarettes smoked per day and resultant blood nicotine levels. This finding occurs because smokers consume different amounts of nicotine from their cigarettes, according to how the cigarettes are smoked. Figure 2 presents data from one of these studies. To explain why nicotine intake is not simply determined by the machine-estimated nicotine yield of the cigarettes or the number of cigarettes smoked, many other aspects of smoking have been measured. This research is described in the remainder of this Section. Smoke Concentration The concentration of tobacco smoke delivered to the lung can be changed by dilution with air. Such dilution is an important means by which the low smoking-machine-estimated ratings (e.g., Federal Trade Commission ratings) of tar and nicotine are achieved in the so- called "light" or "ultra light" cigarettes (Kozlowski 1981, 1982, 1986, 1987). One way to study the possible effects of smoke dilution is to use the ventilated cigarette holders which have been marketed for persons who are trying to quit smoking. In principle, the smoker gradually reduces his or her level of dependence to nicotine by using holders of gradually increasing ventilation level. Three laboratory studies have evaluated the effects of such holders on cigarette smoking behavior (Henningfield and Griffiths 1980; Sutton et al. 1978; Martin et al. 1980). The results of all three were consistent: smoking was more intense at lower smoke concentrations and less intense at the highest concentration. In fact, in one of the studies, expired air CO levels were similar at all four concentration levels, indicating that the changes in smoking intensity were sufficient to defeat the holders' intended purpose of reducing the dose taken (Henningfield and Griffiths 1980). Using a somewhat different strategy, Zacny, Stitzer, and Yingling (1986) studied cigarette smoking with commercially available ventilated cigarettes. When the experimenter systematically blocked the filter vents of "ultra" low-yield cigarettes, there were decreases in puffs per cigarette, puff volume, and puff flow rate, and increases in interpuff interval. These laboratory findings are consistent with findings obtained outside the laboratory when the cigarette butts of vented cigarettes are examined following smoking. Kozlowski, Rickert, Pope, and Robinson (1982) found that the cigarette butts taken from people who blocked the ventilation holes (often inadvertently) were more stained by tar and nicotine, reflecting less effective dilution and hence greater amounts of smoke delivery to the smoker. Data from a laboratory study suggest that 40 percent or more of smokers may inadvertently block the holes (Kozlowski, Rickert, Pope, Robinson, 159 i- 1000 5 0 o- 1 observation P m-2 observations - 800 - E a-3 observations . .- i;j 0-4 observations 0 0 E 8 A: 0 0 iz .- .E s x i ? 10 20 30 40 50 60 70 80 90 100 Number of cigarettes/day N= 137 r=0.15 NS P m oir" 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 . I FTC nicotine yield (mg) FIGURE 2.-Afternoon blood cotinine concentrations, compared by regression analysis with number of cigarettes smoked/day (A) and with U.S. Federal Trade Commission @TOdetermined nicotine yield (B) NOTE: The grouped smokers' values (observations 2-A) were so similar to individual values that plots overlapped Total number 01 subjects in B is lower because data for B few subjects were incomplete. Morning blood cotinine concentrations (not shown) were on average slightly lower, but had similar correlations with number of cigarettes Cr=0.45) and FTC yield (r=O.W. SOURCE: Benowitz et al. (1983). 160 Frecker 1982). These findings imply that there is much greater exposure to cigarette smoke in the general population than one would expect based solely on the market share of ventilated cigarettes (US DHHS 1981; Kozlowski 1987). Cigarette Length When cigarettes are shorter, people smoke more of them (Ashton, Stepney, Thompson 1978; Goldfarb and Jarvik 1972; Gritz, Baer- Weiss, Jarvik 1976; Jarvik et al. 1978; Chait and Griffiths 1982b). Cigarette length may also affect how people smoke each cigarette. Ashton, Stepney, and Thompson (1978) found that smokers short- ened their intervals between puffs and spent a greater proportion of time puffing on two-thirds-length cigarettes compared with full- length cigarettes. Russell, Sutton, and associates (1980) reported that smokers took relatively more puffs and left shorter butts when smoking shortened cigarettes. In another study, subjects smoking half-length cigarettes shortened the interval between puffs, but did not spend more time puffing on these cigarettes relative to full- length cigarettes (Chait and Griffiths 1982b). Puff duration and puff volume were inversely proportional to the length of the tobacco rod, even for the first puff of the cigarette (Chait and Griffiths 1982a; Nemeth-Coslett and Griffiths 1984a,b, 1985). Cigarette Brand Numerous studies have examined the effects of cigarette brand manipulations on cigarette smoking, and several reviews are avail- able (Gritz 1980; Moss and Prue 1982; McMorrow and Foxx 1983). Such studies are of practical importance because smokers often switch to lower tar/nicotine yielding cigarette brands in an effort to reduce this exposure to toxins and to reduce their level of nicotine dependence (see Chapter VII). One finding of these studies is that the number of cigarettes smoked per day is only slightly increased when lower nicotine-yield brands are used. For this reason, it has been suggested that smokers switch to lower yield cigarette brands (1) to reduce exposure to smoke constituents and (2) to help them gradually reduce their dependence on nicotine (see discussion of these issues in US DHHS 1981 and in Chapter VII (nicotine fading)). However, as discussed earlier, several other studies indicate that there is little correlation between the nicotine rating of a cigarette and the plasma nicotine level of the smoker (Russell, Jarvis et al. 1980; Benowitz et al. 1983; Gori and Lynch 1985). Kozlowski (1981, 1982) has observed that increases of only one or two puffs per cigarette and possibly other more subtle changes in cigarette smoking (e.g., blocking ventilation holes and taking deeper inhala- 161 tionst may defeat the intended purpose of the brand-switching procedure. Laboratory studies have provided information on the specific changes in smoking behavior that may reduce the intended impact of switching to lower yield brands of cigarettes. One confounding factor in such studies is that machine-estimated nicotine, tar, and CO yields do not necessarily change to the same degree or even in the same direction from one cigarette brand to the next (Tobacco Reporter 1985); thus, no definitive conclusions can be drawn about which specific smoke component was responsible for observed changes in smoking behavior. Nonetheless, some orderly and consistent findings emerge from a review of this literature. Several measures suggest that when tobacco smoke constituent ratings decline, smoking is more intense so that more smoke is delivered per cigarette; conversely, when tobacco smoke constituent ratings are higher, cigarette smoking becomes less intense (Frith 1971; Ashton, Stepney, Thompson 1979; Stepney 1981; Guillerm and Radziszewski 1978; Rawbone et al. 1978; Adams 1978; Creighton and Lewis 1978a; Ossip- Klein, Epstein et al. 1983; Russell et al. 1982; Ashton and Watson 1970; Epstein et al. 1981; Russell, Epstein, Dickson 1983; Tobin and Sackner 1982; Fagerstrom and Bates 1981; Woodman et al. 1987). The consensus of the foregoing studies is that smokers tend to smoke in ways that minimize the effect of attempted reductions in nicotine intake; however, brand preferences can modulate nicotine intake. One study employing biochemical measures of smoke intake illustrated both of these phenomena (Benowitz and Jacob 1984). Subjects were permitted t,o smoke under each of three cigarette conditions: using their regular cigarette, using a higher nicotine- yield brand, and using a lower nicotine-yield brand. Subjects maintained significant nicotine intake under all three conditions, but the highest intakes of nicotine were with the subject's preferred brand. Nicotine intake from the lower nicotine-yield brands was somewhat lower than intake from the higher yield brands. Taken together, these studies indicate that brand switching may result in somewhat decreased levels of intake of nicotine and other constitu- ents of tobacco smoke. However, because of compensatory changes in how cigarettes are smoked and in the number of cigarettes smoked, the decreases are substantially less than would have been predicted on the basis of the machine-estimated yield of the cigarettes. Cigarette Yield of LVicotine Research cigarettes which vary mainly in machine-estimated nicotine yield ratings but little in the yield of other constituents (e.g., tar, CO) have also been used in laboratory and nonlaboratory studies of cigarette smoking. This literature has been extensively reviewed (Russell 1971, 1976; Gritz 1980; Henningfield 1984; US DHEW 1979; 162 US DHHS 1981). The consensus of the literature indicates that as nicotine yield increases, the number of cigarettes smoked per day tends to decrease, although the converse relationship is not as robust (Russell 1979). Because few of these studies employed measures of smoking other than number of cigarettes smoked per day, the degree to which overall cigarette smoking behavior actually varied as a function of such manipulations may have been underestimated (Henningfield 1984). Laboratory studies in which multiple behavioral measures of cigarette smoking were employed indicate that smoking is sensitive to nicotine dose manipulations. When cigarettes with higher nicotine yield ratings are smoked, there are decreases in measures such as puffs per cigarette, puff duration and puff volume, number of cigarettes, and expired air CO; and increases in interpuff and intercigarette interval (the specific measures were not identical for the three studies summarized) (Herning et al. 1981; Gust and Pickens 1982; McBride et al. 1984). These changes in smoking are consistent with the interpretation that intensity of smoking is inversely related to nicotine dose, indicating that compensatory changes in smoking could be affected by nicotine itself. Urine pH Because some nicotine is normally eliminated in the urine, manipulations of the rate of nicotine excretion might be expected to change cigarette smoking behavior (see Chapter II). Rate of renal excretion is partially determined by the acidity of the urine: lower pH values (higher acidity) increase the rate of nicotine excretion. One study showed that acidification of the urine of cigarette smokers resulted in small increases in cigarettes smoked per day, and alkalinization of urine was accompanied by only very small de- creases in smoking (Schachter, Kozlowski, Silverstein 1977). A subsequent study in which urine pH was varied showed no change in cigarette smoking measures (Cherek, Mauroner, Brauchi 1982); another showed small but significant effects on nicotine intake in the expected direction (Benowitz and Jacob 1985). The fact that there is a direct albeit weak relationship between rate of nicotine excretion and cigarette smoking has suggested to some that alkaline diets might be useful for persons trying to decrease their cigarette smoking (Fix and Daughton 1981; Fix et al. 1983; Grunberg and Kozlowski 1986). However, the relatively small amount of systemic nicotine which is eliminated by this route (approximately 2 percent in alkaline urine, 10 percent in urine without cont.rolled pH) (Rosenberg et al. 1980; Benowitz and Jacob 1985; Chapter II) weakens its practical significance as a determinant of cigarette smoking behavior. The results of clinical studies suggest 163 that such therapies are not useful in the cessation of smoking (see also Grunberg and Kozlowski 1986; Schwartz 1987). Tobacco Administration and Deprivation When tobacco smoke itself is given or withheld, the tendency to smoke, as well as the way cigarettes are smoked, may be affected. Kumar and colleagues (1977) reported that pretreating smokers with a varying number of uniform puffs of tobacco smoke produced dose- related reductions in the subsequent number of puffs taken, volume per puff, and total puff volume during a 40-min period of smoking ad libitum. In a study of similar design, Chait, Russ, and Griffiths (1985) found that an increasing number of uniform pretreatment puffs decreased subsequent puffs per cigarette, cigarette duration, and total puff duration. Analogously, when the number of puffs available during any period of smoking (smoking "bout") during a given day was varied by the experimenter from 1 to 12 while the smokers were free to vary the interbout interval, the intervals between each smoking bout were directly related to the number of puffs that had been given (Griffiths, Henningfield, Bigelow 1982). These studies show that cigarette smoke intake is a function of time since the last cigarette or the smoke dose given at any smoking opportunity. Whereas smoke pretreatment decreases several measures of cigarette smoke intake, other studies have found that deprivation for just 1 hr increases the tendency to smoke and elevates several measures of tobacco smoke intake (Henningfield and Griffiths 1979); furthermore, these effects were not due to "anticipation" by the subjects of the periods of smoke deprivation (Griffiths and Henning- field 1982). Several additional studies have confirmed that smoke deprivation increases one or more measures of cigarette smoking (Karanci 1985; Griffiths and Henningfield 1982; Zacny and Stitzer 1985; Epstein et al. 1981). Sutton and coworkers (1982) found a small, but statistically significant, positive correlation between time since the last cigarette and total puff volume on the subsequent cigarette. Similarily, when the interval between each smoking opportunity was varied from 7.5 to 120 min and subjects were free to take as many puffs per smoking bout as they pleased, the number of puffs per bout was directly related to the duration of the preceding interbout interval (Griffiths, Henningfield, Bigelow 1982). Restricting the number of cigarettes that may be smoked is another way to study tobacco deprivation. When smokers who on average smoked 37 cigarettes/day were permitted to smoke only 5 cigarettes/day, they consumed three times as much nicotine per cigarette compared with unrestricted smoking (Benowitz et al. 1986). The results of studies of the effects of tobacco administration and deprivation on subsequent rates and patterns of cigarette smoking show that tobacco smoke can function as do other primary reinforc- 164 ers such as food, water, and dependence-producing drugs (Thompson and Schuster 1964). Such studies in themselves, however, do not reveal which of the many tobacco smoke constituents are critical. The next two sections will examine evidence that specific manipula- tions of nicotine and nicotine antagonists can produce analogous changes in cigarette smoking. Nicotine Pretreatments One of the basic ways to demonstrate that a psychoactive drug is controlling behavior is to determine if pretreatment with the drug leads to decreases in the amount subsequently taken. Such findings have been obtained with a variety of dependence-producing drugs (e.g., Griffiths, Bigelow, Henningfield 1980; Chapter V), and the strategy has been used to study the role of nicotine in cigarette smoking. These studies have shown that nicotine pretreatment by a variety of routes decreases the amount and/or intensity of subse- quent cigarette smoking although the specific measures that have been reportedly affected vary across studies. It is possible that differences across studies reflect variations in sensitivity of measure- ment techniques and in the measures used. Cigarette smokers may be pretreated with nicotine by giving them nicotine polacrilex gum to chew. The gum is available in similar tasting nicotine dose levels of 2 or 4 mg/piece. A similar tasting placebo preparation with no nicotine is also available. (In the United States, the placebo and 4-mg dose are only available for research.) With various combinations of nicotine gum doses it is possible to provide a wide range of dose levels. In one study, the chewing of nicotine polacrilex gum produced a dose-related (dose range = 0 to 8 mg nicotine) decrease in cigarette consumption during subsequent 90-min cigarette smoking sessions: Total puffs, total cigarettes, and expired-air CO levels were inversely related to nicotine dose; desire to smoke was also inversely related to dose but this effect varied considerably and was not statistically reliable (Nemeth-Coslett et al. 1987). Comparable findings have been obtained in several other studies, although dose manipulations were not as extensive as in the former study (Kozlowski, Jarvik, Gritz 1975; Nemeth-Coslett and Henningfield 1986; Brantmark, Ohlin, Westling 1973; Russell et al. 1976; Herning, Jones, Fischman 1985). Another study showed that nicotine given in capsule form also reduced subsequent cigarette smoking (Jarvik, Glick, Nakamura 19701, although the low dose and poor systemic absorption of nicotine given by this route (see Chapter II) required that much higher dose levels be given (10 mg). Two studies have also demonstrated that intravenous (i.v.1 admin- istration of nicotine decreases cigarette smoking (Lucchesi, Schuster, Emley 1967; Henningfield, Miyasato, Jasinski 1983). Another study found no change in smoking following iv. nicotine infusions (Kumar 165 et al. 1977); however, the dose (equivalent to about 1.7 mg, given in 10 divided doses over 10 min) was probably inadequate, as suggested by results of other studies (Nemeth-Coslett et al. 1987). The finding that even i.v.-delivered nicotine can reduce subsequent cigarette smoking confirms that neither the tobacco vehicle nor the oral/respiratory route is necessary for nicotine to control behavior. The overall consistency of findings using a variety of forms of nicotine pretreatment is evidence for a specific effect of nicotine as a determinant of cigarette smoking. Nicotine Antagonist Pretreatments Another way to evaluate the specific role of nicotine as a determinant of rate and pattern of cigarette smoking is to adminis- ter drugs that block the effects of nicotine on the nervous system. Nicotine antagonists (ganglionic blockers) are available as drugs (e.g., pentolinium and hexamethoniuml that do not readily enter the brain but are active in the peripheral nervous system, and as drugs (e.g., mecamylamine) that do enter the brain and thus work in both the peripheral and central nervous system (CNS) (Taylor 1985b). In theory, such drug administ,ration should produce effects that are analogous to those that would be expected if the nicotine dose of cigarettes was decreased: that is, smoke intake should increase. Moreover, if smoke intake increases, but only when the centrally acting antagonist is given, such data would suggest the critical involvement of the effects of nicotine in the brain. Three studies showed that pretreatment of smokers with mecamyl- amine produced increases in cigarette smoking that resembled those expected if the nicotine dose of the cigarettes had been decreased (Stolerman et al. 1973; Nemeth-Coslett et al. 1986a; Pomerleau, Pomerleau, Majchrzak 1987). In each of these studies, the short-term effect of the nicotine antagonists was studied. Similarly, mecamyl- amine pretreatment increased the preference for high nicotine-yield cigarette smoke (apparently by reducing its nicotinic effects) when subjects were tested with a device which blends smoke from high and low nicotine-yield cigarettes (Rose, Sampson, Henningfield 1985). The role of nicotine action in the brain was demonstrated in the study by Stolerman and colleagues (1973) in which a nicotine blocker (pentolinium) that does not readily enter the brain produced no effects on cigarette smoking. Effects of Nonnicotinic Drugs on Cigarette Smoking In addition to nicotine and nicotine antagonists, the effects of other psychoactive drugs on cigarette smoking have been studied in the laboratory. Such studies are important insofar as they constitute drug-interaction studies whereby it may be determined if the 166 behavioral and physiological actions of nicotine are altered as a function of pretreatment with other drugs. In addition, studies of interactions of nicotine with other dependence-producing drugs are important because tobacco use generally precedes and accompanies use of many other dependence-producing drugs (Chapter V). Several classes of psychoactive drugs have been administered in studies in which cigarette smoking was specifically measured. In general, the results permit a categorization of these drugs into two groups: (1) those drugs that produce increases in smoking under standard test conditions, and (2) those drugs that produce little reliable effect on cigarette smoking under standard test conditions. Sedatives, opioid agonists, and psychomotor stimulants have been shown capable of producing robust and dose-related increases in cigarette smoking. Specifically, alcohol (ethanol) has been shown t.o increase cigarette smoke intake (Griffiths, Bigelow, Liebson 1976; Henningfield, Chait, Griffiths 1984; Nil, Buzzi, Battig 1984; Mintz et al. 1985; Mello et al. 198Ob). In a study in which alcohol was found to increase smoking in all of five alcoholic subjects tested, pentobarbital (a depressant) was found to increase smoking in the two subjects with extensive histories of barbiturate use (Henningfield, Chait, Griffiths 1984). The effects of alcohol and pentobarbital were most robust in heavier drinkers and alcoholics (Henningfield, Chait. Griffiths 1983, 1984). The opioid agonists, heroin and methadone, increase cigarette smoking in opioid users (Mello et al. 1980a; Chait and Griffiths 1984). Methadone produced dose-related increases in number of cigarettes and puffs, and in puff duration in methadone- maintained smokers (Chait and Griffiths 1984). Analogously, num- ber of cigarettes smoked per day gradually decreased as methadone- maintained clients had their daily methadone doses decreased over several weeks (Bigelow et al. 1981). Finally, the psychomotor stimulant d-amphetamine increases a variety of measures of ciga- rette smoking (Henningfield and Griffiths 1981; Chait and Griffiths 1983). Three other drugs have been studied and found to produce little reliable effect on cigarette smoking. Caffeine is of interest because it might be predicted to either increase smoking by its general stimulant (amphetamine-like) effects (Rall 1985) or to decrease smoking by serving as a substitute for some of nicotine's stimulant effects (Kozlowski 1976). Laboratory studies, however, have found the effects of caffeine administration on cigarette smoking to be weak and inconsistent: two studies showed no reliable effect (Chait and Griffiths 1983; Nil, Buzzi, Battig 1984), another showed weak decreases in smoking (Kozlowski 1976), and a fourth showed weak increases in smoking following caffeine administration (Ossip and Epstein 19811. 167 The opioid antagonist naloxone (naloxone blocks effects of heroin- like opioids) is another drug of interest because of the possible role of endogenous opioids as mediators of some of the effects of nicotine (Chapter III: Pomerleau and Pomerleau 1984). In a test paradigm in which several drugs have been shown to produce orderly effects on cigarette smoking (Griffiths and Henningfield 1982), naloxone produced no consistent changes in cigarette smoking over a wide range of dose levels (Nemeth-Coslett and Griffiths 1986). Another study of the effect of naloxone which employed a single dose found a reduction in smoking (Karras and Kane 1980). No clear reconcilia- tion of these disparate findings is evident. Finally, marijuana pretreatment was found to produce no reliable effect on tobacco intake (Mello et al. 1980b; Nemeth-Coslett et al. 1986b) or on the way cigarettes were smoked (Nemeth-Coslett et al. 1986b). Effects of Nonnicotine Constituents of Tobacco Smoke and Citric Acid Aerosol Chemicals presumed to act primarily in the respiratory tract and not in the central nervous system may also affect smoking. The region of the trachea just below the larynx is assumed to be a site of some cigarette smoke related sensations (Cain 1980). This site corresponds to the region 2 cm below the narrow opening of the larynx where particles entering the trachea change direction (Chan and Schreck 1980). The components of cigarette tar and volatile gases in smoke contribute to the taste, olfactory, and tracheobronchial sensations elicited by cigarette smoke. In fact, minimal levels of tar are held by tobacco manufacturers to be important to maintain product satisfac- tion in smokers (Tobacco Reporter 1985; Gori 1980). Besides its causal role in lung cancer and other diseases (US DHHS 1982, 1983, 1984), tar may function to mask the harshness and irritation of nicotine (Herskovic, Rose, Jarvik 1986). Consistent with this hypoth- esis, nicotine aerosols delivering doses of nicotine similar to those in mainstream cigarette smoke are rated as extremely harsh and irritating by cigaret,te smokers (Russell 1986). Similarly, some gaseous components of smoke, such as acrolein and formaldehyde, are irritating and could also contribute to the tracheobronchial sensations elicited by smoke (Lundberg et al. 1983). Levels of tar and other constituents may also contribute to brand preference and, conversely, to the difficulty in finding readily acceptable substitutes for the cigarettes normally smoked by individ- uals. For example, a nonmentholated cigarette may not be a desirable substitute for a mentholated one. Moreover, when given cigarettes made of lettuce or cocoa leaves, smokers complain about the unpleasant smell and taste (Goldfarb, Jarvik, Glick 1970; Herskovic, Rose, Jarvik 1986). Tobacco research cigarettes are often 168 found to be less palatable than commercial brands (Benowitz, Kuyt, Jacob 1982), indicating the importance of specific tobacco blends and/or additives in determining taste and brand preferences. The precise nature of the sensations critical to smoking satisfac- tion has not been elucidated, and the relative roles of taste, olfaction, and tracheobronchial sensations are not clear. One way to assess the importance of local respiratory sensations in the subjective response to cigarette smoke is to block these sensations with a short-acting topical anesthetic. Two studies have used inhalation of a 4-percent lidocaine aerosol and mouth rinses and gargling with lidocaine solutions to assess the importance of airway sensations to cigarette smokers (Rose et al. 1984, 1985). In both studies, the desirability of puffs was decreased by local anesthesia of the respiratory tract. Additionally, the decline in reported craving for cigarettes that usually occurs after smoking was diminished by local anesthesia. A study was also conducted in which smokers inhaled a refined tobacco smoke condensate (Rose and Behm, in press). The condensate produced a low overall nicotine yield (about 0.2 mg,`lO puffs), while maintaining a higher ratio of nicotine to tar and a larger particle size than that of conventional cigarette smoke. Smoke generated in this fashion was rated as stronger and harsher than smoke of equivalent nicotine content delivered by smoking a conventional low-tar and low-nicotine cigarette (Rose and Behm 1987). The subjects also reported significantly greater satisfaction and dimin- ished desire to smoke additional cigarettes after inhaling puffs of refined smoke compared with conventional low-nicotine cigarette smoke (Rose and Behm 1987). These studies demonstrate that local sensory effects of smoke may influence the short-term subjective responses to smoking. The inhalation of aerosols containing citric acid is a standard method of eliciting coughing in human subjects (Pounsford and Saunders 1985). One study found that smokers inhaling puffs of a nebulized 15 percent aqueous solution of citric acid reported sensations of strength and harshness comparable to those produced by their own cigarette brand and considerably stronger than those elicited by an "ultra" low-tar, low-nicotine cigarette (Rose and Hickman 1987). Moreover, some pleasure was reported to be associated with these sensations, and desire for cigarettes was decreased, suggesting that mild irritation of the respiratory airways may be involved in satiation of smoking behavior and may have a role in smoking cessation efforts (Henningfield 1987c; Chapter VII). Nicotine: Psychoactivity, ReinforcIng and Related Behavioral Mechanisms of Nicotine Dependence As the preceding sections have shown, cigarette smoking is an orderly behavioral and pharmacologic process clearly involving 169 maintenance of the desired levels of nicotine in the body. These data are sufficient to label tobacco use as a form of drug self-administra- tion in which the role of nicotine in controlling tobacco self- administration functions as do morphine, ethanol, and cocaine in the use of opium-derived products, alcoholic beverages, and coca-derived products, respectively. However, the question may be asked whether the behavior-controlling pharmacologic properties of nicotine are similar to those of prototypic dependence-producing drugs when evaluated in standard laboratory tests. More specifically, the scien- tific question is whether nicotine itself shares critical dependence- producing properties with drugs such as morphine, cocaine, and alcohol. Standardized testing procedures can be used in both animal and human studies to objectively determine if a drug is dependence producing. These procedures, as well as a review of how addicting drugs control behavior, is presented in Chapter V. Chapter V also presents data obtained when drugs such as morphine, cocaine, and alcohol are tested by identical procedures. In brief, four general kinds of behavior-modifying drug effects can be differentiated on the basis of the test procedure used. These drug effects are discussed in Chapter V and include the following: (1) Drugs may produce interoceptive stimulus effects; that is, they can produce effects that a person or animal can distinguish from the nondrug state. Although not identical in meaning, the following terms are often used to designate interoceptive drug effects: "psy- choactive, " "discriminative," "subjective," "self-reported." (2) Drugs may serve as positive reinforcers or rewards, the presentation of which produces repetition and strengthening of the behaviors which led to their presentation, i.e., "drug self-administration" or "drug seeking." (3) Drugs can serve as unconditioned stimuli, in which case they may directly elicit various responses; these responses may subsequently be elicited by stimuli which are associated with the drug (i.e., conditioned stimuli), including the presence of environ- mental, or even internal, cues. (4) Drug administration or abstinence can also function as "punishers" or aversive stimuli. This Section will present data from studies of nicotine with each of the four testing procedures mentioned above. The convergence of findings from several distinct approaches provides compelling evi- dence that nicotine is a drug that can effectively control behavior, including behavior leading to its own ingestion (i.e., dependence or addiction). Interoceptive, Discriminative, and Subjective Effects of Nicotine Ingested chemicals can serve as stimuli by actions on either peripheral or centrally located receptors or by indirect effects mediated through the release of various biochemicals or neurohor- 170 mones. In general, the term "psychoactive" is reserved for those drugs whose discriminative effects are known to result from their actions in the brain. As described by Lewin (1931) and others (Thompson and Unna 1977) it is, in part, the nature of the discriminative stimulus effects of a drug within the body that sets the dependence-producing drugs apart from other non-nutritive substances. As shown in Chapter II, all commonly used forms of tobacco are effective means of delivering nicotine to the blood from which it is rapidly transported to the brain. Research with animals has shown that nicotine produces distinct effects in the central nervous system (CNS). In addition, nicotine has diverse peripheral and hormonal actions that could serve to intensify its CNS stimulus properties. The biochemical mechanisms of these effects are discuss- ed in Chapter III. Three procedurally distinct methods have been used to character- ize the stimulus properties of nicotine and will be discussed in the following sequence: (1) discrimination testing in animals and hu- mans, (2) assessing subjective effects in humans, and (3) testing for state-dependent learning effects in humans. Each method has been used to help characterize the stimulus properties of a variety of drugs including nicotine (Chapter V). Drug Discrimination Testing in Animals Animal studies of nicotine discrimination show that nicotine produces reliable effects that are readily identified by the subjects. Such studies indicate that fundamental biobehavioral mechanisms mediate the psychoactive properties of nicotine in humans, and that such effects are not unique to human psychological processes. These data also have implications for understanding and treating tobacco dependence and are summarized below. Specificity of the Nicotine Stimulus Although dependence-producing drugs may overlap, to some degree, in the nature of their effects on mood and feeling, each drug class and sometimes drugs within *a class produce unique effects. As this Section shows, nicotine also produces some effects that permit it to be distinguished from most other psychoactive drugs. These studies are also useful for testing new drugs that are thought to produce nicotine-like effects. Rats can learn to accurately discriminate nicotine from placebo regardless of the route of administration as long as the nicotine reaches the brain. Most researchers have utilized the subcutaneous (s.c.) route of administration iRosecrans and Meltzer 1981); however, more recent studies have incorporated other routes of nicotine administration and have found that rats could learn to discriminate 171 nicotine when given nicotine by gavage (oral tube) in a dose of 0.5 mg/kg (Howard and Craft 1987). Oral nicotine-trained rats general- ized to nicotine administered via either the S.C. or transdermal routes (nicotine solution was applied to a 1.5cm circular area on the shaved back of the rat). There was little difference in dose potency between the oral and S.C. routes; however, the transdermal route was much less potent and required eight times the oral dose to establish equivalent response patterns. Taken together, the results of these studies showed that nicotine given by a variety of routes produces time- and dose-related discriminative effects. Several studies have compared nicotine with a variety of drugs by these drug discrimination testing procedures (Rosecrans and Meltzer 1981; Stolerman et al. 1987). Early research involved testing a wide variety of chemicals. These studies showed that nicotine-trained rats did not generalize to drugs of other classes such as the opioids, barbiturates, or hallucinogens (Rosecrans and Meltzer 1981). Of special interest was the prototypical stimulant d-amphetamine, because nicotine also has a variety of stimulant-like actions (Rall 1985). When nicotine-trained rats were tested with amphetamine, however, they only partially generalized to nicotine. In another study, Schechter (1981) observed higher levels of amphetamine generalization to nicotine in a group of rats trained to discriminate amphetamine from pentobarbital. Thus, nicotine may have some amphetamine-like effects which are unmasked under certain condi- tions. Oxotremorine and arecoline are agonists of the cholinergic ner- vous system, but these drugs activate muscarinic, and not nicotinic, cholinergic receptors (Gilman et al. 1985). Consistent with the mechanisms of action of these cholinergic drugs are the findings that neither oxotremorine nor arecoline generalized to nicotine in nicotine-trained animals (Rosecrans and Meltzer 1981). Nicotine analogs and metabolites have also been studied with the discrimination paradigm (Rosecrans and Chance 1977; Stolerman et al. 1987). Such research can help reveal the extent, if any, of the role of these nicotine-related or nicotine-derived chemicals in determin- ing the nature of the discriminative effects that follow nicotine administration. In rats trained to discriminate 100 pgf kg of nicotine, the analogs cytisine and anabasine generalized to nicotine. The alkaloid nornicotine generalized partially to nicotine. Cotinine, the major metabolite of nicotine, was observed to generalize to nicotine only when the cotinine was given intraventricularly in relatively high doses to rats trained to discriminate relatively low dose levels (100 pg/kg) of nicotine. These data show that although metabolites of nicotine may share some stimulus properties with nicotine, the degree of generalization is weak, suggesting that the discriminative 172 stimulus effects of nicotine are mainly due to nicotine itself and not to the metabolites. Synthetic analogs of nicotine have also been evaluated for their possible nicotine-like properties in discrimination studies (Rose- crans, Kallman, Glennon 1978; Rosecrans et al. 1978). Of the several compounds tested, only one, 3-methyl-pyridylpyrollidine, a chemical isomer of nicotine, was observed to generalize to the nicotine stimulus in nicotine-trained rats. This compound was observed to be 8 to 10 times less potent than nicotine. Its effects were significantly antagonized (reduced or blocked) by mecamylamine, which also antagonizes the stimulus generated by both S- and R-nicotine; the naturally occurring tobacco constituent, S-nicotine, is also 8 to 10 times more potent as a stimulus than R-nicotine. The results of these investigations indicate that the stimulus properties of nicotine are highly specific. A finding relevant to pharmacologic treatment efforts (see Chap- ter VII) involved discrimination studies with lobeline (a constituent in several over-the-counter aids for quitting smoking). Lobeline is an alkaloid with some nicotine-like ganglionic effects in the peripheral nervous system (Gilman et al. 1985). Rosecrans and Chance (1977) found that lobeline was neither discriminated as nicotine nor did it block nicotine discrimination in nicotine-trained rats. These results do not support the use of lobeline-containing compounds as treat- ment aids for cigarette smoking (see also Schwartz 1987; Chapter VII). Peripheral Versus Central Discriminative Stimulus Effects of Nicotine The degree to which the stimulus is generated via peripheral rather than central nervous system (CNS or brain) actions is also important in understanding the nature of the nicotine stimulus. As discussed in Chapter III, nicotine has many peripheral autonomic nervous system CANS) effects which might feed back to the CNS, thereby indirectly generating or contributing to stimulus effects. Thus, changes in blood pressure, heart rate, body temperature, and hormone release could be potential mediators of the effects. Several approaches have been utilized to address the role of peripheral actions of nicotine in the generation of the discriminative stimulus. One approach is to attempt to block nicotine with an antagonist not able to enter the CNS. In one study, animals were trained to discriminate a dose of nicotine (Rosecrans and Chance 19771. Then they were pretreated with a series of nicotinic cholinergic antagonists and with muscarin- ic cholinergic antagonists. After pretreatment with an antagonist, the animals were retested with the training dose of nicotine. Mecamylamine, a centrally and peripherally acting nicotine antago- 173 nist, was the only drug observed to completely block the nicotine stimulus. As the dose of this antagonist was increased, percent correct responses on the nicotine-correct lever, after the injection of 200 or 400 pg/kg of nicotine, decreased to placebo response levels, indicating a complete antagonism of the nicotine stimulus. In a similar study, Stolerman, Pratt, and Garcha (1982) increased the nicotine dose in an attempt to overcome the actions of mecamyla- mine: the blockade was not overcome by any dose of nicotine. Thus, these data suggest that mecamylamine is not a competitive antago- nist (blocking at the receptor itself) but rather may functionally antagonize nicotine's effects through another mechanism (Stolerman et al. 1987). In other studies, a 331 ug/kg dose of mecamylamine antagonized the stimulus effects of 200 pg/kg of nicotine, while 835 ug/kg was required for similar antagonism of the 400 ug/kg dose of nicotine (Rosecrans and Meltzer 1981). All such studies found that the peripherally acting nicotinic antagonist, hexamethonium, did not affect nicotine discriminations. The muscarinic antagonist, atropine, was also without effect. The possible relationships of the nicotine stimulus to brain norepinephrine and 5-hydroxytryptamine (seroto- nin or 5-HT) systems were also investigated through the use of the appropriate antagonists/agonists. Similarly, a quaternary analog of nicotine, which does not enter the brain, was evaluated and found to produce no evidence of generalization in nicotine-trained rats (Rosecrans et al. 1978). Such studies do not support the involvement of peripheral systems in the generation of the nicotine stimulus. Another strategy used to investigate the central nature of the nicotine stimulus compared concentrations of nicotine in the brain with the resulting stimulus effects of nicotine (Rosecrans and Chance 1977). It was assumed that if nicotine's stimulus effects are mediated in the brain, then such effects should be related to brain levels of nicotine. This hypothesis was confirmed. In fact, it was found that before nicotine functions as a stimulus, it must achieve a minimal drug level in the brain. In addition to relating drug level in the brain to the stimulus effect induced by nicotine, Rosecrans and Chance (1977) showed that systemically administered :lico%ine generalized to nicotine administered intraventricularly. Taken together, the fore- going studies show that the nicotine-generated discriminative stimu- lus is dependent on the actions of nicotine at central nicotine receptors in the brain. Drug discrimination research has also examined the stimulus properties of the muscarinic cholinergic agonist, arecoline. Arecoline is a constituent of the betel nut mixtures commonly chewed in the East Indies (Taylor 1985al. Three approaches have been utilized to investigate the stimulus properties of arecoline. In the first study, arecoline served as a discriminative stimulus and thereby assumed 174 control of behavior (Rosecrans and Meltzer 19811. These effects of arecoline were blocked by pretreatment with the muscarinic antago- nist, atropine, while the quaternary compound, methyl atropine (which does not readily cross the blood-brain barrier), was ineffec- tive. These results indicate that the stimulus can also be exerted via muscarinic stimulation and confirm that the discriminative stimulus properties of muscarinic agonists. like those of nicotinic agonists, are centrally mediated. Additional studies indicated that mecamylamine was not able to antagonize the stimulus effects of arecoline (Rose- crans and Meltzer 1981). Finally, it was found ihat rats could be trained to discriminate between the muscarinic and nicotinic agonists, arecoline and nicotine. Thus, there appear to be two independent central cholinergic recept,or systems (muscarinic and nicotinic), each of which can exert stimulus control over behavior when appropriately stimulated. These findings have been confirmed by Stolerman and colleagues (1987). Interactions with Noncholinergic Neurons In a preliminary study (Takada et al., 1988) two nic;)tine-trained squirrel monkeys recognized beta-carboline as nicotine. Beta-carbo- line induces symptoms resembling anxiety in animals; these symp- toms can be reduced by administration of the anxiolytic, diazepam (Shephard 1986). In addition to this observation, Colpaert (19771 reported that nicotine can antagonize the diazepam cue, and Heath, Porter, and Rosecrans (1985) noted that nicotine antagonized the effects of diazepam on punished responding in rats. Mecamylamine was also found to attenuate the nicotine-induced antagonism of diazepam's antianxiety effect. Harris and coworkers (1986) found that metrazol (a convulsant) partially generalized (35 percent) to nicotine when tested in the discrimination paradigm in nicotine- trained animals. A greater degree of generalization of the metrazol cue to nicotine (50 percent) was observed 48 hr after the cessation of a 21-day chronic nicotine regimen in rats trained to discriminate metrazol (5 mg/kg) from saline; these generalizations were not antagonized by mecamylamine. Harris and colleagues (1986) suggest- ed that the generalization of metrazol to nicotine was a function of a nicotine abstinence-induced withdrawal syndrome resembling anxie- ty. These studies suggest that nicotine may act, at central receptors capable of eliciting a stimulus cluster which induces anxiety (Chapter III). Subjective Effects of Nicotine in Humans The extensive amount of nicotine discrimination research using a variety of animal species and several routes of administration confirms that nicotine is a potent drug that can induce alterations in 175 nervous system function that are distinct and readily identifiable. In addition, the similar findings observed in studies using different routes of nicotine administration are consistent with the hypothesis that the tobacco vehicle is not necessary to produce nicotine-associ- ated changes of mood and feeling. The next Section examines data from analogous studies in which humans served as research subjects. Psychoactivity of Nicotine The animal research described above indicates that nicotine's psychoactivity is a result of basic biological actions. Human research on nicotine corroborates the validity of the animal research. Results from studies of the interoceptive effects of nicotine in humans are analogous to those obtained in animal studies described above. One of the first human studies that used drug discrimination procedures, as had been developed with animal subjects, was a study of nicotine discrimination. The study involved the systematic manipulation of nicotine dose levels with research cigarettes which varied primarily in the amount of nicotine delivered (Kallman et al. 1982). This study demonstrated that nicotine, as delivered by the inhalation of tobacco smoke, produces discriminative stimulus effects. The degree and rate of acquisition of the discrimination appeared to be dose dependent. The ability of the subjects to make the discriminations did not appear to be related to either autonomic (e.g., heart rate) effects of nicotine or to nicotine's effects on other self-reported measures (e.g., taste of the cigarette). The data from Kallman and associates (1982) are consistent with those of several other studies which have found that human volunteers can differentiate among cigarettes which vary mainly in the amount of nicotine which they deliver (Goldfarb, Jarvik, Glick 1970; Goldfarb et al. 19'76; Herskovic, Rose, Jarvik 1986; Rose 1984; Griffiths, Bigelow, Henningfield 1980; Henningfield, Miyasato, John- son, Jasinski 1985). Furthermore, the conclusion that centrally mediated effects of nicotine are important in such responsivity is supported by findings that pretreatment with mecamylamine re- duced responsivity to nicotine dose levels of the cigarette (Stolerman et al. 1973; Nemeth-Coslett et al. 1986a; Pomerleau et al. 1987). The study by Stolerman and associates (1973) also showed that such antagonism of nicotine's effects was not obtained when peripherally acting pentolinium was given. Other research has confirmed that the tobacco vehicle is not necessary to enable the interoceptive effects of nicotine. Several studies involving i.v. administration of nicotine in human subjects have found that humans readily differentiate among nicotine dose levels given intravenously. In the earliest of these studies, i.v. injections of nicotine were given to 35 volunteers, most of whom were cigarette smokers (Johnston 1942). The conclusions of Johnston 176 TABLE 3.-Summary of early observations regarding psychoactivity of intravenously delivered nicotine in humans 1. "Psychic" effects are directly related to nicotine dose; nonsmokers are much more sensitive to toxic symptoms ieg., nausea) than smokers 2. Effect of nicotine is "specific and readily distinguished from that of cocaine or codeine"' 3. Nicotine injections are "pleasant" to smokers, and are preferred by some over cigarette smoking 4. Orally given nicotine (dissolved in water) also had "psychic" action. but appeared much less potent than intravenously administered nicotine: delayed onset of effect 5. - l-3 mg doses appeared tolerable and equivalent to smoking single cigarette; - 0.11 mg doses appeared to produce "subjective sensation" equivalent to one "deep" cigarette smoke inhalation `More recent research indm&s that higher dose levels of mcotine can produce cocainelike effects (Henning&Id. Miyasato. Jasinski 1985). SOURCE: Johnston (1942). that are especially relevant to characterization of the psychoactivity of nicotine are shown in Table 3. Johnston's findings (Table 3) have been generally confirmed. Jones, Farrell, and Herning (1978) and Rosenberg and colleagues (1980) also found that human volunteers could differentiate i.v. nicotine at dose levels similar to those obtained by smoking cigarettes. In another study which extended the findings of Johnston (1942), both i.v. nicotine and nicotine inhaled from research ciga- rettes across a range of doses were administered to human volun- teers with histories of using a variety of dependence-producing drugs (Henningfield, Miyasato, Jasinski 1985). Subjects clearly distin- guished nicotine from a placebo, and the dose strength estimates were directly related to the nicotine dose level. A subsequent study showed that the immediate subjective effects of nicotine were diminished by pretreatment of subjects with mecamylamine (Hen- ningfield et al. 1983). In a study by Henningfield, Miyasato, Jasinski (1985), measures used to qualitatively describe the nature of the drug stimulus indicated that nicotine met criteria as a euphoriant. At higher doses nicotine was sometimes identified as a stimulant (cocaine or amphetamine); it elevated scores on the Morphine Benzedrine Group ("Euphoria" or "MBG") scale of the Addiction Research Center Inventory (ARCI) (Haertzen and Hickey 1987); and it produced dose- related increases in scores on a drug-liking scale. The high-dose cocaine/amphetamine identifications found in the study by Hen- ningfield, Miyasato, and Jasinski (1985) were not observed by 177 Johnston, but such similarities between nicotine and cocaine may only be clearly identifiable by subjects experienced with both cocaine and nicotine. Nicotine given in the polacrilex gum form has been evaluated with similar measures as described above. These studies involved giving various combinations of 2-mg- and 4-mg-nicotine pieces of polacrilex gum and placebo to cigarette smokers. Human volunteers were given the polacrilex gum to chew in doses ranging from 0 to 4 mg in one study [~Nemeth-Coslett and Henningfield 1986) and 0 to 8 mg in another study (Nemeth-Coslett et al. 1987). Both studies showed that subject ratings of several effects (including "dose strength") were directly related to the total dose of nicotine that was given. In addition, similarity of the stimulus effects to those produced by cigarettes was a direct function of dose level. In these studies "liking" or "positive" effect scores were inversely related to dose level, suggesting that this nicotine delivery system has low potential for causing dependence when compared with that of cigarettes (Chapter VII). The role of centrally mediated nicotinic actions in the ability of humans to differentiate among polacrilex gum-delivered nicotine doses was confirmed in a study by Pickworth, Herning, and Henningfield (in press). These researchers found that mecamyla- mine pretreatment of human volunteers reduced both the EEG and subjective effects of nicotine polacrilex gum administration. Like many other psychoactive drugs (Chapter V), nicotine can also produce unpleasant or dysphoric subjective effects that are related to the dose given and the route of administration. Such effects can be quantified by a psychological scale of the ARCI that is sometimes referred to as the "dysphoria" scale (Jasinski, Johnson, Henningfield 1984) or the "LSD" scale because ii: was constructed from items found to be elevated when lysergic acid diethylamide (LSD) was given to volunteers (Haertzen 1966, 1974). In one study, Henningfield, Miyasato, and Jasinski (1985) found that both inhaled (research cigarette smoke) and i.v. nicotine produced dose-related increases in LSD scale scores. In two other studies, nicotine polacrilex gum was tested (Nemeth-Coslett and Henningfield 1986; Nemeth-Coslett et al. 1987). LSD scale scores were at least slightly increased in both studies and were significantly increased in the study by Nemeth-Coslett and Henningfield (1986). These results with nicotine polacrilex gum, combined with no increases in MBG scale scores, are consistent with the observations described earlier suggesting a low overall dependence potential for this formulation. Sensory Effects of Nicotine As discussed earlier in this Chapter, nonnicotine constituents of tobacco smoke can produce functional sensory effects. Nicotine, too, 178 can produce peripherally mediated sensory effects which could contribute to the taste of the cigarette. Although not generally termed "psychoactive" drug effects, such effects could contribute to the control over behavior as they provide discrete cues which may be associated with centrally mediated nicotinic effects. For example, nicotine has a bitter taste, elicits burning sensations when placed on the tongue, and is irritating to the oral and respiratory mucosa (Windholz et al. 1976). Increasing the nicotine delivery of cigarettes while holding tar delivery constant leads to an increase in perceived strength and harshness. The possible effects of nicotine in the upper respiratory tract on subject ratings cannot be excluded in these studies. Nicotine also stimulates mechanoreceptors sensitive to pressure and stretch (Taylor 1985b), and this local action of nicotine may also contribute to the sensory characteristics of inhaled cigarette smoke. Hexamethonium (the nicotine receptor antagonist that only acts peripherally) has been shown to block cigarette smoke-induced edema in the tracheobronchial mucosa of rats (Lundberg, Saria, Martling 1982). Another study showed that mecamylamine produced dose-related decreases in harshness ratings of individual puffs of cigarette smoke (Rose, Sampson, Henningfield 1985). In this study, subjects were asked to rate their preference at different nicotine concentrations of the smoke: mecamylamine pretreatment shifted preferences to higher smoke concentrations for individual puffs. Another method of producing at least some of the nicotine-related sensations of cigarette smoke is to present nicotine in vapor or aerosol form without any components of tar. Nicotine vapor is likely to be deposited mainly in the mouth and pharynx (Russell 1986); thus it. would be difficult to administer a pharmacologically effective dose of nicotine without producing excessive local irritation and bad taste. However, a low dose of nicotine delivered in this fashion might simulate the sensory effects of smoking, even if the pharmacologic effects are minimal. A low-dose nicotine aerosol delivering droplets 1 to 5 pm in size would be expected to provide respiratory sensations even more similar to cigarette smoking, as particles of this size would impact mainly in the tracheobronchial region. Three studies have evaluated the effects of a commercially marketed nicotine vapor delivery system in human subjects. The delivery system was a version of that originally described by Jacobson, Jacobson, and Ray (1979); it was marketed as a "tobacco product" through February 1987, when the Food and Drug Adminis- tration (FDA) required verification of "safety and efficacy" for continued marketing as a "nicotine delivery system" (see Chapter VII). It consisted of a cigarette-size plastic tube with a nicotine- containing polymer in the end distal from the user's mouth. It was used by sucking air through the tube and inhaling in a manner 179 similar to that when smoking cigarettes. When the system was used in this fashion, two studies found that plasma nicotine levels were not significantly elevated (Sepkovic et al. 1986; Henningfield 1986b). A third study found significant elevations in plasma nicotine following use of the nicotine tube (Russell et al. 1987). However, in the latter study subjects used what may be described as a heroic puffing procedure: they were instructed to puff 1 nicotine tube 10 times, at intervals of 40 set; after a 4-min pause, subjects then "puffed and inhaled as hard and as frequently as possible, continous- ly for the next 20 min, with changes every 5 min to fresh cigarette [nicotine tube]." Symptoms typical of those associated with higher levels of nicotine administration were observed, i.e., dizziness, lightheadedness, and in a few subjects, nausea (Russell et al. 1987). In another study of the nicotine vapor inhaler, four tubes in which none, one, two, or four contained nicotine (the others being denico- tinized) were simultaneously puffed on by volunteers through a specially designed cigarette holder (Henningfield 198613, 1987a). In this study, despite the fact that measurable changes in plasma nicotine levels did not occur, several responses often associated with nicotine delivery were observed: (1) subject ratings of "harshness" were directly related to dose (number of nicotine-containing tubes); (2) post-puffing increases in heart rate occurred as a function of dose; (3) subjective effects were directly related to dose; and (4) desire to smoke tobacco cigarettes was inversely related to nicotine dose level. Taken together, these results show than even with negligible systemic levels, nicotine can induce feelings of satisfaction and can reduce urges to smoke when it produces tobacco-like sensations of throat burn and harshness (Chapter VII). Some of the short-term satisfaction derived from inhaling nicotine may explain the apparent short-term efficacy of the vapor inhaler in reducing desire to smoke despite negligible plasma nicotine levels. This is in contrast to findings obtained when nicotine is given either intravenously or in the polacrilex gum (Henningfield, Miyasato, Jasinski 1983; Nemeth-Coslett et al. 1987). Whether the effects of the nicotine vapor inhaler are conditioned responses, peripheral nicotin- ic actions, or both, it remains to be determined if such effects would provide long-term efficacy as tobacco replacement in the nicotine- dependent tobacco user (Chapter VII). Such effects may not be satisfactory for long-term treatment (i.e., they may not satisfactorily alleviate tobacco withdrawal), although they may prove important in providing sources of pleasure and reduction of urges in people trying to quit smoking (Henningfield 1987b). State-Dependent Learning The potential of nicotine to induce state-dependent learning effects as well as how such effects are studied are discussed in 180 Chapter VI. In the present Section, findings are summarized in so far as they are relevant to assessing the dependence potential of nicotine. In brief, state-dependent learning refers to the phenome- non whereby behavior learned in one set of cues or stimulus conditions (context) is most reliably performed when subsequently attempted in the same context and/or is adversely affected when attempted in a novel context (Chapter VI). Psychoactive drugs can produce state-dependent learning effects, apparently by providing a recognizable context based on the interoceptive stimulus cues provided by the drug (see also Chapter V). Several studies have shown that nicotine exposure can lead to state-dependent learning effects. For example, a series of studies conducted by Andersson and colleagues (Andersson 1975; Andersson and Hockey 1977; Andersson and Post 1974) and by others (Peters and McGee 1982; Warburton et al. 1986) showed that nicotine exposure in the form of tobacco smoke could induce state-dependent learning effects in humans. In a study by Lowe (19851, nicotine's part in the state complex produced by alcohol and nicotine together was also evaluated. There are two implications of the above findings regarding the dependence potential of nicotine. The first is that state-dependent learning could contribute to the dependence potential of cigarettes, in that optimal cognitive/behavioral performance may come to depend upon the continued self-administration of tobacco. These actions might also contribute to the strength of the reinforcing effects of nicotine by producing effects on learning and/or perfor- mance (see also Chapter VI). Nicotine as a Positive Reinforcer The primary biobehavioral mechanism by which dependence-pro- ducing drugs maintain drug seeking is by functioning as positive reinforcers (Thompson and Unna 1977; Thompson and Schuster 1968). That is, drugs can serve as stimuli that strengthen behavior leading to their own presentation (Skinner 1953; Thompson and Schuster 1968). As discussed in Chapter V, studies in the 1960s used the drug self-administration techniques developed to study morphine and other dependence-producing drugs in animals (Weeks 1962; Thompson and Schuster 1964; Chapter V). In the first such study with nicotine, Deneau and Inoki (1967) found that monkeys would also self-administer nicotine intravenously. However, some investi- gators considered these findings equivocal (Russell 1979; Griffiths, Brady, Bradford 19791. In 1981, Goldberg, Spealman, and Goldberg showed conclusively that nicotine itself could function as an efficacious positive reinforcer for animals, although the range of conditions under which it was effective was somewhat more limited than for drugs such as cocaine and amphetamine. Analagous studies with humans in the 1980s (e.g., Henningfield, Miyasato, Jasinski 181 1983) demonstrated that intravenously administered nicotine is a reinforcer. The results leading to the foregoing conclusions are summarized in the present Section. Animal Studies of Nicotine as a Reinforcer Whether a drug functions as a reinforcer can depend critically on the dose of drug, the previous exposure of the subject to that or other drugs, the behavioral history of the subject, and perhaps most importantly, the immediate contingencies relating responses and subsequent injections of drug (contingencies are often referred to as schedules of reinforcement) (Barrett and Witkin 1986; Chapter V). Nicotine differs from some dependence-producing drugs (e.g., co- caine) (Griffiths, Brady, Bradford 1979) in that for animals, the conditions under which it maintains high rates of self-administration behavior appear to be more limited; however, there are other dependence-producing drugs which also serve as reinforcers under a fairly limited range of conditions (e.g., alcohol) (Mello 1973; Meisch 1977). Table 4 (modified from Henningfield and Goldberg 1983b) is a summary of the early studies that found i.v. nicotine injection to be ineffective or marginally effective as a reinforcer as well as more recent studies that conclusively demonstrated the capacity of nicotine to function as a positive reinforcer. The studies listed in this Table employed a variety of species (ranging from rats to human volunteers), different types and parameters of drug injection sched- ules, a variety of training histories, and a wide range of nicotine doses. Much of the research has been reviewed in greater detail elsewhere (Goldberg and Henningfield, 1988; Swedberg, Henning- field, Goldberg, in press). The present Section only reviews some of the more recent studies that have experimentally evaluated nic- otine's reinforcing effects. Until 1981, most experiments of nicotine self-administration involved continuous reinforcement schedules in which each response by an individual subject resulted in the iv. injection of nicotine (Table 4). Under these continuous reinforcement schedules, (1) rates of responding were very low, ranging from about 0.008 to 0.0005 responses/set in different studies; (2) changes in nicotine dose produced only small and inconsistent changes in rates of responding; (3) the differences in rates of responding maintained by nicotine compared with saline were generally small; and (4) marked intersub- ject differences in self-administration of nicotine were often report- ed. In one series of studies (Lang et al. 1977; Singer, Simpson, Lang 1978; Latiff, Smith, Lang 1980; Smith and Lang 1980) a concurrent schedule of periodic deliveries of food pellets to food-deprived rats was found to increase rates of nicotine self-administration respond- ing (Chapter V). The concurrent food reinforcement schedule ap- 182 TABLE 4.-Summary of reports in which nicotine was available under intravenous drug self- administration (S-A) procedures Study Species Reinforcement schedule Main findings Comments Deneau and Inok! Rhesus monkey FR 1; several nicotine doses Two monkeys initiated S-A; Currently accepted reinforcIng 119671 tested others requrcd priming efficacy assessment criteria not procedure achieved Clark Hooded rat FR 1; several nicotine doses and Nicotme a reinforcer relative to No quantitative data (19691 salme tested saline (from study abstract) Yanaglta Rhesus monkey Experiment 1: FR 1; several Nicotme and caffeine not (preliminary report, Yanagita et 119771 mcotine, caffeme, and saline reinforcers, compared with al. (1974) studlesl doses substituted for SPA saline or SPA Experiment 2. FR 1; several Nicotine S-A rates stable in No direct reinlarcmg efficacy mcotme doses continuously most subjects, but not clearly test available dose related Experiment 3: PR procedures; 0.2 my/kg nicotine and lowest Nicotine marginally remforcing two nicotine doses, saline, and cocaine dose (0.03 mg/kg) compared with saline and higher three cocame doses tested maintained similar response cocaine doses rates, which slightly exceeded rates maintained by salme Lang, Latlff, McQueen, Hooded rat FR 1; nicotine and saline tested In food-deprived (not food-sated) Smger in food-sated and food-deprived rata, nicotine a reinforcer. 119771 rats compared with saline -___- Singer. Simpson, Lang Hooded rat CONC ((FR 1:nicotineXF"I' 1 Food satiation decreased nicotine Results similar to ethanol ( 19781 min:food pellet)] in food-deprived S-A rate. but nicotine a testing results rata; rats subsequently food-sated reinforcer in both conditions 6 TABLE 4.-Continued Study Species Reinforcement schedule Main findings Comments Griffiths. Brady. Bradford t19791 Hansen, lvester. Moreton (19791 Raboon Albino rat FR 160 followed bv 3-hr timeout; several nicotine doses and saline substituted for cocaine FR 1: several nicotme doses and saline test-d Number of nicotine injections/day did not exceed saline Mecamylamine (centrally acting antagonist), not pentolinium (peripherally acting antagonist). altered 5.4 behavior Caffeine, rphedrlne. and rar~oub other similarly tested stimulants were reinforcers relative to saline Group data suggest nlcotme as a reinforcer; no clear dose-effect curve Latlff. Smith. Lang (19801 Smith and Lang ,1%401 llooded rat Hooded rat CONC [(FR 1:injectionHFT 1 min:food pellet)]; several nicotine doses and saline tested FR 1; one nicotine dose and salme tested Nicotine a reinforcer, relative to saline; mild effects of urine pH manipulations on S-A rate only during initial nicotine exposure Nicotine a reinforcer with and without CONC food delivery schedule in food-deprived. but not food-sated, rats SA rate mversely dose related during initial nicotine S-A behavior acquisition, not after establishment Goldberg, Spealman. Goldberg 119811 Squirrel monkey Second-order schedule FI 1 or 2 min (FR lfkstimulus). followed by 3.min timeout; one nicotine dose and saline tested Nicotine maintained high rates of respondmg; rates decreased markedly when 11) saline replaced nicotine, 12) brief stimuli omitted, (3) subjects mecamvlamine Dretreated Demonstrated importance of ancillary environmental strmuli in maintaining high rates of responding TABLE I.-Continued Study Species Reinforcement schedule Mam findings Comments Dougherty, Miller, Todd, Kostenbauder 11981) Goldberg and Spealman (1982) Rhesus monkey Squirrel monkey FI 16 and second-order Fl 1 min (FR 4:stimulusl; several nicotine doses and saline tested FI 5 min followed by 1-min timeout: several nicotine and cocaine doses and saline tested Nicotine maintained higher S-A rates than saline under Fl and second-order schedules. but only a marginally effective remforcer when continuously available Nicotine and cocaine qualitatively similar reinforcers, compared with saline; cocaine maintained higher rates of responding in 1 of 2 monkeys: mecamylamine pretreatment reduced nicotine SA rates Establishing nicotine as remforcer required several months. using procedures that estabhsh cocaine or codeine as reinforcers in few days Showed nicotine can be punisher. sinular to electric shock Singer, Wallace, Hall f 1982) Long-Evans rat CONC [(FR 1:nicotineXFT 1 min:fowI pellet)]; one nicotine dose tested Lower nicotine S-A rates in rat group with &OHDA lesions in nucleus accumbens than in sham-lesions group Range of Iwon-Inhibited scheduled-induced behaviors extended Spealman and Goldberg ( 1982) Squirrel monkey Second-order FI 1, 2, or 5 min (FR lOstimulus) and FI 5-min schedules tested; several nicotine and cocaine doses and saline tested Nicotine and cocaine maintained similar rates of respondmg and patterns; nicotine, not cocaine, S-A decreased to saline-like rates when mecamylamine pretreated Under b&h schedules. mcotmr and cocaine reinforcing efficacy comparable TABLE I.-Continued Study Species Reinforcement schedule Main findings Comments Ator and Grlftiths (19831 Baboon Experiment 1: FR 2 followed by 15.sw timeout; several nicotine doses, cocaine, and saline tested Nicotine marginally reinforcing, compared with saline across narrow dose range inverted U-shaped initial doss- response curve; flat final curve (earlier abstract, Ator and Griffiths 11981)1 Experiment 2: FI 5 min followed by 1-min timeout; several nicotine and cocaine doses and saline tested; FI duration varied 1-11 mm Goldberg and Hennmgfvzld (1983a, b) Human and squirrel monkey FR 10 followed by l-min timeout; several nicotine doses and saline tested Nicotine maintamed higher rates of responding than saline, but much lower than cocaine or food Monkey and human patterns of responding qualitatively similar; nicotine injection number exceeded saline injection number in 3 of 4 of both humans and monkevs Nicotine and injections/session responding rates httle changed with varied FI duration In both humans and monkeys, evidence of nicotine having both reinforcing and punishing effects (from study abstracts) Henningfield, Mlyasato, Jasinski (1983) Human FR 10 followed by I-min timeout; several mcotine doses and saline tested Nicotine injection number generally exceeded saline injection number; nicotine injection number inversely related to nicotine dose; nicotine suppressed postsession cigarette smokine Nicotine and intravenous cocaine subjective effects similar; nicotine had both reinforcing effects and punishing effects TABLE 4.-Continued Reinforcement schedule Main findmgs Comments R~sner and Goldberg t lY831 Cox. Goldstein. Nelson (19841 Prada and Goldberg 119851 Slifer and Baister IlYX51 Eieagle dog FR 15 followed by 4.min timeout; several nicolme. cocaine, and salme doses tested: PR schedule also used W1star rat FR 1; several nicotme doses and saline tested; a second inact;vr lever available to assebs nonspecific acti\,ity-incfeasiny nicotine effects __.-__ Squirrel monkey FR 30 followed by 4.mm or lo- set timeout: one nicotme dose tested Rhesus monkey Experiment 1: FR 1 and CON`C [iFR 1:nicotineNlT 5.min:food pellet)]; several nicotine doses and saline tested Nicotme and coca~nr maintamed qualitatively similar patterns "I responding and WWP rrlnforcers relative 1" sahne. mecnmylamine pretreatment reduced nwtiw. not coci~lne. S-A Nicotinv S-A rates higher than salme. but result m part of nonspecific activit) ~nc~wst+ ___-- AL 4.min tImeout. "vwali nicotine-maintained response rate range W-2.4 responses,`sec. at IO-set tlmeout. rrspondina poorly rnainta~nrd -__ At CONC condition, nicotme SPA at rate higher than saline: at FR 1 condition, nicotine S-A without (`ONC food Experiment 2: FR 10; saline and several nicotine doses substituted for cocaine Kicotine a reinforcer relatwe to saline, but response rates Iou relative to single cocaine dose tested TABLE k-continued Study SpfXW Reinforcement schedule Main findings Comments Human and squirrel monkfay Monkeys. FR 10-200. with l-. 2.. or 4.mr timeouts Humans: FR lCL800. with l-, 5., lo-, or 20-min timeouts Nicotine maintained about I.O/sec overall rate of FR responding at high FR and timeout. in both humans and monkeys (from text of talk) Rat FR 1, FR 4, FR 8; several nicotme doses and saline tested Higher nicotine injection doses (10 and 30 pg/kg) maintained responding above saline control levels Nicotine a relatwly weak rwnforcer after IS-da) svailabihty Dr la Garza and Khesus monkeys FR IO; saline and several Nicotine a reinforcer relatw to Johanson nicotme. d-amphetamine, saline, but response rates very Cl9871 dlazepam, and perphenazine low relative to cocaine and d- doses substituted for cocaine amphetamine SOTE FR. !:xrd :a?:~. SPA. !-2 dg+e~y!-1-d ems-thy1 nmlnwthane-tICI. PR. ~rwrrs~ve wtm, Fr, fixed time: FL fixed interval; CONC, concurrent Food deprivatmn sigmficantly mcreascd response rate for low mcotine dose in only 1 of 3 monkeys peared to hasten acquisition of the nicotine self-administration (Smith and Lang 1980). Since 1981, methodology for studying the reinforcing effects of nicotine has shifted away from continuous reinforcement schedules and toward schedules of self-administration in which responses are only intermittently reinforced by nicotine injection (Goldberg et al. 1983). Such intermittent schedules appear to more closely approxi- mate the patterns of human cigarette smoking behavior in which nicotine is taken in intermittent small doses (puffs) and with even greater intervals between dosing resulting from periods of time between cigarettes (Henningfield 1984). On a variety of intermittent schedules, i.v. nicotine was shown to function as an effective reinforcer, maintaining overall rates of responding ranging from 0.1 to more than 1 response/set (Table 4). These increases in behavioral responses maintained by nicotine were obtained without the use of food deprivation or concurrent inducing schedules of food delivery. In one series of experiments with squirrel monkeys, Goldberg and Spealman (1982) and Spealman and Goldberg (1982) utilized a fixed- interval schedule in which the first response to occur after a 5-min interval elapsed produced an i.v. injection of nicotine followed by a l- min period of drug nonavailability ("timeout"). Responses during the 5-min intervals had no specified conseqtiences, and daily sessions ended after 10 intervals or 2 hr. Under these conditions, nicotine functioned as an effective reinforcer: (1) peak rates of responding maintained by nicotine ranged from 0.1 to 0.3 response/set and were similar to those maintained by cocaine; (2) as nicotine dose per injection was increased from 3 to 300 mg/kg, rates of responding first increased and then decreased; (3) rates of responding maintained by nicotine were about fourfold to eightfold higher than those main- tained during saline substitution; and (4) daily intramuscular treatment with 1 mg/kg of mecamylamine reduced rates of respond- ing maintained by nicotine to saline-control levels but had no effect on responding maintained by cocaine. Thus, nicotine satisfied all the criteria discussed in Chapter V as an effective reinforcer. Particular- ly striking was the finding that although injection doses of nicotine above 30 mg/kg produced vomiting during the session, one or more of these higher doses continued to be maintained near maximal rates of responding in four of the six monkeys studied. The results of Goldberg, Spealman, and Goldberg (1981) showing nicotine to be an effective reinforcer have been extended in subsequent studies. For example, high rates of responding were maintained on reinforcement schedules of nicotine injection in which the number of responses per injection was fixed at some intermediate level (e.g., 1 injection/l5 responses; such contingencies are termed fixed-ratio schedules). Risner and Goldberg (1983) used a 15-response fixed-ratio schedule of nicotine injection with 4-min 189 timeout periods following each injection in beagle dogs. Nicotine was an effective reinforcer in all dogs: (1) peak rates of responding were about 0.3 response/set, but higher rates of responding were main- tained by cocaine; (21 as the injection dose of nicotine increased from 10 to 100 mg/kg, response rates first increased and then decreased at the highest dose; (3) peak rates of responding maintained by nicotine were about fifteenfold greater than those maintained by saline; and (4) rates of responding maintained by nicotine but not by cocaine were reduced to saline levels by presession treatment with mecamy- lamine. Although cocaine maintained higher rates of responding than nicotine in the dog, fixed-ratio patterns of responding main- t.ained by nicotine and cocaine were similar: a pause in responding at the start of each fixed ratio was followed by a change to steady responding at a high rate until nicotine or cocaine was injected. In other studies Goldberg and Henningfield (1983a,b, 1986) used lo- to 30-response fixed-ratio schedules of i.v. nicotine injection in squirrel monkeys. When a l-min timeout followed each injection, nicotine maintained rates of responding higher than did saline, although overall rates of responding were very low. When the timeout value was increased to 4 min (Prada and Goldberg 1985; Goldberg and Henningfield 1986) making maximum frequency of nicotine injection comparable to that of earlier studies by Goldberg and colleagues, nicotine maintained high rates of responding that ranged from 0.3 to 2.4 responses/set in different monkeys. Differences between nicotine and cocaine in their overall efficacy as intravenously delivered reinforcers have been found when the drugs are compared on progressive-ratio schedules. Risner and Goldberg (1983) studied beagles under a schedule in which the fixed- ratio requirement was increased daily until responding was no longer maintained. Cocaine maintained higher fixed-ratio values than did nicotine on this progressive-ratio schedule, although maximal fixed-ratio values for nicotine were well above those for saline. Yanagita (1977) obtained similar findings on a progressive- ratio schedule of i.v. nicotine or cocaine injection in rhesus monkeys (Chapter V). Nicotine was also studied in the baboon using an intermittent schedule of reinforcement and was found to be a weak reinforcer. Ator and Griffiths (1983) used a 5-min fixed-interval schedule of i.v. nicotine injection in baboons with 1-min timeout periods. Peak rates of responding were higher than rates maintained during saline substitution. However, rates of responding maintained by nicotine were much lower than those maintained by i.v. injection of cocaine. In addition, as the injection dose of nicotine was increased from 10 to 560 mg/kg, rates of responding first increased and then decreased at the highest doses in one baboon. With the other two baboons, rates of responding either showed little change or decreased as injection dose 190 was increased. These variable dose-response data were consistent with the conclusion that nicotine was only a weak reinforcer in the baboons. When cigarettes are smoked, a variety of environmental stimuli are intermittently associated with the pharmacologic actions of nicotine (e.g., pleasure and relief from withdrawal). These stimuli themselves appear important in controlling and strengthening repetitive cigarette smoking (e.g., removal of the sight and smell of cigarette smoking) (Gritz 1978). An experimental model for investi- gating the role of drug-associated stimuli is the second-order schedule of drug reinforcement. Second-order schedules of reinforce- ment involve the intermittent pairing or association of an environ- mental stimulus with the primary reinforcer; these stimuli are used as "secondary" or "conditioned" reinforcers to maintain chains of behavior leading eventually to the delivery of the primary reinforcer (Goldberg, Kelleher, Morse 1975; Katz and Goldberg, in press). These schedules add an additional component of relevance to the st,udy of cigarette smoking: cigarette smoking involves the pairing of many such environmental stimuli (visual, olfactory, tast.e, and tactile) with the effects of nicotine administration. Studies of i.v. nicotine on second-order schedules of reinforcement have shown that (1) nicotine can establish previously neutral stimuli (e.g., colored lights) as conditioned reinforcers when injections are paired with light presentations, (2) such schedules can result in high and persistent rates of drug-seeking behavior, and (3) the presenta- tion of the stimuli themselves (in the absence of nicotine injections) could sustain substantial amounts of drug-seeking behavior. Gold- berg, Spealman, and Goldberg (1981) and Spealman and Goldberg (1982) used a second-order schedule of nicotine injection in which completion of each lo-response fixed ratio during a 2-, 3-, or 5-min interval produced a brief visual stimulus; the first fixed ratio completed after the specified fixed interval elapsed produced both the visual stimulus and iv. injection of drug. In these studies, nicotine functioned as a powerful reinforcer: (1) peak rates of responding maintained by nicotine ranged from 0.8 to 1.7 respons- es/set and were similar to those maintained by cocaine; (2) as nicotine dose increased from 3 to 100 mg/kg, rates of responding first increased and then decreased; (3) rates of responding maintained by nicotine were twofold to eightfold greater than those maintained during saline substitution; and (4) rates of responding maintained by nicotine, but not by cocaine, were reduced to saline control levels by presession administration of 1 mg/kg of mecamylamine; (5) the brief visual stimuli functioned as conditioned reinforcers, as demonstrated by the finding that rates of responding fell markedly when they were omitted during the intervals. 191 Taken together, the results of the studies described in this Section confirm that nicotine is self-administered in several animal species and in the absence of either tobacco or unique human cultural factors. It appears t.o be most effective as a reinforcer when intermittently available and when environmental stimuli are paired with nicotine delivery. Under these conditions, nicotine injections functioned to motivate behavior as did cocaine injections; however, cocaine injections maintained more total work output than did nicotine. Finally, studies with nicotine antagonists further con- firmed that effects of nicotine in the brain were necessary to maintain its reinforcing actions. Human Studies of Nicotine as a Reinforcer The methods developed in animal studies have also been used to demonstrate the reinforcing effects of i.v. nicotine injections in human volunteers (Henningfield, Miyasato, Jasinski 1983; Henning- field and Goldberg 1983a; Goldberg and Henningfield 1983a,b, 19861. In these studies all subjects had histories of tobacco use and subjects were not allowed to smoke 1 hr before or during 3-hr sessions: During test sessions every 10th lever press produced an i.v. injection of either nicotine or saline followed by a 1-min timeout. In one study (Henningfield, Miyasato, Jasinski 19831, nicotine was available on some days, while saline was available on other days. In other studies (Henningfield and Goldberg 1983a; Goldberg and Henningfield 1983a,b), nicotine and saline were concurrently available for re- sponding on alternate levers. With both approaches, all of the subjects initiated self-administration of nicotine. Nicotine injections were regularly spaced throughout each session, and the rate of self- administration was inversely related to dose. When saline was substituted for nicotine, rates of responding usually decreased; responding that did occur for saline occurred predominantly at the start of each session and was erratic in temporal patterns. In another study, the fixed-ratio value was then increased to 100; following each injection, subjects then had to wait 20 min before another injection could be obtained (Swedberg, Henningfield, Gold- berg, in press). Under these conditions rates of responding increased and ranged from 0.4 to 2 responses/set, similar to those seen with squirrel monkeys and dogs in the studies previously described. These studies of i.v. nicotine self-administration demonstrated conclusively that nicotine itself can serve as an effective reinforcer in humans. Nicotine as an Aversive Stimulus Even dependence-producing drugs do not have invariant positive reinforcing effects; they may be aversive under some conditions (see Chapter V). Furthermore, aversive effects are an additional mechan- 192 ism by which drugs can modify behavior and may be important in gradually increasing the total amount of control which is exerted by the drug over the individual. Such effects of nicotine could be important in limiting the total amount of cigarett,e smoking or even in determining when the cigarette is discarded. The potential effects of nicotine to produce severe discomfort and thereby limit further intake have been part of the history of nicotine which has developed over the centuries (Lewin 1931: Dixon and Lee 1912). Two types of laboratory studies have been conducted to assess possible aversive effects of nicotine. The studies, involving animals and/or humans, showed that nicotine (at high levels) can serve as a punisher to suppress behavior leading to the delivery of another reinforcer, and as an aversive stimulus or negative reinforcer to maintain behavior that either terminates or prevents injections of nicotine. In one series of studies (Goldberg and Spealman 1982, 1983), squirrel monkeys responded on a two-component fixed-ratio schedule of food presentation. In both components, every 30th lever press produced a food pellet,. In the punishment component, which was signaled by a red light, the first response in each fixed ratio produced an i.v. injection of nicotine. When responding produced lo- or 30- mg/kg injections of nicotine during the punishment component, responding was selectively suppressed in that component in a dose- related manner. When saline was injected, however, rates of responding for food were no longer suppressed. Similar findings were obtained when electric shock was compared with nicotine in the same studies. Administration of mecamylamine, but not hexametho- nium, reduced the punishing effects of the nicotine, showing that the effects were centrally mediated. Futhermore, these antagonists did not reduce the aversive effects of the electric shock, confirming that the effects of nicotine were due to nicotine actions at nicotinic receptors and not to more general possible effects of nicotine. The potential aversive effects of nicotine have been experimental- ly demonstrated in human subjects in a preliminary experiment by Henningfield and Goldberg (1983a). Human volunteers who had been recruited for studies of i.v. nicotine self-administration and who did not self-administer nicotine during initial sessions were tested under a concurrent schedule of nicotine avoidance and nicotine self- administration. Two levers were present, and injections of nicotine were programmed to occur every 15 or 30 min. Pressing the left lever 10 times avoided the impending injection, while pressing the right lever 10 times produced an injection. Higher doses of nicotine (1.5 to 4 mg/injection given over 10 set) resulted in increased rates of pressing on the left lever, and fewer injections occurred. Subjects never completed the 10 responses on the alternate lever required to produce an injection. When saline was subst.ituted for nicotine, 193 responding decreased and the number of injections received marked- ly increased. Analogously, in these same subjects scores on a visual line analog scale for rating "negative or undesirable" effects were directly related to nicotine dose, and declined to zero when saline was substituted for nicotine. Nicotine as an Unconditioned Stimulus The preceding studies have largely evaluated the effects of nicotine administration on some behavior which was associated with the drug by a specific behavioral contingency. But drugs can also directly elicit responses which then might become conditioned to occur in the presence of whatever stimuli were associated with those effects. The effects may be seen as positive or negative and may be associated with either increasing or declining drug levels in the body (i.e., drug taking or drug withdrawal). Two general conditioning paradigms are used to evaluate the unconditioned stimulus effects of drugs and have been used to test nicotine: the conditioned place preference and aversion paradigm, and the conditioned taste aversion paradigm. In addition to a discussion of these paradigms, data obtained from t.he practical application of such findings in the treatment of tobacco dependence will be summarized. Conditioned Place Preference and Aversion The place preference and aversion paradigm has been increasingly used to evaluate the potential of drugs to produce dependence (Bozarth 1983). It may be used to assess the positive and negative subjective states induced by drugs and other chemicals. In the place- conditioning procedure, an animal is exposed to the effects of a drug in a novel, distinctive environment. Another environment is paired wit.h the administration of the drug vehicle (e.g., saline). Subsequent- ly, the subject is given a free choice of both environments while not under the influence of the drug. It is currently hypothesized that the formation of place preferences or place aversions depends on the association of the interoceptive drug effect with an external stimulus (e.g., the particular environmental context of the place-conditioning apparatus). Nicotine has been shown to condition both positive and negative effects in this paradigm. The first published study of the place-conditioning effects of nicotine (Fudala, Teoh, Iwamoto 1985) indicated that nicotine, at doses from 0.1 to 1.2 mgikg administered S.C. to rats, produced both a place preference and p!ace aversion depending upon the dose. As discussed in Chapter V, the ability to condition both place prefer- ences as well as place aversions is characteristic of several depen- dence-producing drugs. A dose of 0.8 mg/kg was found to condition a 194 place preference for previously nicotine-paired environmental cues in the greatest proportion of animals. At the lowest effective place- conditioning dose of nicotine, 0.1 mg/kg, an almost equal proportion of animals exhibited place preferences and place aversions. This investigation also indicated that mecamylamine, but not hexametho- nium, blocked the place preference-producing effects of nicotine, suggesting t,hat this nicotine-induced effect was cent,rally mediated. Subsequent studies have extended the findings of Fudala, Teoh, and Iwamoto (1985) discussed above. Using a more conservative classification method in categorizing their subjects, Fudala and Iwamoto (1986) observed that nicotine produced a conditioned place preference only within the dose range previously tested. Further- more, nicotine conditioned a place preference when the drug was administered immediately prior to conditioning sessions, but not when administered from 20 to 120 min prior to conditioning. Depending on the timing of nicot,ine administration, either place preferences or place aversions may be produced. For example, at doses between 0.2 and 0.8 mg/kg, a dose-dependent place aversion was induced when nicotine was administered 5 min or less following an animal's exposure to the conditioning environment (Fudala and Iwamoto 1987). One other group of investigators, Clarke and Fibiger (1987), using the same dose range of nicotine as in the two aforementioned studies, found no nicotine-induced conditioned place preference in rats. However, the two investigative groups used experimental methods that differed considerably, including differ- ences in apparatus design, olfactory cues, number of conditioning trials performed, and time of conditioning relative to nicotine administration. The finding that nicotine administration can lead to conditioned responses in animals provides additional evidence of nicotine's potential to control behavior by this basic learning process (i.e., Pavlovian or classical conditioning, see Chapter V). Conditioned Taste Aversion and Rapid Smoking During conditioned taste aversion experiments, the presentation of an aversive stimulus after the consumption of a distinctively flavored solution causes rejection of the solution when it is presented at a later time (Palmerino, Rusiniak, Garcia 1980; Chapter V). A variety of dependence-producing drugs have been found to be effective at inducing taste aversions (for example, Wise, Yokel, DeWit 1976; Suzuki et al. 1983; Hunt and Amit 1987; Chapter V). Findings specific to nicotine are presented here. Etscorn (1980) reported that a large intraperitoneal (i.p.) dose of nicotine, 2 mg/kg, conditioned taste aversions to 20 percent (weight per volume) sucrose in Swiss-Webster mice with the two-bottle choice test paradigm. Etscorn and colleagues (1986) also reported that i.p. injections of 1, 3, and 9 mg/kg of nicotine in gold?-n Syrian hamsters 195 induced dose-related conditioned taste aversions to 0.1 percent sodium saccharin solutions with a single-bottle choice paradigm. Kumar, Pratt, and Stolerman (19831 reported that S.C. injections of nicotine bitartrate could condition taste aversions to either 0.1 percent sodium saccharin or 0.9 percent sodium chloride solutions at doses as low as 0.08 mg/kg in Lister hooded rats with a two-bottle choice paradigm. The conditioned taste aversion was induced by nicotine in a dose-related manner; stronger taste aversions were induced by nicotine after four conditioning trials than after one or two trials. The S-nicotine (the nicotine form normally delivered in cigarette smoke) was approximately five times as potent as its stereoisomer in conditioning taste aversions. Mecamylamine, 0.1 to 2 mg/kg administered before each conditioning trial, blocked the development of taste aversions produced by 0.4 mg/kg of nicotine; hexamethonium, 1 to 10 mg/kg, had no effect. Other studies have confirmed the pharmacologic specificity of nicotine-induced taste aversions; that is, Iwamoto and Williamson (1984) also found that the development of nicotine-conditioned taste aversions could be prevented in rats by pretreatment with mecamy- lamine, 3 mg/kg, but not with 1 mg/kg of hexamethonium. In an analogous study, the pharmacologic specificity of apomorphine- (dopamine agonist chemically derived from morphine) conditioned taste aversions was investigated in rats by establishing the response to both apomorphine and nicotine following pretreatment of the animals with pimozide (Kumar, Pratt, Stolerman 1983). Pimozide is a dopamine antagonist that blocks many of the effects of apomor- phine. Pimozide pretreatment reduced the strength of the condi- tioned test aversions to apomorphine but not to nicotine, confirming a certain degree of pharmacologic specificity of the conditioning effects of these two chemicals. Finally, an intraventricular microin- jection of 5 mg/kg of the quaternary nicotinic cholinergic ganglionic antagonist, chlorisondamine, in hooded Lister rats blocked the development of conditioned taste aversions to 0.1 percent sodium saccharin or 0.9 percent sodium chloride induced by nicotine injected 9 to 16 days after the chlorisondamine (Reavill et al. 1986). These data indicate that nicotine, like some other drugs, is capable of conditioning taste aversions in a dose-related manner in rodents (see Chapter V). Because mecamylamine, but not hexamethonium, blocks nicotine-conditioned taste aversions, the mechanism by which nicotine conditions taste aversions appears to be centrally mediated. Conditioned taste aversion studies in which various combinations of nicotinic agonists and antagonists are given have also been useful in helping to identify specific brain mechanisms of nicotine's behavior modifying properties (see review by Stolerman, in press; also see Chapters III and VA 196 The fact that nicotine can be used to elicit aversive effects has been put to practical application in the treatment of cigarette smoking (Chapter V), generally to associate aversive effects of high doses of nicotine with the taste, smell, and inhalation of cigarette smoke. Variations on this procedure have been termed "rapid" smoking or "aversive" smoking procedures; the clinical results of these procedures have been mixed (see Chapter VII). Nicotine: Withdrawal Reactions (Physical Dependence) The preceding Sections have shown that cigarette smoking is an orderly form of drug self-administration. The role of nicotine in controlling this behavior is similar to the role of other psychoactive drugs in the determination of other forms of drug dependence (see Chapter V). Nicotine can serve as a highly effective positive reinforcer, and deprivation of cigarette smoking and presumably of nicotine itself can increase the reinforcing efficacy of cigarettes (Henningfield and Griffiths 1979). If longer periods of deprivation are associated with a discomforting withdrawal syndrome, this would constitute an additional mechanism by which the reinforcing efficacy of nicotine would be further increased. The drug effect which enables such discomforting withdrawal is physical depen- dence. Physical dependence refers to physiological and behavioral alterations that become increasingly manifest after repeated expo- sure to a pharmacologic agent. The primary indication of physical dependence is an abstinence-associated withdrawal syndrome, al- though tolerance is a frequent concomitant (Kalant 1978; Cochin 1970; Kalant, LeBlanc, Gibbons 1971; Eddy 1973; Clouet and Iwatsubo 1975; Yanagita 1977). Physical dependence and tolerance are discussed in greater detail in Chapter V. Tolerance to nicotine has been studied since the 19th century and is well documented (Langley 1905; Dixon and Lee 1912; Gillman et al. 1985). As reviewed in Chapters II and V, nicotine produces tolerance to a variety of behavioral and physiological responses. Until the 197Os, however, physical dependence on tobacco was not rigorously studied, although there was evidence for a syndrome of withdrawal that could accompany abstinence from chronic cigarette smoking (Lewin 1931; Weybrew and Stark 1967) and that was significantly involved in attempts to quit smoking (Dorsey 1936). The clinical significance of the tobacco withdrawal syndrome has also been formally recognized by professional organizations such as the American Psychiatric Association (APA) (1980, 1987) and the American College of Physicians (1986). These observations, along with the evidence that nicotine produces tolerance (Chapter II), led to the conclusion that nicotine exposure produced physical depen- 197 dence (Jaffe 1985; Jaffe and Jarvik 1978; US DHHS 1986b; APA 1980). Conclusions that nicotine exposure produced physical dependence' were also consistent with early data which suggested that i.v. nicotine delivery seemed to relieve withdrawal from cigarettes and may have produced physical dependence in a nonsmoker (Johnston 19421. Other supporting observations included the finding that abrupt, reduction of the nicotine in cigarettes (i.e., low nicotine-yield cigarettes) resulted in behavioral and physiological withdrawal signs including discomfort and the seeking of regular cigarettes (Finnegan, Larson, Haag 1945; Knapp, Bliss, Wells 1963). However, the rigorous scientific methods of the kind that were developed to evaluate withdrawal from opioids and sedatives (Himmelsbach 1942; Isbell 1948; Isbell et al. 1955; Chapter V) were not applied to the study of the tobacco withdrawal syndrome until the late 1970s. Therefore, the data available at the time of the 1964 Report of the Surgeon General's Advisory Committee on Smoking and Health were not considered conclusive (US DHEW 1964). The present Section reviews characteristics of physical dependence on nicotine, including the relationship of nicotine intake to the magnitude of withdrawal signs and symptoms, and the role of both environmental and pharmacolog- ic factors which influence the course of the withdrawal syndrome. Criteria for Physical Dependence on Nicotine and Clinical Characteristics of the Withdrawal Syndrome Similar kinds of phenomena characterize withdrawal syndromes from all drugs that produce physical dependence. If physical dependence on nicotine occurs, these same phenomena should be observed (see Chapter V; Martin 1977; Thompson and Unna 1977; Woods, Katz, Winger 1987). Based on these phenomena, criteria for establishing that physical dependence on nicotine occurs include the following: (1) Termination of cigarette smoking should be accompa- nied by changes in mood, behavior, and physical functioning. (2) Some of these changes should be in a direction which is opposite to those produced by cigarette smoking and should return to the baseline levels observed during chronic tobacco administration ("rebound effects"). (3) Physiological withdrawal effects should be reversible by nicotine administration. The tobacco withdrawal syndrome as described by the APA in the revised Diagnostic and Statistical Manual (DSM III-R) (APA 1987), provides a clinical description (Table 5). Several of the symptoms of the nicotine withdrawal syndrome correspond to effects of nicotine that are either known or suspected to promote tobacco dependence as discussed in Chapter VI. It should be noted that the sequelae of tobacco abstinence include a range of responses which do not share the same underlying mechanisms. For example, some symptoms are 198 transient responses which are opposite those produced when nicotine is given and which subside within a few days or weeks of nicotine abstinence; such responses are presumed to reflect a physiological rebound occurring in the absence of chronic drug exposure. Other responses are also opposite those produced by nicotine administra- tion but appear to primarily reflect the removal of nicotine exposure, and which may occur whether or not sufficient nicotine had been taken to produce physical dependence. An example of the latter type of response is body weight. Nicotine can directly suppress appetite and body weight, often below the value at which it would have been had nicotine not been taken; removal of nicotine is then accompa- nied by a stable increase in body weight. Various lines of scientific evidence are available to characterize physical dependence on tobacco and to evaluate the specific role of nicotine. These data include surveys, treatment studies, and experi- mental laboratory studies and are briefly reviewed in this Section. Retrospective Survey Data Retrospective studies have been conducted with ex-smokers who were participating in major surveys (Wynder, Kaufman, Lesser 1967; Hughes, Gust, Pechacek 1987) or who were patients with chronic respiratory problems (Burns 1969; Mausner 1970). Other studies were conducted using subjects who responded to advertisements in newspapers (Pederson and Lefcoe 1976) or were contacted by word of mouth (Trahir 1967). The subjects in these studies had either quit smoking recently, had quit smoking for more than 1 year, or had at least one episode of remaining abstinent for 24 hr. Although the reliability of these data is limited because they are from retrospec- tive self-reports, they provide information on the prevalence and nature of symptoms which may be experienced by smoke-deprived persons and acutely abstinent smokers. Symptoms reported by significant numbers of ex-smokers includ- ed: "craving" for tobacco (Hughes, Gust, Pechacek 1987; Trahir 1967; Burns 1969; Mausner 1970; Pederson and Lefcoe 19761; restlessness, nervousness, or irritability (Trahir 1967; Wynder, Kaufman, Lesser 1967; Burns 1969; Mausner 1970; Hughes, Gust, Pechacek 1987); anxiety (Hughes, Gust, Pechacek 1987); impatience (Hughes, Gust, Pechacek 1987); difficulty concentrating (Trahir 1967; Wynder, Kaufman, Lesser 1967; Hughes, Gust, Pechacek 1987); somatic or physical complaints (Hughes, Gust, Pechacek 1987; Pederson and Lefcoe 1976); increased appetite (Wynder, Kaufman, Lesser 1967; Hughes, Gust, Pechacek 1987); increased food intake (Wynder, Kaufman, Lesser 1967); and weight gain (Trahir 1967; Wynder, Kaufman, Lesser 1967; Mausner 1970; Pederson and Lefcoe 1976). Measures of the incidence and magnitude of signs and symptoms vary across studies, at least partly because of the diversity of the 199 TABLE &-Diagnostic categorbation and criteria for nicotine withdrawal measuring instruments and techniques used, questions asked, and populations examined. Collectively, the results of many such studies suggest that most nicotine-deprived cigarette smokers experience at least, one symptom of the tobacco withdrawal syndrome, that between one-fourth and one-half show significant withdrawal, and that about one-fourth report no withdrawal at all (Pederson and Lefcoe 1976; Wynder, Kaufman, Lesser 1967; Hughes, Gust, Pecha- cek 1987; Gritz 1980; Henningfield 1984). Of those persons who retrospectively report experiencing no withdrawal symptoms, it is unclear whether they were not physicaily dependent, whether the assessment instruments were not sufficiently sensitive, or whether some persons are less impaired or discomforted by withdrawal symptoms. Prospective Data from Laboratory and Nonlaboratory Studies Cigarette smokers have been studied both in laboratory and nonlaboratory settings using a variety of self- and observer-adminis- tered tests measuring subjective, behavioral, and physiological signs and symptoms that accompany tobacco deprivation. The studies have examined changes in functioning resulting after periods of tobacco deprivation ranging from 1 hr to 21 days. Most studies have obtained both baseline and deprivation measures; a few studies have incorpo- rated a control group of continuing smokers or nonsmokers; and a few have obtained data after smokers resumed smoking or were given nicot.ine polacrilex gum. The studies included ones which were conducted while the subjects were residing on a research ward, were living in their usual environment, or were paying occasional visits to a clinic for smoking cessation treatment. The symptoms reported in these studies were similar to those obtained from the retrospective studies, demonstrating generality across method and setting. These symptoms included the following: "craving" for tobacco (Gritz and Jarvik 1973; Hatsukami et, al. 1984: Gilbert and Pope 1982; Shiffman and Jarvik 1976; Cummings et al. 1985; Hughes and Hatsukami 1986), irritabi1it.y or anger (Myrsten, Elgerot, Edgren 1977; Elgerot 1978; Weybrew and Stark 1967; Hughes and Hatsukami 1986), anxiety and tension (Mrysten. Elgerot, Edgren 1977; Hughes and Hatsukami 1986), restlessness (Hughes and Hatsukami 1986), impa- tience (Hughes and Hatsukami 1986), depression (Hatsukami et al. 1984), problems with concentration (Hatsukami et al. 1984; Weybrew and Stark 1967; Myrsten, Elgerot, Edgren 1977; Frankenhaeuser et al. 1971; Hughes and Hatsukami 1986), drowsiness or fatigue (Weybrew and Stark 19673, sleep disturbances (Hatsukami et al. 1984; Larson, Haag, Silvette 1961; Weybrew and Stark 1967; Myrsten, Elgerot, Edgren 1977; Hughes and Hatsukami 1986), and increased hunger or appetite (Myrsten, Elgerot, Edgren 1977; Hughes and Hatsukami 1986). In one study (Hughes and Hatsukami 1986), each subject had a spouse, relative, or friend rate some of the symptoms of withdrawal to verify self-report. These observer ratings of irritability, anxiety, restlessness, drowsiness, fatigue, impatience, and somatic complaints were all significantly related to their respective subject's ratings, thus adding to the validity of reports of these symptoms. These researchers found that the most common self-report symptoms were increased irritability (80 percent), anxiety (87 percent), difficulty concentrating (73 percent), restlessness (71 percent), impatience (76 percent), insomnia (84 percent), and craving for tobacco (62 percent). 201 Seventy-eight percent of the subjects reported four or more DSM-III criteria. This degree of prevalence was higher than that found in a retrospective study conducted by Hughes, Gust, and Pechacek (1987), possibly reflecting differences in the measuring instruments or the populat,ions themselves. The physiological changes which have been found to occur after cigarette deprivation include decreased heart rate (Knapp, Bliss, Wells 1963; Murphee and Schultz 1968; Parsons, Avery et al. 1975; Benowitz, Kuyt, Jacob 1984; Hatsukaml et al. 1984; Weybrew and Stark 1967; Gilbert and Pope 1982; Hughes and Hatsukami 1986; West and Russell 1987; Elgerot 1978; West, Jarvis et al. 1984; Henningfield 1987a) and decreased cortical arousal as evidenced by decreases in peak alpha frequency and increases in low frequency activity which appear to be associated with drowsiness and decreased vigilance (Knott and Venables 1977, 1979; Ulett and Itil 1969; Herning, Jones, Bachman 1983; Herning 1987). Knott and Venables (1978) have also found that the visual evoked response in tobacco- deprived smokers showed faster latencies and larger amplitudes for low-stimulus intensities than among nondeprived smokers and nonsmokers. They concluded that deprived smokers experience CNS hypersensitivity and, as a result, may experience visual stimulus input more easily and strongly. Hall and colleagues (1973) reported reduced auditory evoked response (AER) amplitudes during tobacco withdrawal. Blood pressure (Benowitz, Kuyt, Jacob 1984; Murphee and Schultz 1968; Knapp, Bliss, Wells 1963) and respiratory rate (Parsons et al. 1976) have also been found to decrease during abstinence. Studies have also reported an increase in skin tempera- ture among tobacco-deprived smokers (Gilbert and Pope 1982; Myrsten, Elgerot, Edgren 1977) or no change (West and Russell 1987), and either a decrease (FagerstrBm 1978) or no significant change (Hatsukami et al. 1984) in body temperature among those who are classified as more dependent. Although some studies have reported insomnia and sleep disturbance following tobacco depriva- tion, tobacco-deprived smokers' total sleep time may be longer during withdrawal (Soldatos et al. 1980). Reported changes in sleep pattern include decreased latency to rapid-eye-movement (REM) sleep (Kales et al. 1970), decreased latency to light (delta electroen- cephalogram (EEG) wave) sleep onset (Parsons, Luttrell et al. 1975; Parsons and Hamme 1976), and increased total REM sleep time (Soldatos et al. 1980; Kales et al. 1970; Parsons, Avery et al. 1975). Another physical change found among tobacco-deprived smokers is an increase in weight (Grunberg 1986; see also Chapter VI). Weight increase has also been found among those who quit smoking in a number of longitudinal survey studies (Bosse, Garvey, Costa 1980). This increase in weight has been attributed to increased caloric intake (Hatsukami et al. 1984; Grunberg 1982; Myrsten, Elgerot, 202 Edgren 1977; Burse et al. 1975; Gilbert and Pope 1982; Wack and Rodin 1982), decreased basal metabolism (Glauser et al. 1970; Wack and Rodin 1982), decreased energy expenditure (Hofstetter et al. 1986), or increased activity of lipoprotein lipase (Carney and Goldberg 1984) (see also Chapter VI). Several studies have examined the effects of cigarette deprivation and administration on reaction time and psychomotor performance. These are reviewed in detail in Chapter VI and are only briefly summarized here. Two early studies each found considerable across- subject variability, with some subjects showing distinct deprivation- induced performance impairments which were reversed by tobacco administration, and other subjects showing impairments under the tobacco administration conditions (Bates 1922; Carver 1922). Since the studies by Bates and Carver, investigators have developed increasingly sophisticated methods of performance assessment which have led to a clearer understanding of the performance- related effects of nicotine administration and deprivation (see details in Chapter VI). For example, Heimstra, Bancroft, and DeKock (1967) used a simulated driving task and found that deprived smokers made significantly more errors on tracking and vigilance tasks than did nondeprived smokers or nonsmokers, who did not significantly differ from each other. Other research has demonstrated that smokers who were allowed to smoke cigarettes during the experimental session exhibited either no decrease or an improvement in speed and accuracy in reaction time, cognitive tests, and/or vigilance perfor- mance tasks, whereas deprived smokers most frequently show some impairment in performance tasks (Myrsten et al. 1972; Franken- haeuser et al. 1971; Elgerot 1978; Kleinman, Vaughn, Christ 1973; Andersson 1975; Wesnes and Warburton 1984; Edwards et al. 1985; Snyder and Henningfield, in press; Henningfield 1986a, 1987a). A recent study using a computerized battery of such tasks found clear impairments beginning within 8 hr of the last cigarette and improving only somewhat across 10 consecutive days of tobacco deprivation; resumption of smoking was accompanied by complete restoration of performance (Henningfield 1987a). The specificity of these performance effects of nicotine was confirmed by the findings that administration of nicotine in the polacrilex gum form produced a dose-related reversal of all performance impairments (Snyder and Henningfield, in press; Henningfield 1987a); this effect was not related to satisfaction or reduction of "craving" because the gum produced dose-related decreases in "liking" scores and produced no reliable decrease in "desire to smoke" (Henningfield 1987a). Other changes occurring in tobacco-deprived cigarette smokers include increases in aggression scores on the Buss aggression machine (Schechter and Rand 1974) and increases in frequency of spontaneous jaw contractions (a putative analog of aggression) 203 (Hutchinson and Emley 1973). Analogously, monkeys withdrawn from chronic oral nicotine exposure (nicotine was placed in their drinking water) exhibited an increase in frequency of post-shock biting (Hutchinson and Emley 1973). The magnitude of tobacco withdrawal is related to the environ- mental context (see Chapter V for a comparison to other dependence- producing drugs). For example, Hatsukami, Hughes, and Pickens (1985) reported that smokers who were deprived of cigarettes on an outpatient basis experienced more withdrawal symptoms than those who underwent withdrawal on a clinical research ward. These findings are consistent with those of Suedfeld and Ikard (1974), who found that deprivation of normal sensory stimulation reduced tobacco abstinence-associated discomfort. It has also been observed that the diurnal variation of withdrawal discomfort found among abstinent smokers (greater discomfort in the evenings) appears to be associated with diurnal variation in the social environment (e.g., meals, departure from work, or social contact) (Shiffman 1979). Time Course of Responses to Nicotine Abstinence Drug withdrawal syndromes generally include some signs and symptoms which are opposite those produced by administration of the drug and which then return to approximately the same values observed when drug intake was stable (rebound phenomena). The time course of different responses varies (Chapter V). The most recent studies show that several signs and symptoms of withdrawal appear to rebound within the first few days following cigarette abstinence; these signs and symptoms include increases in the urge to use tobacco, anxiety, problems with concentration, increased caloric intake, sleep disturbance, performance impairment, and general subjective distress (Hatsukami et al. 1984; Hughes and Hatsukami 1986; Schneider and Jarvik 1984; Cummings et al. 1985; Henningfield 1987a). Heart rate has been found to decrease to levels found among nonsmokers (Weybrew and Stark 1967) and may include some rebound, returning to stable levels between those maintained during normal cigarette smoking and those recorded during the first week of abstinence (Henningfield 1987a). The P300 response, a cognitive evoked potential component which is related to the ability to evaluate auditory stimuli (i.e., differentiate one sound from another by counting only certain sounds), showed a rebound (decrease in amplitude), with values returning to preabstinence (cigarette smoking) levels after about 3 to 5 days (Herning 1987). West, Russel, Jarvis, Pizzey, and Kadam (1984) reported that urinary epinephrine concentrations rebounded with a significant decrease during the first 3 days of abstinence followed by a significant increase. Finally, in the squirrel monkey study of nicotine absti- nence-associated biting, Hutchinson and Emley (1973) found a 204 distinct rebound pattern in some subjects with biting levels sharply increasing and then returning to the levels observed during chronic oral nicotine administration. Other signs and symptoms associated with tobacco abstinence do not return to levels observed during cigarette smoking. For example, weight gain has persisted for long periods of time (Blitzer, Rimm, Giefer 1977) and has also been reported to approach levels of nonsmokers (Khosla and Lowe 1971; Lincoln 1969; Chapter VI). In addition, some levels of performance impairment and associated reduction of a cognitive evoked cortical potential (NlOO), which is related to attention, persist at least 10 days and may last longer (Henningfield 1987a; Herning 1987). As the preceding studies suggest, the duration of withdrawal reactions varies among studies and as a function of the measure (Shiffman 1979; West 1984). Urges to smoke cigarettes among ex- smokers have been reported to occur intermittently, although sometimes with great intensity, for up to 9 years after cessation of cigarette smoking. These reported symptoms may represent condi- tioned responses to environmental stimuli associated with either cigarette smoking or deprivation, may represent a protracted physiological phase of withdrawal, or both (e.g., Wikler 1965; Jasinski 1981; Chapter VI. Alleviation of Withdrawal Symptoms by Cigarette Smoking Several studies have demonstrated that the signs and symptoms resulting from cigarette deprivation are alleviated by the resump- tion of cigarette smoking. These signs and symptoms include heart rate (Murphee and Schultz 1968; Weybrew and Stark 1967; Henning- field 1987a), blood pressure (Murphee and Schultz 19681, skin temperature (Myrsten, Elgerot, Edgren 19771, epinephrine and norepinephrine levels (Myrsten, Elgerot, Edgren 19771, EEG changes (Ulett and Itil 1969; Herning 1987), weight (Noppa and Bengtsson 19861, desire for food (Burse et al. 19751, hand tremor (Myrsten, Elgerot, Edgren 19771, desire to smoke (Gritz and Jarvik 19731, and fatigue, irritation, sleeplessness, problems with alertness and con- centration (Weybrew and Stark 19671, and performance (Henning- field 1987a). Hughes, Hatsukami, Pickens, and Svikis (1984) examined the consistency of tobacco withdrawal signs and symptoms using an experimental design in which periods of cigarette smoking and abstinence were alternated in the same subjects. This study demon- strated both the consistency of the withdrawal symptomology within subjects as well as the efficacy of resumed smoking in reversing it. The most consistent withdrawal effects across subjects were supine heart rate changes, insomnia, caloric intake, irritability, rest- lessness, drowsiness, general mood disturbance (measured by the 205 Profile of Mood States). and withdrawal discomfort. Furthermore, the intensities of the withdrawal discomfort of subjects during the two deprivation periods were similar. Similarly, a study at the Addiction Research Center (Baltimore, Maryland) showed that resumption of cigarette smoking after 10 days of tobacco abstinence was accompanied by a return to preabstinence levels of all measures including EEG, evoked cortical electrical potentials, heart rate, behavioral performance, and measures of mood (Henningfield 1987a; Herning 1987). Relationship Between Preabstinence Nicotine Intake and Magnitude of Withdrawal Syndrome The observation that the magnitude of tobacco withdrawal reac- tions is directly related to preabstinence levels of nicotine intake provides specific evidence that nicotine is the pharmacologic cause of the physical dependence. The clinical significance of these relation- ships is that. both the magnitude of the tobacco withdrawal syndrome and difficulty in quitting smoking are directly related to the daily levels of nicotine that were being ingested. The relationship has not always been observed, however, when only crude indices of nicotine dosing were used. For example, correlations between number of cigarettes smoked per day (a poor marker of nicotine intake) (Benowitz 1983; Abrams et al. 1987; Chapter II) and withdrawal reaction severity are mixed across studies. Some investigators have observed a positive correlation between the number of cigarettes smoked per day and withdrawal severity (Wynder, Kaufman, Lesser 1967; Shiffman 1979; Burns 1969; Hall, Ginsburg, Jones 1986). Others have report,ed no differences in severity of craving or other measures of withdrawal between light and heavy smokers or as a function of number of cigarettes smoked (Gritz and Jarvik 1973; Shiffman and Jarvik 1976; Myrsten, Elgerot, Edgren 1977; Mausner 1970). Cummings and coworkers (1985) reported that although heavy smokers reported more withdrawal symptoms than light smokers, differences between heavy and light smokers were statistically significant only with respect to irritability. The most reliable measure of day-to-day nicotine exposure appears to be cotinine in biological specimens or nicotine itself (Benowitz 1983; Chapter II). Recent studies using such measures have found significant relationships between either nicotine or cotinine levels and severity of withdrawal reactions. Pomerleau, Fertig, and Shan- han (1983) divided subjects by their baseline plasma cotinine levels (high or low quartiles). They found that subjects in the low-cotinine quartile exhibited less withdrawal change on the Shiffman Craving and Perception of Physical Signs subscales compared with subjects in the high-cotinine quartile. They also found a significant correlation between preabstinence baseline plasma cotinine levels and absti- 206 nence-associated craving for cigarettes. Hatsukami, Hughes, and Pickens (1985) established a similar significant correlation between craving for tobacco and plasma nicotine level, as well as nicotine boost. Zeidenberg and associates (1977) found that preabstinence serum cotinine was correlated significantly with the degree of difficulty in smoking cessation among males but not females. Finally, West and Russell (1985b I determined that whereas preabsti- nence plasma nicotine levels significantly predicted craving, hunger, restlessness, inability to concentrate, and overaii withdrawal severi- ty, preabstinence rates of daily cigarette consumption did not significantly predict any withdrawn1 effects. Smokeless Tobacco Withdrawal Syndrome A study of withdrawal reactions accompanying abstinence from smokeless tobacco products helped to determine that the syndrome did not require inhalation of smoke and its constituents. which are not present in smokeless tobacco (e.g., tar and CO.). This study showed that signs and symptoms of smokeless tobacco deprivation are similar to those occurring in smokers after cigarette deprivation (Hatsukami, Gust, Keenan 1987). In persons who had been using a high nicotine containing brand of chewing tobacco, Hatsukami, Gust, and Keenan (1987) measured a number of potential withdrawal signs and symptoms over a 6-day period. Baseline data were collected during 3 days of regular smokeless tobaco use. The significant changes which occurred during smokeless tobacco deprivation rela- tive to the baseline included decreased heart rate and an increase in craving for tobacco, confusion, eating, number of awakenings, and total scores on a withdrawal symptom checklist for both self-rated and observer-rated measures. These changes were similar to those found among cigarette smokers who underwent a similar experimen- tal protocol, although the smokeless tobacco withdrawal syndrome appeared to be less severe than the cigarette withdrawal syndrome (Hatsukami, Gust, Keenan 1987). Nicotine Polacrilex Gum: Treatment and Physical Dependence Nicotine polacrilex gum has been used to evaluate the specific role of nicotine in tobacco dependence. Experimental research and clinical observations of the ability of nicotine in the polacrilex gum form to alleviate tobacco withdrawal symptomatology provide con- clusive evidence that the tobacco withdrawal syndrome is pharmaco- logically determined by physical dependence on nicotine. To the extent that the tobacco withdrawa! nhenomena described above are specific to nicotine and not characteristic of the delivery system (e.g., cigarette smoke), alternate forms of nicotine delivery should be able to sustain the physical dependence. This would be evidenced by (1) 207 blockade of signs and symptoms of withdrawal by nicotine delivery and (2) subsequent emergence of a t.obacco withdrawal-like syndrome upon abrupt abstinence from nontobacco-delivered nicotine. Treatment of Withdrawal S-ymptoms Clinical trials and experimental studies in which nicotine polacri- lex gum is evaluated as a means to alleviate signs and symptoms of tobacco withdrawal are of relevance to the treatment of tobacco dependence (Chapter VII). In addition, however, such data are analogous to data from the classic "substitution" study methodology used to help det,ermine the pharmacologic specificity of withdrawal reactions following use of opioids, sedatives, and alcohol (described in Chapter V). In brief, however, the objective is to determine if the withdrawal reaction from the primary substance upon which the person is dependent can be alleviated by administration of a test drug. Several studies have examined the effects of nicotine polacrilex gum on tobacco withdrawal (Jarvis et al. 1982; Schneider, Jarvik, Forsythe 1.984; West, Jarvis et al. 1984; Hughes, Hatsukami, Pickens, Krahn et al. 1984; Snyder and Henningfield, in press; Henningfield 1987a). These studies have examined two groups of cigarette smokers who were assigned in a double-blind fashion (with the exception of West, Jarvis, and colleagues (19841, who used a single-blind design) to receive 2-mg polacrilex gum or placebo. The duration of cigarette deprivation during which the polacrilex gum (or placebo) was used varied from 24 hr to 6 weeks. In general, the results consistently showed an attenuation of withdrawal signs and symptoms. For example, nicotine polacrilex gum significantly re- duced irritability (Jarvis et al. 1982; Hughes, Hatsukami, Pickens, Krahn et al. 1984; West, Jarvis et al. 1984), total withdrawal discomfort (Schneider, Jarvik, Forsythe 1984; Hughes, Hatsukami, Pickens, Krahn et al. 19841, somatic complaints (Hughes, Hatsuka- mi, Pickens, Krahn et al. 19841, sleepiness (Jarvis et al. 1982), unsociability (West, Jarvis et al. 19841, cognitive performance deficits (Snyder and Henningfield, in press; Henningfield 1987a), heart rate decreases (Schneider, Jarvik, Forsythe 1984; West, Jarvis et al. 1984; Henningfield 1987a1, and EEG effects including changes in cortical evoked potentials (Herning 1987; Pickworth, Herning, Henningfield, 19881. Other measures were less reliably alleviated; these included depression (Jarvis et al. 1982; West, Jarvis et al. 1984), anxie- ty/tension (Jarvis et al. 1982; Hughes, Hatsukami, Pickens, Krahn et al. 19841, difficulty concentrating (Hughes, Hatsukami, Pickens, Krahn et al. 1984; West, Jarvis et al. 19841, and restlessness (Hughes, Hatsukami, Pickens, Krahn et al. 1984; West, Jarvis et al. 1984). The urge to smoke cigarettes has not been found to be reliably alleviated 208 by nicotine polacrilex gum administration (West and Schneider 1987; West 1984; Henningfield 1987a; Hughes, Hatsukami, Pickens, Svikis 1984) except possibly at high dose levels (Nemeth-Coslett, Henningfield, O'Keefe, Griffiths 1987). Interpretation of such data is complicated by the diverse strategies used to measure the urge to smoke or "craving" as discussed further in this Section. Of these studies, two showed nonsignificant effects of nicotine polacrilex gum on hunger (Hughes, Hatsukami, Pickens, Krahn et al. 1984; West, Jarvis et al. 1984) and one showed significant effects in decreasing hunger (Jarvis et al. 1982). More recent research shows that the anorectic effect of nicotine polacrilex gum during tobacco abstinence is directly related to the dose level (i.e., number of doses taken per day) (Stitzer and Gross 1988; Fagerstrom 1987; Chapter VI). The dose-response relationship may explain the diversity in results when studies are compared; in some of these studies, dosing was either poorly controlled or not reported, or there was no verification of subject compliance with a dose regimen. As would be expected, depending on the dose administered, the efficacy of nicotine polacrilex gum for most measures of withdrawal symptomology ranges from complete reversal of withdrawal to no effect. In a study in which periods of tobacco abstinence (3 days) were alternated with periods of cigarette smoking (4 days), subjects were given either 0-, 2-, or 4-mg-nicotine-containing pieces of the polacri- lex gum (Henningfield 1987a). The subjects were given the polacrilex gum at 1-hr intervals (for 12 hr), and they chewed under the direction of research staff. Blood nicotine and cotinine levels confirmed that this procedure resulted in dose-related nicotine administration; plasma cotinine and nicotine levels at 4 mg were similar to those obtained during cigarette smoking (ad libitum smoking); plasma levels at 2 mg were between those at 4 and 0 mg. Measures included cognitive performance, heart rate, EEG, and self- reported symptomology. At 4 mg, all signs and symptoms of withdrawal were reduced or completely reversed except the desire to smoke. The 2-mg dose produced partial reversal of withdrawal effects. Maintenance of Physical Dependence Two studies have examined withdrawal effects after deprivation of nicotine polacrilex gum. West and Russell (1985a) conducted a study in which they examined withdrawal symptoms in six people who used nicotine polacrilex gum for at least 1 year. Baseline measures of possible withdrawal effects were collected during days that the subjects were chewing 2-mg pieces of nicotine polacrilex gum. These days were the first and third days of a 4-day experiment. On the second and fourth days, subjects were given either 0.5 mg unbuffered polacrilex gum (nicotine absorption is negligible in the unbuffered 209 formulation) to chew or no polacrilex gum. West and Russell (1985a) found significant changes for measures of withdrawal symptomology including irritability, ability to concentrate, and heart rate and for composite subjective withdrawal scores. Withdrawal reaction magni- tude was slight,ly, but not significantly, less in the unbuffered gum than in the no gum condition. Hughes, Hatsukami. and Skoog (1986) extended the findings of West and Russell (1985a) with a longer period of observation (1 week) and a double-blind, placebo-controlled design. In the study by Hughes, Hatsukami, and Skoog (1986), eight former smokers who had been using nicotine polacrilex gum for at least 1 month participated. The main finding was that when the maintenance dose levels (2-mg polacrilex gum) were replaced with placebo, reliable symptoms of withdrawal were produced. The effects included "craving" for tobacco, irritability/hostility, anxiety, depression, restlessness, impatience, difficulty concentrating, hunger, and total withdrawal discomfort; reports from observers verified several of the effects (i.e., observer estimates of irritability, anxiety, restlessness, impatience, and total withdrawal discomfort). The scales used to measure withdrawal discomfort in the study by Hughes and col- leagues were similar to those used in a previous study of cigarette withdrawal conducted by the same investigators (Hughes and Hatsukami 19861, thus enabling an across-study comparison between abstinence from cigarettes and abstinence from nicotine in the polacrilex gum form. Intensities and numbers of withdrawal symp- toms, except heart rate and insomnia, were similar. Taken together, the results of the above-described studies with nicotine polacrilex gum have helped to confirm that tobacco withdrawal is pharmacologically caused by physical dependence on nicotine. Furthermore, the results of such work are of clinical significance because they indicate that much of tobacco withdrawal symptomology can be treated with nicotine polacrilex gum. Two studies show that nicotine polacrilex gum can maintain physical dependence; this emphasizes the importance of gradually giving up use of the gum to minimize the abruptness and severity of withdrawal symptoms (see Chapter VII). Tobacco Craving The measurement of self-reported craving for tobacco and inter- pretation of resulting data are among the more complicated issues in tobacco research. Findings discussed in this Chapter that nicotine polacrilex gum administration can suppress cigarette smoking and alleviate physical signs of tobacco withdrawal while having little effect on the urge to smoke indicate that such urges are not solely determined by nicotine deprivation. Similar observations regarding urges to use other dependence-producing drugs are discussed in 210 Chapter V (see also Childress et al., in press!. The elicitation and alleviation of the urge to use tobacco, as for other dependence- producing substances, can be effected by a variety of pharmacologic and other environmental stimuli as well as changes in the physiolog- ical and/or behavioral state of the person (Chapter V). Conclusions regarding the measurement and treatment of urges to use drugs are complicated because the questions about urges have been worded differently among studies. For example, subjects are somtimes asked to report their "craving." Unfortunately, subjects vary widely in their interpretations of the word "craving" and in their answers to questions about it (Kozlowski and Wilkinson 1987; Ludwig and Stark 1974). In addition, results concerning "craving" are sometimes discussed when the word was not even used in study questionnaires, and sometimes craving was inferred from other observations (e.g., self-reported discomfort or drug abstinence) (Koz- lowski and Wilkinson 1987). These and other problematic issues have been discussed in several recent papers (Kozlowski and Wilkinson 1987; Shiffman 1987; West 1987; Hughes 1987; Marlatt 1987; Stockwell 1987; Henningfield 1987b; Henningfield and Brown 1987; West and Schneider 1987). One consensus that seems to emerge is that the term "craving" be replaced with "urge" or "desire" to smoke, and that subjects be asked to report the "strength" of such responses and not simply whether or not the response occurred (Kozlowski and Wilkinson 1987; Henningfield 1987b). In consideration of the above reports and commentaries and the data reviewed in the present Chapter, the following conclusions may be drawn regarding the urge to smoke. Many means of measuring urges are reliably associated with early abstinence from tobacco; however, urges can also be elicited by a variety of other stimuli including cigarette smoking itself, tobacco-associated stimuli (e.g., sight, smell, advertisements), consumption of other psychoactive drugs, food deprivation, and mood changes. Furthermore, although urges are reliably associated with tobacco abstinence, the levels to which plasma nicotine must fall to produce it are unclear; for example, West, Russell, Jarvis, and Feyerbend (1984) found that smokers who switched to a low-nicotine cigarette reported only slight craving for their usual brand in spite of a drop in nicotine intake of around 60 percent. In addition, as discussed earlier, some sensory stimuli are effective at eliciting urges, whereas other sensory cues accompanying the inhalation of cigarette smoke may be effective at diminishing such urges (Rose et al. 1985). Chapter V provides a discussion of these issues in the context of analogous observations which have been made with other dependence-producing drugs and Chapter VII discusses the implications for replacement therapy used in treating tobacco dependence. 211 Alternate Nicotine Delivery Systems Certain effects of nicotine depend little upon the specific type of delivery system that is used (see also Chapters, II, III, and VI). For instance, it appears likely that all forms of nicotine delivery resulting in systemic absorption are capable of producing tolerance and maintaining physical dependence (see also Chapter II). Similar- ly, it follows that a variety of nicotine delivery systems have potential utility in the treatment of cigarette smoking by the alleviation of withdrawal symptoms. However, the safety, including the potential to produce dependence, may vary considerably as a function of characteristics of the nicotine delivery system itself. Kinds of Nicotine Delivery Systems Because nicotine is well absorbed through the common routes of drug delivery and because the commonly used tobacco vehicle is not necessary to efficaciously deliver nicotine, nicotine can potentially be placed in a variety of vehicles and administered via a variety of delivery systems (Chapter II; Benowitz 1986; Jarvik and Henning- field, 1988). The nicotine delivery systems thus far discussed in this Chapter are tobacco smoke, nicotine polacrilex gum, i.v. nicotine, transdermal nicotine, and a nicotine vapor inhaler. Other potential therapeutic nicotine delivering systems under development include a nasal spray (Perkins et al. 1986) and nasal nicotine solutions given in droplet form (Russell, Jarvis, Feyerabend, Ferno 19831, both of which have been discussed by Russell (1988). Two other nicotine delivery systems are a chewable food product (Tobacco International 19871 and a "toothpaste" formulation which contains ground tobacco. Other nicotine delivering systems (in which the tobacco may be incidental and not necessary for nicotine delivery) are under development or consideration for over-the-counter retail marketing (R.J. Reynolds "Smokeless Cigarette" European Patent Application 1985, 1986; Cleghorn 1987; Mintz 1987). As noted earlier, the nicotine vapor inhaler was removed from the retail market in February of 1987 by the FDA because it was a "nicotine delivery system intended to satisfy nicotine dependence" which had not been tested for safety and efficacy @lade and Connolly 1987). At least through the end of 1987, the toothpaste-like formula- tion was available as an over-the-counter product but was under review by the FDA (FDA letter to Congressman Waxman); this formulation is distributed in Indian food stores. The chewable nicotine delivering product marketed by Pinkerton Inc. was test- marketed as a "tobacco product" for approximately 6 months during 1987. The FDA removed it from the market ruling that it was a "food product" ["chewing gum"] which was "unlike traditional smokeless tobacco products," and contained a "food additive [tobacco] deemed 212 unsafe" for human consumption (FDA letter to Congressman W'axman). Safety of Alternate Nicotine Delivery Systems Alternate nicotine delivery systems may be evaluated with respect to at least three categories of safety issues. These are: (1) short- and long-term toxic effects resulting from use of the system; (2) the ease and convenience of using the system; and (3) the dependence po- tential of the system. All of these factors can affect initiation and maintenance of nicotine dependence. The first safety issue is related to the direct behavioral and physiological toxicity of the preparation itself. In the moderate nicotine doses that each of these and previously marketed systems deliver, acute nicotine toxicity would not appear to be a significant health risk. However, adverse health effects from chronic exposure to nicotine may occur (see Appendix B), and other potentially absorbed constituents of the system (e.g., tar) are markedly toxic. Existing nicotine delivery systems vary widely in their potential overall toxicity. One product was found to meet FDA criteria for safety as well as efficacy (i.e., nicotine polacrilex gum). On the other hand, cigarette smoking is a cause of lung cancer and other cancers, emphysema, heart disease, and a variety of other diseases; smokeless tobacco use causes oral cancer and other forms of gum and mouth disease (US DHEW 1979; US DHHS 1982, 1983, 1984; US DHHS 1986b). Traditional tobacco products have historically been considered by the FDA to be outside its regulatory purview (Action on Smoking and Health vs. Harris 1980). New products, which contain either small amounts of tobacco (e.g., tobacco-containing food products) or which appear to contain possibly nonessential amounts of tobacco (e.g., possibly the case with the R.J. Reynolds smokeless cigarette (European Patent Application 1985, 1986)) and which are not regarded as traditional tobacco products, may not be exempt from such review. The second safety issue is the potential for the product to actually sustain tobacco use by alternating use of the substitute with use of the traditional tobacco product. This is analogous to the nonmedical- ly approved use of methadone by opioid-dependent individuals when their drug of choice (e.g., heroin) is not available, and they are not involved in treatment for opioid dependence. The use of non-tobacco nicotine products to sustain tobacco use is, similarly, medically contraindicated and hence a form of nicotine abuse Glade 1986; Richards 1987). While any alternative nicotine delivery system can theoretically be used for this purpose, two commercial products (the chewable nicotine-delivering "food" product and the nicotine vapor inhaler) were marketed specifically as temporary substitutes for 213 cigarettes when it was inconvenient to smoke (Bosy 1986; Tobacco International 1987). In contrast, the instructions for use of nicotine polacrilex gum clearly specify that this preparation should not be used along with cigarettes (Physicians' Desk Reference 1988). In addition to product design and formulation, factors such as labeling, packaging, marketing, retail distribution, and regulatory oversight might influence the degree to which any particular preparation is associated with an individual's continued use of the nicotine delivery system. The third potential safety concern is related to the dependence potential of the system. As shown in Chapter V, the potential of a drug to addict users is associated with its effects on mood, feeling, and behavior; such effects are related to the bioavailability of the drug. Systems with a controlled rate of bioavailability or a lesser rate of absorption than is obtained from conventional tobacco products may have a lesser dependence potential than tobacco products. Other factors related to availability of the preparation and cost (both economic and behavioral) may also affect the likelihood that dependence will develop in users. For example, nicotine polacrilex gum is available by prescription only, and use of the gum is recommended as a temporary treatment aid. Active chewing is required to extract the nicotine, and swallowing the nicotine too quickly reduces the amount absorbed. These factors appear relevant to the observation that less than 10 percent of all subjects entering smoking treatment trials continue to use nicotine polacrilex gum after 1 year (Tonnesen et al. 1988; Jarvis et al. 1982). Among people who have used the polacrilex gum to quit smoking and who have maintained their tobacco abstinence for 1 year or more, a higher percentage of polacrilex gum use has been reported (13 to 38 percent); however, it is not clear to what degree such use may be necessary for some people to avoid relapse to tobacco use (see further discussion of these issues in Hughes 1988; Jasinski and Henningfield 1988; Hall et al. 1985; Tonnesen et al. 1988; Chapter VII). In contrast to nicotine polacrilex gum, smokeless tobacco products (particularly one in which finely ground snuff is placed in a small tea bag-like pouch) readily lend themselves to initiating as well as to maintaining nicotine dependence (US DHHS 1986b). Table 6 compares nicotine polacrilex gum and cigarettes on a number of dimensions, most of which have been reviewed in either Chapters II, V, or VII. As shown in the Table, there is considerable disparity between these two delivery systems: the polacrilex gum provides a generally safe and medically beneficial form of nicotine delivery; cigarettes are a known cause of substantial amounts of death and disease each year (Chapter I; US DHEW 1979; US DHHS 1981, 1982, 1983, 1984, 1985). Such a disparity in potential safety 214 TABLE 6.-Comparison of tobacco cigarettes and nicotine polacrilex gum on indices related to safety, including potential to cause dependence Tobacco cigarettes Nicotine polacrilex gum Proven carcinogen Ava&bility Widely available consumer product. mcludmg vending machme availabdit~ Taste Carefully formulated with flaror enhancers Ease of mcotine cxtractmn Readdy awulable with little effort Nicotme kinetxs Inltiatmn of dependence Psychoactivity Reinforcing effects Withdrawal symptoms associated with abstinence Rapid uptake Highly effective Dose-related "hkmg" P0WerfUl Yes Socml factors Often used in soaal settings as part of social interactions Primary regulatory 1T.S Bureau of Alcohol. ovewght Tobacco, and Firearms h-0 Prescription only Not formulated to provide dewable taste Much effort required Sluw uptake No reported problem Dose-related "disliking" Weak Yes L'sed for specific therapeutic benefit U.S. Food and Drug Administration across systems would suggest that any new system be submitted to evaluations of safety including dependence-potential testing. Conclusions 1. Cigarettes and other forms of tobacco are addicting. Patterns of tobacco use are regular and compulsive, and a withdrawal syndrome usually accompanies tobacco abstinence. 2. Nicotine is the drug in tobacco that causes addiction. Specifi- cally, nicotine is psychoactive ("mood altering") and can provide pleasurable effects. Nicotine can serve as a reinforcer to motivate tobacco-seeking and tobacco-using behavior. Toler- ance develops to actions of nicotine such that repeated use results in diminished effects and can be accompanied by increased intake. Nicotine also causes physical dependence characterized by a withdrawal syndrome that usually accompa- nies nicotine abstinence. 215 3. The physical characteristics of nicotine delivery systems can affect their toxicity and addictiveness. Therefore, new nicotine delivery systems should be evaluated for their toxic and addictive effects. 216 References ABRAMS, D.B., FOLLICK, M.J., BIENER, L., CAREY, K.B., HITTI, J. Saliva cotinine as a measure of smoking status in field settings. American Journal of Public Health 77(7):846-848, July 1987. ADAMS, L., LEE, C., RAWBONE, R., GUZ, A. Patterns of smoking: Measurement and variability in asymptomatic smokers. Clinical Science 65(4):38%392, October 1983. ADAMS, PI. The influence of cigarette smoke yields on smoking habits. In: Thornton, R.E. (ed.) Smoking Behaviour. Physiological and Psychological Influences. Edin- burgh: Churchill Livingstone, 1978, pp. 349-600. AMERICAN COLLEGE OF PHYSICIANS. Methods for stopping cigarette smoking. Annuls of Internal Medicine 105(2):281-291, August 1986. AMERICAN PSYCHIATRIC ASSOCIATION. Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM-III). Washington, D.C.: American Psychiat- ric Association, 1980, pp. 159-160, 176-178. AMERICAN PSYCHIATRIC ASSOCIATION. Diagnostic and Statistical Manual of Mental Disorders (revised), Third Edition Washington, D.C.: American Psychiatric Association, 1987. ANDERSSON, K. Effects of cigarette smoking on learning and retention. Psychophar- macologia 41:1-5, 1975. ANDERSSON, K., HOCKEY, G.R.J. Effects of cigarette smoking on incidental memory. Psychopharmacologia 52(3):223-226, 1977. ANDERSSON, K., POST, B. Effects of cigarette smoking on verbal rote learning and physiological arousal. Scandinavian Journal of Psychology 15263-267, 1974. ASHTON. H., STEPNEY, R.. THOMPSON, J.W. Smoking behaviour and nicotine intake in smokers presented with a `two-thirds' cigarette. In: Thornton, R.E. fed.) Smoking Behauiour. Physiological and Psychological Influences. Edinburgh: Chur- chill Livingstone, 1978. ASHTON, H., STEPNEY, R., THOMPSON, J.W. Self-titration by cigarette smokers. British Medical Journal 2(6186):357-360, August 11, 1979. ASHTON, H., WATSON, D.W. Puffing frequency and nicotine intake in cigarette smokers. British Medical Journal 3(5724):679-681, September 19, 1970. ATOR, N.A.. GRIFFITHS, R.R. Nicotine self-administration in baboons. Pharmacolo- gy Biochemistry and Behavior 19(6):993-1003, 1983. AUSTIN, G.A. Perspectives on the History of Psychoactive Substance Use, NIDA Research Monograph 24. U.S. Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse. DHEW Publication No. (ADM) 79-810, 1979. BARRETT, J.E., WITKIN, J.M. The role of behavioral and pharmacological history in determining the effects of abused drugs. In: Goldberg, S.R., Stolerman, I.P. (eds.1 Behavioral Analysis of Drug Dependence. Orlando: Academic Press, 1986, pp. 195-223. BATES, R.L. The effects of cigar and cigarette smoking on certain psychological and physiological functions: I. Dart throwing. Journal of Comparative Psychology 2:371-423, 1922. BA'MTG, K., BUZZI, R., NIL, R. Smoke yield of cigarettes and puffing behavior in men and women. Psychopharmacology 76:139-148, 1982. BENOWITZ, N.L. The use of biological fluid samples in assessing tobacco smoke consumption. In: Grabowski, J., Bell, C.S. feds.1 Measurement in the Analysis and Treatment of Smoking Behauior, NIDA Research Monograph 48. U.S. Department of Health and Human Services, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse. 1983, pp. 6-26. BENOWITZ, N.L. Clinical pharmacology of nicotine gum. In: Ockene, J.K. fed.1 The Pharmacologic Treatment of Tobacco Dependence: Proceedings of the World Congress. Cambridge, Massachusetts: Institute for the Study of Smoking Behavior and Policy. 1986, pp. 108-119. 217 BENOWITZ, N.L., HALL, SM., HERNING. R.I., JACOB, P. III, JONES, R.T., OSMAN, A.-L. Smokers of low-yield cigarettes do not consume less nicotine. .veul England Journal vf Medicrne 309(31:139-142, July 21. 1983. BENOWITZ. N.L.. JACOB, P. III. Nicotine and carbon monoxide intake from high- and low-yield cigarettes. Clinical Pharmacology and Therapeutics 36(2):265-270, August 1984. BENOWITZ, N.L., JACOB. P. III Nicotine renal excretion rate influences cigarette intake during cigarette smoking. +Jvurnal of Pharmacology and Experimental Therapeutics 234(11:153-155. 1985. BENOWITZ, N.L.. KUYT. F., JACOB. P. III. Circadian blood nicotine concentrations during cigarette smoking. Clinical Pharmacology and Therapeutics 32(6):75%764, December 1982. BENOWITZ, N.L., KUYT. F., JACOB, P. Influence of nicotine on cardiovascular and hormonal effects of cigarette smoking. Clinical Pharmacologv Therapeutics 36(1):74-81, 1984. BENOWITZ. N.L., JACOB, P. III, KOZLOWSKI, L.T., YU, L. Influence of smoking fewer cigarettes on exposure to tar, nicotine. and carbon monoxide. A;eus England Journal of Medicine 315(211:1310-1313, November 20, 1986. BIGELOW, G.E., STITZER. M.L.. GRIFFITHS, R.R., LIEBSON, LA. Human metha- done detoxification: Opioid self-administration behavior, cigarette smoking, and withdrawal signs and symptoms as a function of progressive dose reductions. (Abstract.) Federation Proceedings 40:296, 1981. BLITZER, P.H., RIMM, A.A.. GIEFER, E.E. The effect of cessation on body weight in 57,032 women: Cross-sectional and longitudinal analyses. Journal of Chronic Diseases 30(71:415-429, July 1977. BOSSE, R., GARVEY, A.J., COSTA, P.T. Jr. Predictors of weightshange following smoking cessation. International Journal of the Addictions 15(7):969-991, 1980. BOSY, L. Physician touts tobacco-free cigaret. American Medical News July 11, 1986. BOZARTH, M.A. Opiate reward mechanisms mapped by intracranial self-administra- tion. In: Smith, J.E.. Lane. J.D. ceds.1 The Neurobiology of Opiate Reward Processes. New York: Elsevier Biomedical Press. 1983. pp. 331-359. BRANThIARK, B.. OHLIN. P.. WESTLING. H. Nicotine-containing chewing gum as an anti-smoking aid. Pswhvphnrmacologia 31(33:191-200, 1973. BRIDGES, R.B., HUMBLE, J.W., TIJRBEK, J.A., REHM, S.R. Smoking history, cigarette yield and smoking behavior as determinants of smoke exposure. European Journal of Hespiratov Diseases 69tSuppIement 146):129-137, 1986. BURLING, T.A., SINGLETON, E.G., BIGELOW, G.E.. BAILE, W.F., GO'ITLIEB, S.H. Smoking following myocardial infarction: A critical review of the literature. Health Psychology 3(1):83-96, 1984. BURLING, T.A., STITZER. M.L., BIGELOW, G.E., MEAD, A.M. Smoking topography and carbon monoxide levels in smokers. Addictitje Behaviors 10:319-323, 1985. BURNS, B.H. Chronic chest disease, personality and success in stopping cigarette smoking. British Journal of Preuentice and Social Medicine 23:23-37, 1969. BURSE, R.L., BYNUM G.D., PANDOLF. K.B.. GOLDMAN, R.E., SIMS, E.A.H., DANFORTH, E.R. Increased appetite and unchanged metabolism upon cessation of smoking with diet held constant. Physiologist 18:157, 1975. BUZZI, R., NIL, R.. BATTIG. K. Development of puffing behavior along burning time of a cigarette-No relation to alveolar inhalation or nicotine delivery of the cigarettes? Psychopharmacology 86~1/2):102-107, May-June 1985 CAIN, W.S. Sensory attributes of cigarette smoking. In: Gori, G.B., Bock, F. (eds.) Banbury Report 3: A Safe Cigarette? New York: Cold Spring Harbor Laboratory, 1980, pp. 239-249. CARh'EY, R.M., GOLDBERG, A.P. Weight gain after cessation of cigarette smoking. A possible role for adipose-tissue lipoprotem lipase. The 1Veu: England Journal of Medicine 310!10'1:614-616, March 8, 1984. 218 CARVER, D.J. The immediate psychological effects of tobacco smoking. Comparative Psychology 2(4):279-301, 1922. CHAIT. L.D., GRIFFITHS. R.R. Differential control of puff duration and interpuff interval in cigarette smokers. Pharmacology Biochemistry and Behaoior 17(1):155158, July 1982a. CHAIT, L.D., GRIFFITHS, R.R. Smoking behavior and tobacco smoke intake: Response of smokers to shortened cigaret.tes Clinical Pharmacology and Therapeu- tics 32(11:9@-97, July 1982b. CHAIT, L.D., GRIFFITHS, R.R. Effects of caffeine on cigarette smoking and subjective response. Clinical Pharmarology and Therapeutics 3415):612622, November 1983. CHAIT, L.D., GRIFFITHS, R.R. Effects of methadone on human cigarette smoking and subjective ratings. Journal of Pharmacology and Experimental Therapeutics 229(3):63&640, June 1984. CHAIT, L.D., RUSS, N.W., GRIFFITHS, R.R. Effects of graded smoke inhalation on subsequent cigarette smoking behavior. Addictive Behariiors 10:273-280, 1985. CHAMBERLAIN, A.T., HIGENBOTTAM, T.W. Nicotine and cigarette smoking: An alternative hypothesis. Medical Hypotheses 17(4):285-297, August 1985. CHAN, T.L., SCHRECK, R.M. Effect of the laryngeal jet on particle deposition in the human trachea and upper bronchial airways. Journal of Aerosol Science 11(5/6):447459, 1980. CHEREK, D.R., MAURONER, R.F., BRAUCHI, J.T. Effects of increasing urinary pH on cigarette smoking. Clinical PharmacoZog.v and Therapeutics 32(2):253-260, 1982. CHILDRESS, A.R., McLELLAN;. A.T., EHRMAN, R., O'BRIEN, C.P. Classical conditioned responses in opioid and cocaine dependency; a role in relapse? In: Ray, B. (ed.1 Learning Factors in Substance Use, NIDA Research Monograph. U.S. Department of Health and Human Services, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse, in press. CLARK, M.S.G. Self-administered nicotine solutions preferred to placebo by the rat. British Pharmacological Society :367, January 2-3, 1969. CLARKE, P.B.S., FIBIGER, H.C. Apparent absence of nicotine-induced conditioned place preference in rata. Psychopharmacology 92(11:84-88, May 1987. CLEGHORN, J. "Smokeless cigarette" burns RJR. Charlotte Obseruer, November 14, 1987, p. 22. CLOUET, D.H., IWATSUBO, K. Mechanisms of tolerance to and dependence on narcotic analgesia drugs. In: Elliot, H.W., George, R., Okun, R. (eds.) Annual Review of Pharmacology, Volume 15. Palo Alto, California: Annual Reviews, Inc., 1975, pp. 49-71. COCHIN, J. Possible mechanisms in development of tolerance. Federation Proceedings 29(1):19-27, January-February 1970. COLPAERT, F.C. Discriminative stimulus properties of benzodiazepines and barbitu- rates. In: Lal, H. (ed.1 Discriminatiue Stimulus Properties of Drugs. New York: Plenum Press, 1977, pp. 93-106. CORTI, E.C. A History of Smoking. Translated by P. England. London: George G. Harrap, 1931. COX, B.M., GOLDSTEIN, A., NELSON, W.T. Nicotine self-administration in rata. British Journal of Pharmacology 83(1):49-55, September 1984. CREIGHTON, D.E., LEWIS, P.H. The effect of different cigarettes on human smoking patterns. In: Thornton, R.E. (ed.) Smoking Behauiour. Physiological and Psycholog icaf Influences. Edinburgh: Churchill Livingstone, 1978a, pp. 289-300. CREIGHTON, D.E., LEWIS, P.H. The effect of smoking pattern on smoke deliveries. In: Thornton, R.E. (ed.1 Smoking Behauiour. Physiological and Psychological Influences. Edinburgh: Churchill Livingstone, 197813, pp. 301-314. 219 CREIGHTON, D.E., NOBl,E. M.J., WHEWELL. R.T. Instruments to measure, record snd duplicate human amokmg patt.erns. In: Thornton, R.E. (ed.) Smoking Behoui- our: Physrolrgrml and Ps.rho!ogit~al Influences. London: Churchill Livingstone, 1978. pp. 277-288. C'UMMINGS. K.M., GIOVINO, G., JAEN, C.R., EMRICH, L.J. Reports of smoking withdrawal symptoms over a 21 day period of abstinence. Addictive Behaviors 10:373-381. March 1985. DE LA CARZA R., JOHANSON. C.E. The effects of food deprivation on the self- administration of psychoactive drugs. Drug and Alcohol Dependence 19(1):17-27, 1987. DENEAIJ, GA., INOKI, R. Nicotine self-administration in monkeys. Annals of the ,Ver:! York Academy of` Science 142:carticle 1):277-279, 1967. DIXON, W.E., LEE, W.E. Tolerance to nicotine. Journal of Experimental Physiology 5:353-383. 1912. DORSEY. .J.L. Control of the tobacco habit. Annals oflnternal Medicine 10(4~:628-631, 1936. DOUGHERTY, J , MILLER, D., TODD, G., KOSTENBAUDER, H.B. Reinforcing and other behavioral effects of nicotine. AVeur-oscience and Biobehauioral Reviews 5(4):487-495, Winter 1981. EDDY, N.B. The I&tional Research Council Involr~ement in the Opiate Problem: 1928- 1971. Washington, D.C.: National Academy of Sciences, 1973. EDWARDS, J.A.. WESNES, K., WARBURTON. D.M., GALE, A. Evidence of more rapid stimulus evaluation following cigarette smoking. Addictive Behaviors 1012):113-126, 1985. ELGEROT, A. Psychological and physiological changes during tobacco-abstinence in habitual smokers. Journal of Clmical Psychology 34(3):759-764, July 1978. EPSTEIN, L.H., DICKSON, B.E., OSSIP, D.J., STILLER, R., RUSSELL, P.O., WINTER, K. Relationships among measures of smoking topography. Addictive Behar:iors 7:307-310, 1982. EPSTEIN, L.H.. OSSIP. D.J., COLEMAN, D., HUGHES, J., WIIST, W. Measurement of smoking topography during withdrawal or deprivation. Behat*ior Therapy 12(41:507-519, September 1981. ETSCORN, F. Sucrose aversions in mice as a result of injected nicotine or passive tobacco smoke inhalation. Bulletin of the Psychonomic Society 15(1):54-56, 1980. ETSCORN, F.. MOORE, G.A., HAGEN. L.S.. CATON, T.M., SANDERS, D.L. Saccha- rin aversions in hamsters as a result of nicotine injections. Pharmacology Biochemistv and Behaclior 24:567-570, 1986. E\`ANS, R.I.. HENDERSON, A., HILL, P., RAINES, B. Smoking in children and adolescents: Psychosocial determinants and prevention strategies. In: Krasnegor, N.A. (ed.1 The Behatlioral Aspects of Smoking, NIDA Research Monograph 26. U.S. Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse. DHEW Publication No. (ADM) 79-882, 1979, pp. 69-96. EVANS. R.I., RAINES. B.E. Control and prevention of smoking in adolescents: A psychosocial perspective. In: Coates. T.J.. Petersen, A.C., Perry, C. (eds.1 Promoting Ado!cscent Health. New York: Academic Press, Inc., 1982, pp. 101-136. FAGERSTROM, K.-O. Measuring degree of physical dependence to tobacco smoking with reference to individualization of treatment. Addictive Behaviors 313;4):235-241, 1978. FAGERSTROM, K.-O. Reducing the weight gain after stopping smoking. Addictive Behac'iors 12:91-93, 1987. FAGERSTROM, K.-O.. BATES, S. Compensation and effective smoking by different nicotine dependent smokers. Addicttve Behaviors 6(4):331-336, 1981. FINNEGAN, J.K., LARSON. P.S., HAAG, H.B. The role of nicotine in the cigarette habit. Science 102:94--96, 1945. 220 FIORE, M., NOVOTNY, T.. LYNN, W.. MAKLAN, D.. DAVIS, H. Smoking cessation: Data from the 1986 Adult Use of Tobacco Survey. Proceedings of the 6th World Conference on Smoking and Health, November 9-12, 1987. In press. FISCHMAN, M.W., SCHUSTER, C.R. Cocaine self-administration in humans, Federa- tion Proceedings 41(21:241-246, February 1982. FISCHMAN. M.W., SCHUSTER, CR., RESNEKOV, I... SHICK, J.F.E.. KRASNE- GOR, N.A.. FENNELL. W., FREEDMAN, D.X. Cardiovascular and subjective effects of intravenous cocaine administration in humans. Archives uf General Psych&t?, 3318c983-989. August 1976. FIX, A.J., DAUGHTOK, D.M. Smoking cessation and acid-base balance. International .Journal of Biosociczl Rcseurch 2:9-l 1. 1981. FIX, A.J.. DAUGHTON, D.. KASS, I., SMITH, J.L., WICKISER, A., GOLDEN, C.J. Urinary alkalinization and smoking cessation. Clinical Psychology 39(4):617-623, 1983. FRANKENHAEUSER, %I., MYRSTEN. A.L.. POST, B., JOHANSSON, G. Behaviour- al and physiological effects of cigarette smoking in a monotonous situation. ~~.vchopharmacologia 22(1):1-7, October 20. 1971. FRITH, CD. The effect of varying the nicotine content of cigarettes on human smoking behavior. Psychopharmncologin 19(2):188-192, January 20, 1971. FUDALA, P.J., IWAMOTO, E.T. Further studies on nicotine-induced conditioned place preference in the rat. Pharmacology BiochemistT and Behavior 25:1041-1049, November 1986. FUDALA, P.J., IWAMOTO, E.T. Conditioned aversion after delay place conditioning with nicotine. Psychopharmacology 92:376-381. 1987. FUDALA. P.J., TEOH. K.W.. IWAMOTO, ET. Pharmacologic characterization of nicotine-induced conditioned place preference. Pharmacology, Biochemistry and Behavior 22:237-241. 1985. GALLUP, G. Jr. Majority backs ban on smoking in public places. The Gallup Poll, April 3, 1987, pp. l-2. GILBERT, R.M., POPE, M.A. Early effects of quitting smoking. Psychopharmacology 78(2):121-127, October 1982. GILLMAN, A.G., GOODMAN, L.S., RALL, T.W., MURAD, F. feds.1 Goodman and Gilman's The Pharmacological Basis of Therapeutics. New York: MacMillan Publishing Company, 1985. GLAUSER, S.C.. GLAUSER, E.M., REIDENBERG, M.M., RUSY. B.F., TALLARIDA., R.J. Metabolic changes associated with the cessation of cigarette smoking. Archives of Environmental Health 20:377-381, 1970. GOLDBERG, S.R., HENNINGFIELD, J.E. Fixed-ratio responding maintained by intravenous nicotine injections in humans and squirrel monkeys. Pharmacologist 25:219, 1983a. GOLDBERG, S.R., HENNINGFIELD, J.E. Intravenous nicotine self-administration in humans and squirrel monkeys. Neuroscience Letters 146upplement): S140, 1983b. GOLDBERG, S.R., HENNINGFIELD, J.E. Nicotzne as n Reinforcer in Humans and Experimental Animals. Paper presented at symposium on Progress in Understand- ing the Relationship Between the Pharmacological Effects of Nicotine and Human Tobacco Dependence, held at annual meeting of .4merican Society for Pharmacolo- gy and Experimental Therapeutics, Baltimore. Maryland, August 1986. GOLDBERG, S.R., HENNINGFIELD. J.E. Reinforcing effects of nicotine in humans and experimental animals responding under intermittent schedules of IV drug injection. Phnrmaco1og.v Biochemistq and BehaLszor 30:227-234, 1988. GOLDBERG, S.R., KELLEHER. R.T.. MORSE, W.H. Second-order schedules of drug injection. Federation Proceedings 34t9):1771-1776, 1975. GOLDBERG, S.R., SPEALMAN. R.D. Maintenance and suppression of behavior by intravenous nicotine injections in squirrel monkeys. Federatzon Proceedings 41t2):216-220. February 1982. 221 GOLDBERG, S.R., SPEALMAN, R.D. Suppression of behavior by intravenous injections of nicotine or by electric shocks in squirrel monkeys: Effects of chlordiazepoxide and mecamylamine. Journal of Pharmacolog? and Experimental Therapeutic.5 224(23:334-340, February 1983. GOLDBERG, S.R., SPEALMAN, R.D., GOLDBERG, D.M. Persistent behavior at high rates maintained by intravenous self-administration of nicotine. Science 214(4520!:573-575. October 30, 1981. GOLDBERG, S.R., SPEALMAN, R.D.. RISNER, M.E., HENNINGFIELD, J.E. Control of behavior by intravenous nicotine injections in laboratory animals. Pharmacolo- go Biochemistp and Behavior 19(6):1011-1020, December 1983. GOLDFARB, T.L., GRIT& E.R., JARVIK, M.E., STOLERMAN, I.P. Reactions to cigarettes as a function of nicotine and "tar". Clinical Pharmacology and Therapeutics 19(6):767-772, June 1976. GOLDFARB. T.L.. JARVIK, M.E. Accommodation to restricted tobacco smoke intake in cigarette smokers. International Journal of the Addictions 7(3):559565, 1972. GOLDFARB, T.L., JARVIK, M.E., GLICK, S.D. Cigarette nicotine content as a determinant of human smoking behavior. Psychopharmacologia 17(1):89-93, 1970. GORI, G.B. Observed no-effect thresholds and the definition of less hazardous cigarettes. Journal of Environmental Pathology and Toxicology 3:193-203, 1980. GORI, G.B., LYNCH, C.J. Analytical cigarette yields as predictors of smoke bioavailability. Regulatov Toxicology and Pharmacology 5(3):314-326, September 1985. GRABOWSKI, J., BELL, C.S. (eds.) Measurement in the Analysis and Treatment of SmokingBehavior, NIDA Research Monograph 48. US. Department of Health and Human Services, Public Health Service, Alcohol, Drug .4buse, and Mental Health Administration, National Institute on Drug Abuse. DHHS Publication No. (ADM) 83-1285, 1983. GRABOWSKI, J.. HALL, S.M. (eds.) Pharmacological Adjuncts in Smoking Cessation, NIDA Research Monograph 53. U.S. Department of Health and Human Services, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse. DHHS Publication No. IADMI 85-1333, 1985. GRAHAM, S., CROUCH, S., LEVIN, M.L., BOCK, F.G. Variations in amounts of tobacco tar retrieved from selected models of smoking behavior simulated by smoking machine. Cancer Research 23:1025-1030, August 1963. GRIFFITHS, R.R.. BIGELOW, G.E., HENNINGFIELD, J.E. Similarities in animal and human drug-taking behavior. In: Mello, N.K. (ed.) Advances in Substance Abuse, Volume 1. Greenwich, Connecticut: JAI Press, 1980, pp. l-90. GRIFFITHS. R.R., BIGELOW, G.E., LIEBSON, I. Facilitation of human tobacco self- administration by ethanol: A behavioral analysis. Journal of the Experimenfal Analws of Behaclior 25(3):279-292, May 1976. GRIFFITHS, R.R., BRADY, J.V., BRADFORD, L.D. Predicting the abuse liability of drugs with animal drug self-administration procedures: Psychomotor stimulants and hallucinogens. In: Thompson. T., Dews, P.B. (eds.1 AdLlances in Behavioral Pharmacolog.v. Volume 2. Neu- York: Academic Press, 1979, pp. 163-208. GRIFFITHS. R.R., HENNINGFIELD, J.E. Experimental analysis of human cigarette smoking behavior. Federation Proceedings 41(21:234-240, February 1982. GRIFFITHS, R.R.. HENNINGFIELD. J.E., BIGELOW, GE. Human cigarette smok- ing: Manipulation of number of puffs per bout. interbout interval and nicotine dose. Journal of Pharmacolog> and Experimental Therapeutics 220(2):256-265, February 1982. GRITZ. E.R. Patterns of puffing in cigarette smokers. In: Krasnegor, N.A. (ed., Self- Administration of Abused Substances: Methods for Study, NIDA Research Mono- graph 20. U.S. Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse. DHEW Publication No. tADMl78-727, 1978, pp. 221-235. 222 GRIT& E.R. Smoking behavior and tobacco use. In: Mello, N.K. (ed.) Ad~tznces in Substance Abuse, Volume 1. Greenwich, Connecticut: JAI 3ress, Inc., 1980, pp. 91-158. GRITZ, E.R., BAER-WEISS, V., JARVIK. M.E. Titration of nicotine intake with full- length and half-length cigarettes. Clinical Pharmacology and Therapeutics 2&5):552-556, November 1976. GRITZ, E.R., JARVIK, M.E. Preliminary study: Forty-eight hours of abstinence from smoking. Proceedings of the 81st Annual Convention, American Psychological Association 8:1039-1040, 1973. GRITZ, E.R., ROSE, J.E., JARVIK, M.E. Regulation of tobacco smoke intake with paced cigarette presentation. Pharmacology, Biochemist? and Behavior 18(3):457-462, March 1983. GRUNBERG, N.E. The effects of nicotine and cigarette smoking on food consumption and taste preferences. Addictive Behaviors 7(4):317-331, 1982. GRUNBERG, N.E. Nicotine as a psychoactive drug: Appetite regulation. Psychophar- macology Bulletin 22(3):875-881, 1986. GRUNBERG, N.E., KOZLOWSKI, L.T. Alk a me therapy as an adjunct to smoking 1' cessation programs. International Journal of Biosocial Research 8(11:43-52, 1986. GUILLERM, R., RADZISZEWSKI, E. Analysis of smoking pattern including intake of carbon monoxide and influences of changes in cigarette design. In: Thornton, R.E. (ed.1 Smoking Behaviour. Physiological and Psychological Znfiruences. Edinburgh: Churchill Livingstone, 1978, pp. 361-370. GUST, SW., PICKENS, R.W Does cigarette nicotine yield affect puff volume? Clinical Pharmacology and Therapeutics 32(4):418-422,- October 1982. GUST, SW., PICKENS, R.W., PECHACEK, T.F. Recording puff volume in smoking. Behavior Research Methods and Instrumentation X(3):341-343, June 1983a. GUST, S.W., PICKENS, R.W., PECHACEK, T.F. Relation of puff volume to other topographical measures of smoking. Addictive Behaviors 8(2):115-119, 1983b. HAERTZEN, CA. Changes in correlation between responses to items of the Addiction Research Center Inventory produced by LSD-25. Journal of Psycho-pharmacology 1:2736, 1966. HAERTZEN, C.A. An Overview ofAddiction Research Center Znventory Scales (ARCI): An Appendix and Manual of Scales. U.S. Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse. DHEW Publication No. (ADM) 74-92, 1974. HAERTZEN, C.A., HICKEY, J.E. Addiction Research Center Inventory (ARCI): Measurement of euphoria and other drug effects. In: Bozarth, M.A. (ed.) Methods of Assessing the Reinforcing Properties ofdbused Drugs. New York: Springer Verlag, 1987, pp. 489-524. HALL, S.M., GINSBERG, D., JONES, R.T. Smoking cessation and weight gain. Journal of Consulting and Clinical Psychology 54(3):342-346, June 1986. HALL, R., RAPPAPORT, M., HOPKINS, H.K., GRIFFIN, R. Tobacco and evoked potential. Science 180(4082):2X?-214, April 13, 1973. HANSON, H.M., IVESTER, C.A., MORTON, B.R. Nicotine self-administration in rats. In: Krasnegor, N.A. fed.) Cigarette Smoking as a Dependence Process, NIDA Research Monograph 23. U.S. Department of Health, Education and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse. DHEW Publication No. (ADMi 74800, 1979, pp. 70-90. HARRIS, C.M., EMMETT-OGLESBY, M.W., ROBINSON, N.G., LAL, H. Withdrawal from chronic nicotine substitutes partially for the interoceptive stimulus produced by pentylenetetrazol (PTZ). Psychopharmacologia 9085-89, 1986. 223 HATSUKAMI, D.K., GUST, S.W., KEENAN, R.M. Physiologic and subjective changes from smokeless tobacco withdrawal. Clinical Phatmacology and Thempeutics 41(1~:10,3-107, 1987. HATSUKAMI, D.K., HUGHES, J.R., PICKENS, R.W. Characteristics of tobacco withdrawal: Physiological and subjective effects. In: Grabowski, J., Hall, S.M. feds.) Pharmacological Adjuncts in Smoking Cessation, NIDA Research Monograph 53. U.S. Department of Health and Human Services, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse. DHHS Publication No. (ADM) 851333, 1985, pp. 56-67. HATSUKAMI, D.K., HUGHES, J.R., PICKENS, R.W., SVIKIS, D. Tobacco withdraw- al symptoms: An experimental analysis. Psychopharmacology 84(2):231-236, Octo- ber 1984. HEATH, G.F., PORTER, J.H., ROSECRANS, J.A. @-Nicotine Blocks the Effects of Diazepam on Punished Responding in Rats. Eastern Psychological Association Meeting, Philadelphia, 1985. HEIMSTRA, N.W., BANCROFT, N.R., DEKOCK, A.R. Effects of smoking upon sustained performance in a simulated driving task. Annals of the New York Academy of Sciences 142:295-307, 1967. HENNINGFIELD, J.E. Behavioral pharmacology of cigarette smoking. In: Thompson, T., Dews, P.B., Barrett, J.E. (eds.) Adoances in Behaoioml Pharmacology, Volume 4. Orlando: Academic Press, 1984, pp. 131-210. HENNINGFIELD, J.E. How tobacco produces drug dependence. In: Ockene, J.K. (ed.) The Pharmacologic Treatment of Tobacco Dependence: Proceedings of the World Congress, November 4-5, 1985. Cambridge, Massachusetts: Institute for the Study of Smoking Behavior and Policy, 1986a, pp. 19-31. HENNINGFIELD, J.E. Principle investigator. Annual Progress Report: Biology of Dependence and Abuse Potentral Assessment Labomtory. In: Annual Report of the Addiction Research Center, Addiction Research Center, National Institute on Drug Abuse, 1986b. HENNINGFIELD, J.E. Principle investigator. Annual Progress Report: Biology of Dependence and Abuse Potential Assessment Labomtory. In: Annual Report of the Addiction Research Center, Addiction Research Center, National Institute on Drug Abuse, 1987a. HENNINGFIELD, J.E. Redefining craving. NZDA Notes 2(1):9, 1987b. HENNINGFIELD, J.E. Reducing the urge to smoke. Chest 92(6)5X3, 1987c. HENNINGFIELD, J.E., BROWN, B.S. Do replacement therapies t.reat craving? NZDA Notes 2(1):3-g, 1987. HENNINGFIELD, J.E., CHAIT, L.D., GRIFFITH& R.R. Cigarette smoking and subjective response in alcoholics: Effects of pentobarbital. Clinical Pharmacology and Thempeutics 33(6):8X-812, June 1983. HENNINGFIELD, J.E., CHAIT, L.D., GRIFFITH& R.R. Effects of ethanol on cigarette smoking by volunteers without histories of alcoholism. Psychopharmacol- ogy 82(1/2):1-5, 1984. HENNINGFIELD, J.E.. GOLDBERG, S.R. Control of behavior by intravenous nicotine injections in human subjects. Pharmacoiogy Biochemistry and Behavior 19(6):1021-1026, December 1983a. HENNINGFIELD, J.E., GOLDBERG, S.R. Nicotine as a reinforcer in human subjects and laboratory animals. Pharmacology Biochemistry and Behavior 19(6):98%992, 1983b. HENNINGFIELD, J.E., GRIFFITHS, R.R. A preparation for the experimental and analysis of human cigarette smoking behavior. Behavior Research Methods Instrumentation 11(6):538-544, December 1979. HENNINGPIELD, J.E., GRIFFITH& R.R. Effects of ventilated cigarette holders on cigarette smoking by humans. Psychopharmacology 68(2):115-119, May 1980. 224 HENNINGFIELD, J.E., GRIFFITHS, R.R. Cigarette smoking and subjective response: Effects of d-amphetamine. Clinical Pharmacology and Therapeutics 30(4):497-505, October 1981. HENNINGFIELD, J.E., MIYASATO, K., JASINSKI, D.R. Cigarette smokers self- administer intravenous nicotine. Pharmacology Biochemistry and Behaoior 19(5):887-890, November 1983. HENNINGFIELD, J.E., MIYASATO, K.. JASINSKI, D.R. Abuse liability and pharmacodynamic characteristics of intravenous and inhaled nicotine. JournaZ of Pharmacology and Experimental Therapeutics 234(1):1-12, July 1985. HENNINGFIELD, J.E., MIYASATO, K., JOHNSON, R.E., JASINSKI, D.R. Rapid physiologic effects of nicotine in humans and selective blockade of behavioral effects by mecamylamine. In: Harris, L.S. (ed.) Problems ofDrug Dependence, 1982, NIDA Research Monograph 43. U.S. Department of Health and Human Services, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse. DHHS Publication No. (ADM) 83-1264,1983, pp. 259-265. HENNINGFIELD, J.E., YINGLING, J., GRIFFITHS. R.R., PICKENS, R. An inexpen- sive portable device for measuring puffing behavior by cigarette smokers. Pharmacology Biochemistry and Behavior 12(5):811-813, 1980. HERNING, R.I. Principle investigator. Annual Progress Report: Cognitive Studies and Human Performance Laboratory, Annual Report of the Addiction Research Center, Fiscal Year 1986. U.S. Department of Health and Human Services, Public Health Service, Alchol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse. 1987. HERNING, R.I., HUNT, J.S., JONES, R.T. The importance of inhalation volume when measuring smoking behavior. Behavior Research Methods and Instrumentation 15(6):561-568, 1983. HERNING, RI., JONES, R.T.. BACHMAN, J. EEG changes during tobacco withdraw- al. Psychophysiology 20(5):507-512, September 1983. HERNING, R.I., JONES. R.T., BACHMAN, J., MINES, A.H. Puff volume increases when low-nicotine cigarettes are smoked. British Medical Journal 283(6285):187-189, July 18, 1981. HERNING, R.I., JONES. R.T., BENOWITZ, N.L., MINES, A.H. How a cigarette is smoked determines blood nicotine levels. Clinical Pharmacology and Therapeutics 33(1):84-90, January 1983. HERNING, R.I., JONES, R.T., FISCHMAN, P. The titration hypothesis revisited: Nicotine gum reduces smoking intensity. In: Grabowski, J., Hall, S.M. feds.) Pharmacological Adjuncts in Smoking Cessation, NIDA Research Monograph 53. U.S. Department of Health and Human Services, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse. DHHS Publication No. (ADM) 85-1333, pp. 27-41, 1985. HERSKOVIC, J.E., ROSE, J.E., JARVIK, M.E. Cigarette desirability and nicotine preference in smokers. Pharmacology Biochemistry and Behavior 24(2):171-175, February 1986. HILDING, A.C. On cigarette smoking, bronchial carcinoma and ciliary action. I. Smoking habits and measurement of smoke intake. New England Journal of Medicine 254(17):775-781, April 26, 1956. HIMMELSBACH, C.K. Clinical studies of drug addiction. Physical dependence, withdrawal and recovery. Archives of Internal Medicine 69:766-772, 1942. HOFSTET'I'ER, A., SCHUTZ, Y., JEQUIER, E., WAHREN, J. Increased 24-hour energy expenditure in cigarette smokers. New England Journai of Medicine 314(2)2:79-82, January 9, 1986. HOWARD, J.L., CRAFT, R.M. Cue properties of nicotine by oral and transdermal routes. (Abstract.) Federation Proceedings 45(4):1132, March 5, 1986. HUGHES, J.R. Craving as a psychological construct. British Journal of Addictions 82(1):38-39, 1987. HUGHES, J.R. Dependence potential and abuse liability of nicotine replacement therapies. In: Pomerleau, O.F., Pomerleau, C.S., FagerstrGm, K.O., Henningtield, J.E., Hughes, J.R. (eds.) Nicotine Replacement: A Critical Euoluation. New York: Alan R. Liss, 1988, pp. 261-277. HUGHES, J.R., GUST, SW., PECHACEK, T.F. Prevalence of tobacco dependence and withdrawal. The American Journal of Psychiatry 144:205-208, 1987. HUGHES, J.R., HATSUKAMI, D. Signs and symptoms of tobacco withdrawal. Archives of General Psychiatry 43(3):289-294. March 1986. HUGHES, J.R., HATSUKAMI, D.K., PICKENS, R.W., KRAHN, D., MALINS, S., LUKNIC, A. Effect of nicotine on the tobacco withdrawal symptom. Psychophar- macology 83(1):82-87, April 1984. HUGHES, J.R., HATSUKAMI, D.K., PICKENS, R.W., SVIKIS, D.S. Consistency of the tobacco withdrawal syndrome. Addictive Behaoiors 9:409-412, 1984. HUGHES, J.R., HATSUKAMI, D., SKOOG, K.P. Physical dependence on nicotine gum: A placebo substitution trial. Journal of the American Medical Association 255(23):3277-3279, June 20, 1986. HUGHES, J.R., PICKENS, R.W., GUST, SW., HATSUKAMI, D.K., SVIKIS, D.S. Smoking behavior of Type A and Type B smokers. Addictiue Behaviors 11:11.%118, 1986. HUNT, T., AMIT, 2. Conditioned taste aversion induced by self-administered drugs: Paradox revisited. Neuroscience and Biobehauioml Reviews 11:107-130, 1987. HUTCHINSON, R.R., EMLEY, G.S. Effect of nicotine on avoidance, conditioned suppression and aggression response measures in animals and man. In: Dunn, W.L. ted.) Smoking Behavior: Motives and Zncentioes. Washington, D.C.: V.H. Winston and Sons, 1973. pp. 171-196. ISBELL, H. Methods and results of studying experimental human addiction to the newer synthetic analgesics. Annals of the New York Academy of Sciences 51(1):10&122, 1948. ISBELL, H., FRASER, H.F., WIKLER, A., BELLEVILLE, R.E., EISENMAN, A.J. An experimental study of the etiology of "rum fits" and delirium tremens. Quarterly Journal of Studies on Alcohol 16:1-33, 1955. IWAMOTO, E.T., WILLIAMSON, E.C. Nicotine-induced taste aversion: Characteriza- tion and preexposure effects in rats. Pharmacology Biochemistry and Behavior 21:527-532, 1984. JACOBSON, N.L., JACOBSON, A.A., RAY, J.P. Non-combustible cigarette: Alterna- tive method of nicotine delivery. (Abstract.) Chest 76(3):35&356, September 1979. JAFFE, J.H. Drug addiction and drug abuse. In: Gilman, A.G., Goodman, L.S., Rail, T.W. Murad, F. (eds.1 Goodman and Gilman's The Pharmacologic Basis of Thempeutics, Seventh Edition. New York: MacMillan Publishing Company, 1985, pp. 532-581. JAFFE, J.H., JARVIK, M.E. Tobacco use and tobacco use disorder. In: Lipton, M.A., DiMascio, A., Killam, K.F. (eds.) Psychopharmacology: A Generation of Pmgress. New York: Raven Press, 1978, pp. 1665-1676. JARVIK, M.E., CULLEN, J.W., GRITZ, E.R., VOGT, T.M., WEST, L.J. (eds.) Research on Smoking Behauior, NIDA Research Monograph 17. U.S. Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse. DHEW Publication No. (ADM) 78581, 1977. JARVIK, M.E., GLICK, S.D., NAKAMURA, R.K. Inhibition of cigarette smoking by orally administered nicotine. Clinical Pharmacology and Thempeutics 1X4):574-576, 1970. JARVIK, M.E., HENNINGFIELD, J.E. Pharmacological treatment of tobacco depen- dence. Pharmacology Biochemistry and Behavior 30~279-294, 1988. JARVIK, M.E., POPEK, P., SCHNEIDER, N.G., BAER-WEISS, V., GRITZ, E.R. Can cigarette size and nicotine content influence smoking and puffing rates? Psycho- pharmacoloa 58(3):303-306, 1978. JARVIS, M.J., RAW, M., RUSSELL, M.A.H., FEYERABEND, C. Random&d controlled trial of nicotine chewing-gum. British Medical Journal 285(6341):537540, August 21, 1982. JARVIS, M.J., TUNSTALLPEDOE, H., FEYERABEND, C., VESEY, C.. SALOOJEE, Y. Comparison of tests used to distinguish smokers from nonsmokers. American Journal of Public Health 77~1435-1438, 1987. JASINSKI, D.R. Opiate withdrawal syndrome: Acute and protracted aspects. Ann& of the New York Academy of Sciences 362:18%186, 1981. JASINSKI, D.R., HENNINGFIELD, J.E. Conceptual basis of replacement therapies for chemical dependence. In: Pomerleau, O.F., Pomerleau, C.S., Fagerstrom, K.-O., Henningfield, J.E., Hughes, J.R. cods.) Nicotine Replacement: A Critical Eualu- ation. New York: Alan R. Liss, 1988, pp. 13-34. JASINSKI, D.R., JOHNSON, R.E., HENNINGFIELD, J.E. Abuse liability assessment in human subjects. Trends in Pharmacological Sciences M5):196-200, May 1984. JENKINS, R.A., GAYLE, T.M. An instrumental cigarette smoke monitor designed for the direct measurement of smoke particulate matter generated in human smoking studies. Behavior Research Methods, Instruments, and Computers 1@3):263-267, 1984. JOHNSTON, L.M. Tobacco smoking and nicotine. Luncet 2:742, 1942. JONES, R.T., FARRELL, T.R. III, HERNING, R.I. Tobacco smoking and nicotine tolerance. In: Krasnegor, N.A. (ed.1 SelfAdministmtion of Abused Substances: Methods for Study, NIDA Research Monograph 20. U.S. Department of Health, Education and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse. July 1978, pp. 202-208. KALANT, H. Behavioral criteria for tolerance and physical dependence. In: Fishman, J. (ed.) The Bases of Addiction Berlin: Dahlem Konferenzen, pp.199-220, 1978. KALANT, H., LEBLANC, A.E., GIBBONS, R.J. Tolerance to, and dependence on, some non-opiate psychotropic drugs. Pharmacological Reviews 23(3):135-191,197l. KALES, J., ALLEN, C., PRESTON, T.A., TAN, T.-L., KALES, A. Changes in REM sleep and dreaming with cigarette smoking and following withdrawal. (Abstract). Psychophysiology 7(2):347-348, September 1970. KALLMAN, W.M., KALLMAN, M.J., HARRY, G.J., WOGDSON, P.P., ROSECRANS, J.A. Nicotine as a discriminative stimulus in human subjects. In: Colpaert, F.C., Slangen, J.L. cods.1 Drug Discrimination: Applications in CNS Pharmacology. Amsterdam: Elsevier Biomedical Press, 1982, pp. 211-218. KARANCI, N.A. Individual nicotine requirements: The relationship between differ- ences in nicotine intake and physiological response. Biological Psychology 21Gk27-42, August 1985. KARRAS, A., KANE, J.M. Naloxone reduces cigarette smoking. Life Sciences 27(17):1541-1545, 1980. KATZ, J.L., GOLDBERG, S.R. Second-order schedules of drug injection: Implications for understanding reinforcing effects of abused drugs. In: Mello, N.K. (ed.1 Advances in Substance Abuse, Volume 3. Greenwich, Connecticut: JAI Press, Inc., in press. KHOSLA, T., LOWE, C.R. Obesity and smoking habits. British Medic& Journal 4(5778):X)-13, October 2, 1971. KLEINMAN, K.M., VAUGHN, R.L., CHRIST, T.F. Effect of cigarette smoking and smoking deprivation on paired-associate learning of high and low meaningful nonsense syllables. Psychological Report 32(3):963-966, 1973. KNAPP, P.H., BLISS, CM., WELLS, H. Addictive aspects in heavy cigarette smoking. American Journal of Psychiatry 119(10):966972, April 1963. 227 KNOTT, V.J., VENi\BLES, P.H. EEG alpha correlates of non-smokers, smokers, smoking, and smoking deprivation. Psychophysiology 14(2):15&156, 1977. KNOTT, V.J., VENABLES, P.H. Stimulus intensity control and the cortical evoked response in smokers and non-smokers. Psychophysiology X(3):186192, May 1978. KNOTT, V.J., VENABLES, P.H. EEG alpha correlates of alcohol consumption in smokers and nonsmokers. Effects of smoking and smoking deprivation. Journal of Studies on Alcohol 40(3):247-257, March 1979. KOZLOWSKI, L.T. Effects of caffeine consumption on nicotine consumption. Psycho- pharmacology 47(2):16&168, 1976. KOZLOWSKI, L.T. Psychosocial influences on cigarette smoking. In: Krasnegor, N.A. (ed.) The Behaoioral Aspects of Smoking, NIDA Research Monograph 26. U.S. Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse. DHEW Publication No. 79882, 1979, pp. 99-125. KOZLOWSKI, L.T. Tar and nicotine delivery of cigarettes: What a difference a puff makes. Journal of the American Medical Association 245(2):158159, 1981. KOZLOWSKI, L.T. Tar and Nicotine Ratings May Be Hazardous to Your Health, Toronto: Alchoholism and Drug Addiction Research Foundation, 1982. KOZLOWSKI, L.T. Blocking the filter vents of cigarettes. (Letter). JournaE of the American Medical Association 2%X23):3214, December 19, 1986. KOZLOWSKI, L.T. Less hazardous smoking and the pursuit of satisfaction. American Journal of Public Health 77(5):539-541, May 1987. KOZLOWSKI, L.T., JARVIK, M.E., GRITZ, E.R. Nicotine regulation and cigarette smoking. Clinical Pharmacology and Thempeutics 17:93-97, January 1975. KOZLOWSKI, L.T., RICKERT, W.S., POPE, M.A., ROBINSON, J.C. A color-matching technique for monitoring tar/nicotine yields to smokers. American Journal of Public Health 72(6):597-599, June 1982. KOZLOWSKI, L.T., RICKERT, W.S., POPE, M.A., ROBINSON, J.C., FRECKER, R.C. Estimating the yield to smokers of tar, nicotine, and carbon monoxide from the "lowest-yield" ventilated filter-cigarettes. British Journal of Addiction 77(2):159-X5, June 1982. KOZLOWSKI, L.T., WILKINSON, D.A. Use and misuse of the concept of craving by alcohol, tobacco, and drug researchers. British Journal of Addiction 82:31-36, 1987. KRASNEGOR, N.A. (ed.1 Self-Administration of Abused Substances: Methods for Study, NIDA Research Monograph 20. U.S. Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse. DHEW Publication No. (ADM) 78727, 1978. KRASNEGOR, N.A. (ed.) Behavioml Analysts and Treatment of Substance Abuse, NIDA Research Monograph 25. U.S. Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse. DHEW Publication No. (ADM) 79-839, 1979a. KRASNEGOR, N.A. (ed.) The Behavioral Aspects of Smoking, NIDA Research Monograph 26. U.S. Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse. DHEW Publication No. (ADM) 79-882, 1979b. KRASNEGOR, N.A. (ed.1 Cigarette Smoking as a Dependence Process, NIDA Research Monograph 23. U.S. Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse. DHEW Publication No. (ADM) 79800, 1979c. KUMAR, R., COOKE, E.C., LADER, M.H., RUSSELL, M.A.H. Is nicotine important in tobacco smoking? Clinical Pharmacology and Therapeutics 21(51:520-529, May 1977. 228 KUMAR, R., PRATT, J.A., STOLERMAN, I.P. Characteristics of conditioned taste aversion produced by nicotine in rats. British Journal of Pharmacology 79:245-253, 1983. LANG, W.J., LATIFF, A.A., McQUEEN, A., SINGER, G. Self-administration of nicotine with and without a food delivery schedule. Pharmacology Biochemistry and Behavior 7(l)%-70, June 1977. LANGLEY, J.N. On the reaction of cells and of nerve-endings to certain poisons, chiefly as regards the reaction of striated muscle to nicotine and to curari. Journal of Physiology (London) 33:374-413, 1905. LARSON, P.S., HAAG, H.B., SILVE'ITE, H. Tobacco: Experimental and Clinical Studies. A Comprehensiue Account of the World Literature. Baltimore: Williams and Wilkins Co., 1961. LARSON, P.S., SILVE'ITE, H. Tobacco. Experimental and Clinical Studies. A Comprehensive Account of the World Litemture, Supplement 1. Baltimore: Williams and Wilkins Co., 1968. LARSON, P.S., SILVE'ITE, H. Tobacco. Experimental and Clinical Studies: A Comprehensive Account of the World Literature, Supplement II. Baltimore: Williams and Wilkins Co., 1971. LARSON, P.S., SILVETTE, H. Tobacco. Experimental and Clinical Studies. A Comprehensive Account of the World Literature, Supplement III. Baltimore: Williams and Wilkins Co., 1975. LATIFF, A.A., SMITH, L.A., LANG, W.J. Effects of changing dosage and urinary pH in rata self-administering nicotine on a food delivery schedule. Pharmacology Biochemistry and Behavior 13(2):209-213, August 1980. LEVITT, E.E. Reasons for smoking and not smoking given by school children. Journal of School Health 41(2):101-105, February 1971. LEWIN, L. Phantastica: Narcotic and Stimulating Drugs, Their Use and Abuse. London: Paul, Trench, Trubner, 1931. LICHTENSTEIN, E., ANTONUCCIO, D.O. Dimensions of smoking behavior. Addic- tiue Behauiors 6(4):365-367, 1981. LINCOLN, J.E. Weight gain after cessation of smoking. (Letter). Journal of the American Medical Association 210(9):1765, December 1, 1969. LOWE, G. Combined effects of alcohol and nicotine on human statedependent learning. IRCS Medical Science 13:813, 1985. LUCCHESI, B.R., SCHUSTER, CR., EMLEY, G.S. The role of nicotine as a determinant of cigarette smoking frequency in man with observations of certain cardiovascular effects associated with the tobacco alkaloid. Clinical Pharmacology and Therapeutics 8(6):789-796, November-December 1967. LUDWIG, A.M., STARK, L.H. Alcohol craving: Subjective and situational aspects. Quarterly Journal of Studies on Alcohol 35:899-905, 1974. LUNDBERG, J.M., MARTLING, C.-R., SARIA, A., FOLKERS, K., ROSELL, S. Cigarette smoke-induced airway oedema due to activation of capsaicin-sensitive vagal afferents and substance P release. Neuroscience 10(4):1361-1368, 1983. LUNDBERG, J.M., SARIA, A., MARTLING, C.-R. Capsaicin pretreatment abolishes cigarette smoke-induced oedema in rat trachea-bronchial mucosa. European Journal of Pharmacology 86(2):317-318, December 24, 1982. MARLATT, G.A. Craving notes. British Journal of Addiction 82(1):4244, 1987. MARTIN, J.E., PRUE, D.M., COLLINS, F.L. Jr., THAMES, C.J. The Effects of Graduated Filters on Smoking Rate, Topogmphy and Carbon Monoxide Levels in Smokers, Paper presented before the Society of Behavioral Medicine, New York, November, 1980. MARTIN, W.R. Assessment of Depressant Abuse Potentiality. Baltimore: University Park Press, 1977, pp. 9-15. MAUSNER, J.S. Cigarette smoking among patients with respiratory disease. Ameri- can Review of Respiratory Disease 102(2):704-713, November 1970. MCBRIDE, M.J., GIJYATT. A.R., KIRKHAM, A.J.T., CUMMING, G. Assessment of smoking behaviour and ventilation with cigarettes of differing nicotine yields. Clinical Science 67(61:619-631, December 1984. McMORROW. M.J., FOXX, R.M. Nicotine's role in smoking: An analysis of nicotine regulation. Psychological Bulletin 93(21:302-327, March 1983. MEDICAL ECONOMICS COMPANY. Physician's Desk Reference. Oradell, New Jersey: Medical Economics Company, Inc., 1988. MEDICI, T.C., UNGER, S., RUEGGER, M. Smoking pattern of smokers with and without tobacco-smoke-related lung diseases. American Review of Respimtory Disease 131(31:385-388, March 1985. MEISCH, R.A. Ethanol self-administration: Infrahuman studies. In: Thompson, T., Dews, P.B. teds.) Advances in Behauioml Pharmacology, Volume 1.. New York: Academic Press, 1977, pp. 35-84. MELLO, N.K. Theoretical review: A review of methods to induce alcohol addiction in animals. Pharmacology Biochemistry and Behavior 1:89-101, 1973. MELLO, N.K.. MENDELSON, J.H., SELLERS, M.L., KUEHNLE, J.C. Effects of heroin self-administration on cigarette smoking. Psychopharmacology 67:45-52, 198Oa. MELLO, N.K., MENDELSON, J.H., SELLERS, M.L., KUEHNLE, J.C. Effect of alcohol and marihuana on tobacco smoking. Clinical Pharmacology and Thempeu- tics 27(2):202-209, February 1980b. MINTZ, M. Tobacco lawyer said to concede risk. Alleged comment could hurt industry in court; R.J. Reynolds denies report. The Washington Post, December 2, 1987, pp. Fl, F4. MINTZ, J., BOYD, G., ROSE, J.E., CHARUVASTRA, V.C., JARVIK, M.E. Alcohol increases cigarette smoking: A laboratory demonstration. Addictiue Behaviors 10(3):203-207, 1985. MOODY, P.M. The relationships of qualified human smoking behavior and demo- graphic variables. Social Science and Medicine 14A(1):49-54, January 1980. MOSS, R.A.. PRUE, D.M. Research on nicotine regulation. Behavior Therapy 13:31-46, 1982. MURPHEE, H.B., SCHULTZ, R.E. Abstinence effects in smokers. (Abstract.1 Fe&ml Proceedings 27(2):220, March-April 1968. MYRSTEN, A.-L., ELGEROT, A., EDGREN, B. Effects of abstinence from tobacco smoking on physiological and psychological arousal levels in habitual smokers. Psychosomatic Medicine 39(1):25-38, January-February 1977. MYRSTEN, A.-L., POST, B., FRANKENHAEUSER, M., JOHANSSON, G. Changes in behavioral and physiological activation induced by cigarette smoking in habitual smokers. Psycholpharmacologia 27(4):30&312, 1972. NARUSE, T., ASAMI, T., IKEDA, N., OHMURA, I. Rapid establishment of nicotine intravenous self-administration behavior in rata. Yakubutsu, Seishin, Kodo 6(3):367-371, 1986. NEMETH-COSLE'M', R., GRIFFITHS, R.R. Determinants of puff duration in cigarette smokers: I. Pharmacology Biochemistry and Behavior 20(6):965-971, June 1984a. NEMETH-COSLETT, R.. GRIFFITHS, R.R. Determinants of puff duration in cigarette smokers: II. Pharmacology Biochemistry and Behavior 21(61:903--912, December 1984b. NEMETH-COSLETT. R., GRIFFITH8 R.R. Effects of cigarette rod length on puff volume and carbon monoxide delivery in cigarette smokers. Drug and Alcohol Dependence 15(1/2):1-13, May 1985. NEMETH-COSLETT, R.. GRIFFITHS, R.R. Naloxone does not affect cigarette smoking. Psychopharmacology 89(3):261-264, July 1986. NEMETH-COSLE'M', R., HENNINGFIELD, J.E. Effects of nicotine chewing gum on cigarette smoking and subjective and physiologic effects. Clinical Pharmacology and Therapeutics 3916):625-630, June 1986. 230 NEMETH-COSLETT, R.. HENNINGFIELD, J.E.. O'KEEFE, M.K., GRIFFITH& R.R. Effects of mecamylamine on human cigarette smoking and subjective ratings. Psychopharmacology 88(4):42G425, 1986a. NEMETHCOSLETT, R., HENNINGFIELD, J.E.. O'KEEFE, M.K., GRIFFITHS. R.R. Effects of marijuana smoking on subjective ratings and tobacco smoking. Pharma- cology Biochemist?] and Aehatvior 25(3):659-665, September 1986b. NEMETH-COSLETT, R., HENNINGFIELD, J.E., O'KEEFE, M.K., GRIFFITHS, R.R. Nicotine gum: Dose-related effects on cigarette smoking and subjective ratings. Psychopharmacology 92(1):424-430, May 1987. NIL. R.. BUZZI, R., BW'ITIG, K. Effects of single doses of alcohol and caffeine on cigarette smoke puffing behavior. Pharmacalog.v Bzochemist~ and Behavior 20(4):583-590. April 1984. NIL, R., BUZZI, R.. BliTTIG. K. Effects of different cigarette smoke yields on puffing and inhalation: Is the measurement of inhalation volumes relevant for smoke absorption? Pharmacolog,y Biochemistry and BehaLxtor 24(3):587-595, 1986. NIL, R., WOODSON, P.P., BiiTl'IG, K. Smoking behavior and personality patterns of smokers with low and high CO absorption. Clinica/ Science 71(5):595-603, November 1986. NOPPA, H., BENGTSSON, C. Obesity in relation to smoking: A population study of women in Goteborg, Sweden. Preuentirle Medicine 9(4):534-543, July 1986. OSSIP, D.J., EPSTEIN, L.H. Relative effects of nicotine and coffee on cigarette smoking. Addictive Behaciors 6:35-39, 1981. OSSIP-KLEIN, D.J., EPSTEIN, L.H., WINTER, M.K., STILLER, R., RUSSELL, P., DICKSON, B. Does switching to low tar/nicotine/carbon monoxide-yield cigarettes decrease alveolar carbon monoxide measures? A randomized controlled trial. Journal of Consulting and Clinical Psychology 51(2):234-241. April 1983. OSSIP-KLEIN, D.J., MARTIN, J.E., LOMAX, B.D., PRUE, D.M., DAVIS, C.J. Assessment of smoking topography generalization across laboratory. clinical, and naturalistic settings. Addictive Behaviors 8(1):11-17, 1983. PALMERINO. C.C., RUSINIAK, K.W., GARCIA, J. Flavor-illness aversions: The peculiar roles of odor and taste in memory for poison. Science 208:753-755, 1980. PARSONS, L.C., AVERY, S., CHRISTMAN, S., HOPKINS, J., SEAL, M. The effects of 48 hour nicotine withdrawal on heart rate and respiration through continuous monitoring of all night sleep patterns in adult females. (Abstract.) Virginia Journal of Science 26(2):92, Summer 1975. PARSONS, L.C., BELL, N., COMER, L., SWARTZ, A., WEISSENBORN, C. The effects of short-term nicotine withdrawal on day vigilance as measured electrophysiologi- tally. (Abstract.) Virginia Journal of Science 27(2):86, Summer 1976. PARSONS, L.C., HAMME, S. The effects of nicotine withdrawal on the sleep awake cycle. (Abstract.) Virginia Journal of Science 27(2):86, Summer 1976. PARSONS, L.C., LUTTRELL, N., GABE, J., POLLOCK, P. The effect of 48 hour nicotine withdrawal on all night sleep patterns in adult females. Virginia Journal of Science 26(2):92, Summer 1975. PEDERSON, L.L., LEFCOE, N.M. A psychological and hehavioural comparison of ex- smokers and smokers. Journal of Chronic Diseases 29c7b431-434, July 1976. PERKINS, K.A., EPSTEIN, L.H., STILLER, R., JENNINGS, J.R., CHRISTIANSEN, C., MCCARTHY, T. An aerosol spray alternative to cigarette smoking in the study of the behavioral and physiological effects of nicotine. Behavior Research Methods, Instruments and Computers 18(5):426426, 1986. PETERS, R., MCGEE, R. Cigarette smoking and state-dependent memory. E'sy&ophar- macology 76(3):232-235 March 1982. PICKWORTH, W.B., HERNING, R.I., HENNINGFIELD, J.E. Mecamylamine reduces some EEG effects of nicotine chewing gum in humans. Pharmacology Biochemistry and Behacior 30:149-153. 1988. 231 POMERLEAU, C.S., POMERLEAU, O.F., MAJCHRZAK, M.J. Mecamylamine pre- treatment increases subsequent nicotine self-administration as indicated by changes in plasma nicotine level. Psychopharmacology 91(31:391-393, March 1987. POMERLEAU, O., FERTIG, J., SHANHAN, S. Nicotine dependence in cigarette smoking: An empirically based, multivariate model. Pharmacology Biochemistry and Behavior 19(2):291-299, August 1983. POMERLEAU, O.F., POMERLEAU, C.S. Neuroregulators and the reinforcement of smoking: Towards a biobehavioral explanation. Neuroscience and Biobehavior Reviews 8:503-513, 1984. POUNSFORD, J.C., SAUNDERS, K.B. Diurnal variation and adaptation of the cough response to citric acid in normal subjects. Thorax 40(9):657661, September 1985. PRADA, J.A., GOLDBERG, S.R. Effects of caffeine or nicotine pretreatments on nicotine self-administration by the squirrel monkey. (Abstract). Pharmacologist 27(3):226, 1985. PUUSTINEN, P., OLKKONEN, H., KOLONEN, S., TUOMISTO, J. Microcomputer- assisted measurement of inhalation parameters during smoking. Archives of Toxicology (Supplement 9):111-114, 1986. PUUSTINEN, P., OLKKONEN, H., KOLONEN, S., TUOMISTO, J. Microcomputer- aided measurement of puff parameters during smoking of low- and medium-tar cigarettes. Scandinavian Journal of Clinical Laboratory Investigation 47:65.5fXQ 1987. RALL, T.W. Central nervous system stimulants: The methylxanthines. In: Gilman, A.G., Goodman, L.S., Rall. T.W., Murad, F. (eds.) Goodman and Gilman$ The Pharmacological Basis of Therapeutics, Seventh Edition. New York: Macmillan Publishing Co., 1985, pp. 589-603. RAWBONE, R.G., MURPHY, K., TATE, M.E., KANE, S.J. The analysis of smoking parameters: Inhalation and absorption of tobacco smoke in studies of human smoking behaviour. In: Thornton, R.E. (ed.1 Smoking Behaviour. Physiological and Psychological Influences. Edinburgh: Churchill Livingstone, 1978, pp. 171-194. REAVILL, C., STOLERMAN, I.P., KUMAR, R., GARCHA, H.S. Chlorisondamine blocks acquisition of the conditioned taste aversion produced by (-l-nicotine. Neuropharmacology 25(91:1067-1069, September 1986. REEDER, L.G. Sociocultural factors in the etiology of smoking behavior: An assessment. In: Jarvik, M.E., Cullen, J.W., Gritz, E.R., Vogt, T.M., West, L.J. (eds.) Research on Smoking Behavior, NIDA Research Monograph 17. U.S. Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse. DHEW Publication No. 78-581, 1977, pp. 186-206. RICHARDS, J.W. Cigarette Smoking and Nicorette Gum. (Letter.1 Annak; of Internal Medicine 106(3):482-483, 1987. RICKERT, W.S., ROBINSON, J.C., COLLISHAW, N.E., BRAY, D.F. Estimating the hazards of "less hazardous" cigarettes. III. A study of the effect of various smoking conditions on yields of hydrogen cyanide and cigarette tar. Journal of Toxicology and Environmental Health 1211k39-54, July 1983. RISNER, M.E., GOLDBERG, S.R. A comparison of nicotine and cocaine self-adminis- tration in the dog: Fixed-ratio and progressive-ratio schedules of intravenous drug infusion. Journal of Pharmacology and Experimental Therapeutics 224(2):319-326, February 1983. R.J. REYNOLDS TOBACCO COMPANY. Smoking article. European patent applica- tion no. 0174645, filed Sept. 11, 1985. R.J. REYNOLDS TOBACCO COMPANY. Smoking article. European patent applica- tion no. 0212234, tiled July 14, 1986. RODENSTEIN, D.G., STANESCU, D.C. Pattern of inhalation of tobacco smoke in pipe, cigarette, and never smokers. American Review of Respimtory Disease 132(31:628-632, September 1985. 232 ROSE, J.E. Discriminability of nicotine in cigarette smoke: Implications for titration. Addictive Behaviors 9(21:189-193. 1984. ROSE, J.E., BEHM, F.M. Refined cigarette smoke as a method for reducing nicotine intake. Pharmacology Biochemistry and Behavior 28:305-310, 1987. ROSE, J.E., HICKMAN, C.S. Citric acid aerosol as a potential smoking cessation aid. Chest 92(6):10051008, December 1987. ROSE, J.E., SAMPSON, A., HENNINGFIELD, J.E. Blockage of smoking satisfaction with mecamylamine. Paper presented to the American Psychological Association, Los Angeles, California, August 26, 1985. ROSE, J.E., TASHKIN, D.P., ERTLE, A., ZINSER, M.C., LAFER, R. Sensory blockade of smoking satisfaction. Pharmacology Biochemistry and Behatlior 23(2):289-293, August 1985. ROSE, J.E., ZINSER, M.C., TASHKIN, D.P., NEWCOMB, R., ERTLE, A. Subjective response to cigarette smoking following airway anesthetization. Addictive Behav- iors X2):211-215, 1984. ROSECRANS, J.A., CHANCE, W.T. Cholinergic and noncholinergic aspects of the discriminative stimulus properties of nicotine. In: Lal, H. (ed.) Discriminative Stimulus Properties of Drugs. New York: Plenum Publishing Company, 1977, pp. 155-185. ROSECRANS, J.A., KALLMAN, M.J., GLENNON, R. The nicotine cue: An overview. In: Colpaert, F.C., Rosecrans, J.A. feds.1 Stimulus Properties of Drugs: Ten Years of Progress. Amsterdam: Elsevier/North-Holland Biomedical Press, 1978, pp. 69-81. ROSECRANS, J.A., MELTZER, L.T. Central sites and mechanisms of action of nicotine. Neuroscience and Biobehavioml Reviews X41:497501, Winter 1981. ROSECRANS, J.A., SPENCER, R.M.. KRYNOCK, G.M., CHANCE, W.T. Discrimina- tive stimulus properties of nicotine and nicotine-related compounds. In: Blttig, K. fed.1 International Workshop on Behavioral Effects of Nicotine. Basel: S. Karger, 1978, pp. 76-82. ROSENBERG, J., BENOWITZ, N.L., JACOB, P., WILSON, K.M. Disposition kinetics and effects of intravenous nicotine. Clinical Pharmacology and Therapeutics 28(4):517-522, October 1980. RUSSELL, M.A.H. Cigarette smoking: Natural history of a dependence disorder. British Journal of Medical Psychology 44(1):1-16, May 1971. RUSSELL, M.A.H. Tobacco smoking and nicotine dependence. In: Gibbins, R.J., Israel, Y., Kalant, H., Popham, R.E., Schmidt, W., Smart, R.G. (eds.) Research Adoances in Alcohol and Drug Problems, Volume 3. New York: John Wiley and Sons, 1976, pp. l-47. RUSSELL, M.A.H. Tobacco dependence: Is nicotine rewarding or aversive? In: Krasnegor, N.A. (ed.) Cigarette Smoking as a Dependence Process, NIDA Research Monograph 23. U.S. Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse. DHEW Publication No. 79600, 1979, pp. 100-122. RUSSELL, M.A.H. Conceptual framework for nicotine substitution. In: Ockene, J.K. (ed.) The Pharmacologic Treatment of Tobacco Dependence: Proceedings of the World Congress. Cambridge, Massachusetts: Institute for the Study of Smoking Behavior and Policy, 1986, pp. 90-107. RUSSELL, M.A.H. Nicotine replacement: The role of blood nicotine levels, their rate of change, and nicotine tolerance. Pomerleau, O.F., Pomerleau, C.S., Fagerstrom, K.O., Henningfield, J.E., Hughes, J.R. feds.) Nicotine Replacement. A Critical Evaluation. New York: Alan R. Liss, Inc., 1988, pp. 63-94. RUSSELL, M.A.H., COLE, P.V., IDLE, MS., ADAMS, L. Carbon monoxide yields of cigarettes and their relation to nicotine yield and type of filter. British Medical Journal 3(59751:71-73, July 12, 1975. 233 RUSSELL, M.A.H., JARVIS, M.J., FEYERABEND, C., FERNO, 0. Nasal nicotine solution: A potential aid to giving up smoking? British Medical Journal 286(6366):683-684, February 26, 1983. RUSSELL, M.A.H., JARVIS, M.. IYER, R., FEYERABEND, C. Relation of nicotine yield of cigarettes to blood nicotine concentrations in smokers. British Medical Journal 280:972-976, 1980. RUSSELL, M.A.H., JARVIS, M.J., SUTHERLAND, G., FEYERABEND, C. Nicotine replacement in smoking cessation: Absorption of nicotine vapor from smoke-free cigarettes. Journal of the American Medical Association 257(23):3262-3265, June 19, 1987. RUSSELL, M.A.H., SUTTON, S.R., FEYERABEND, C., SALOOJEE, Y. Smoker's response to shortened cigarettes: Dose reduction without dilution of tobacco smoke. Clinical Pharmacology and Therapeutics 27(2):21C-218, February 1980. RUSSELL, M.A.H., SUTTON, S.R., IYER, R., FEYERABEND, C., VESEY, C.J. Long- term switching to low-tar low-nicotine cigarettes. British Journal of Addiction 77(2):145-158, June 1982. RUSSELL, M.A.H.. WILSON, C., FEYERABEND, C., COLE, P.V. Effect of nicotine chewing gum on smoking behaviour and as an aid to cigarette withdrawal. British Medical Journal 2(6032):391-395, August 14, 1976. RUSSELL, P.O., EPSTEIN, L.H., DICKSON, B.E. Behavioral and physiological effects of low-nicotine cigarettes during rapid smoking. Journal of Consulting and Clinical Psychology 51(2):312, 1983. SCHACHTER. S., KOZLOWSKI, L.T., SILVERSTEIN, B. Studies on the Interaction of Psychological and Pharmacological Determinants of Smoking. The effects of urinary pH on cigarette smoking. Journal of Experimental Psychology 106(1):13-19, 1977. SCHECHTER, M.D. Effect of fenfluramine and nicotine upon a stimulant-depressant continuum. Pharmacology Biochemistry and Behavior 15371-375, 1981. SCHECHTER, M.D., RAND, M.J. Effect of acute deprivation of smoking on aggression and hostility. Ps.ychopharmacologia 35:19-28, 1974. SCHNEIDER, N.G.. JARVIK, M.E. Time course of smoking withdrawal symptoms as a function of nicotine replacement. Psychopharmacology 82(1/2):143-144, Decem- ber 1984. SCHNEIDER. N.G., JARVIK, M.E., FORSYTHE, A.B. Nicotine gum vs. placebo gum in the alleviation of withdrawal during smoking cessation. Addictive Behaviors 9(2):149-156, 1984. SCHULZ, W., SEEHOFER, F. Smoking behaviour in Germany-the analysis of cigarette butts (KIPA). In: Thornton, R.E. (ed.) Smoking Behaviour: Physiological and Psychological Influences. Edinburgh: Churchill Livingstone, 1978. SCHUMAN, L.M. Patterns of smoking behavior. In: Jarvik, M.E., Cullen, J.W., Gritz, E.R., Vogt, T.M., West, L.J. teds.1 Research on Smoking Behavior, NIDA Research Monograph 17. U.S. Department of Health, Education and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse. DHEW Publication No. (ADM) 78581, 1977, pp. 36-66. SCHWARTZ, J.L. Relaiew and Evaluation of Smoking Cessation Methods: The United States and Canada, 1978-1985. US. Department of Health and Human Services, Public Health Service, National Institutes of Health. NIH Publication No. 87-2940, April 1987. SEPKOVIC, D.W.. COLOSIMO, S.G., AXELRAD, C.M., ADAMS, J.D., HALEY, N.J. The delivery and uptake of nicotine from an aerosol rod. American Journal of Public Health 76(11):1343-1344, November 1986. SHEAHAN, N.F.. PAVIA, D., BATEMAN, J.R.M., AGNEW, J.E., CLARKE, S.W. A technique for monitoring the inhalation of cigarette smoke in man, using Krypton- 81 m. International Journal of Applied Radiation and Isotopes 31(7):438-441, July 1980. 234 SHEPHARD, R.A. Neurotransmitters, anxiety and benzodiazepines: A behavioral review. Neunmcience and Biobehaviomi Reviews 10~449-461, 1986. SHIFFMAN, S. Craving: Don't let us throw the baby out with the bathwater. British Journal of Addiction 82(1):37-38, 1987. SHIFFMAN, S.M. The tobacco withdrawal syndrome. In: Krasnegor, N.A. fed.) Cigarette Smoking as a Dependence Process, NIDA Research Monograph 23. U.S. Department of Health and Human Services, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse. DHHS Publication No. (ADM) 84800, 1979, pp. 158-185. SHIFFMAN, S., JARVIK, M.E. Smoking withdrawal symptoms in two weeks of abstinence. Psychopharmacology 5035-39, 1976. SINGER, G., SIMPSON, F., LANG, W.J. Schedule induced self injections of nicotine with recovered body weight. Pharmacology Biochemistry and Behavior 9(3, Supplement):387-389, September 1978. SINGER, G., WALLACE, M., HALL, R. Effects of dopaminergic nucleus accumbens lesions on the acquisition of schedule induced self injection of nicotine in the rat. Pharmacology Biochemistry and Behavior 17(3):579-581, September 1982. SKINNER, B.F. Science and Human Behavior. New York: MacMillan, 1953. SLADE, J. Alternative nicotine delivery systems (AND@. Cancer Update 7(l)& Fall 1986. SLADE, J., CONNOLLY, G. Nicotine from aerosol rod. (Letter.) American Journal of Public Health 77(9):1229, September 1987. SLIFER, B.L., BALSTER, R.L. Intravenous self-administration of nicotine: With and without schedule-induction. Pharmacology Biochemistry and Behavior 22(1):61-69, January 1985. SMITH, L.A., LANG, W.J. Changes occurring in self administration of nicotine by rata over a 28day period. Pharmacology Biochemistry and Behavior 13(2):215220, August 1980. SNYDER, F.R., HENNINGFIELD, J.E. Effects of nicotine administration following 12 hours of tobacco deprivation: Assessment on computerized performance tasks. Psychopharmacology, in press. SOLDATOS, C.R., KALES, J.D., SCHARF, M.B., BIXLER, E.O., KALES, A. Cigarette smoking associated with sleep difficulty. Science 207(4430):551-553, February 1, 1980. SPEALMAN, R.D., GOLDBERG, S.R. Maintenance of schedule-controlled behavior by intravenous injections of nicotine in squirrel monkeys. Journal of Pharmacology and Experimental Thempeutics 223(2):402-408, 1982. STEPNEY, R. Would a medium-nicotine, low-tar cigarette be less hazardous to health? British Medical Journal 283(6302):X&Q-1303, November 14, 1981. STITZER, M.L., GROSS, J. Smoking relapse: The role of pharmacological and behavioral factors. In: Pomerleau, O.F., Pomerleau, C.S. Fagerstriim, K.O., Henningfield, J.E., Hughes, J.R. (eds.) Nicotine Replacement: A Critical Evalu- ation. New York: Alan R. Liss, Inc., 1988, pp. 163-184. STOCKWELL, T. Is there a better word than "craving"? British Journal of Addiction 82c044-45, 1987. STOLERMAN, I.P. Characterization of central nicotinic receptors by studies on the nicotine cue and conditioned taste aversion in rata. Pharmacology Biochemistry and Behavior, in press. STOLERMAN, I.P., GOLDFARB, T., FINK, R., JARVIK, M.E. Influencing cigarette smoking with nicotine antagonists. Psychopharmacologia 28(3):247-259, 1973. STOLERMAN, I.P., KUMAR, R., PRATT, J.A., REAVILL, C. Discriminative stimulus effects of nicotine: Correlation with binding studies. In: Martin, W.R., Van Loon, G.R., Iwamoto, E.T., Davis, L. (eds.) Tobacco Smoking and Nicotine. A Neumbiologi- cal Approach. New York: Plenum Press, 1987, pp. 113-124. STOLERMAN, I.P., PRA'IT, J.A., GARCHA, H.S. Further analysis of the nicotine cue in rata. In: Colpaert, F.C., Slangen, J.L. (eds.) Drug Discrimination: Applications in CNS Pharmacology. Amsterdam: Elsevier Biomedical Press, 1982, pp. 203-210. SUEDFELD, P., IKARD, F.F. Use of sensory deprivation in facilitating the reduction of cigarette smoking. Journal of Consulting and Clinical Psychology 42c6k888-895, 1974. SUTTON, S.R., FEYERABEND, C., CCI,E, P.V., RUSSELL, M.A.H. Adjustment of smokers to dilution of tobacco smoke by ventilated cigarette holders. CZinical Pharmacology and Therapeutics 24(4):395-405, 1978. SUTTON, S.R., RUSSELL, M.A.H., IYER, R., FEYERABEND, C., SALOOJEE, Y. Relationship between cigarette yields, puffing patterns, and smoke intake: Evidence for tar compensation? British Medical Journal 285(6342):6OCMO3, August 28September 4, 1982. SUZUKI, T., MASUKAWA, Y., YOSHII, T., KAWAI, T., YANAURA, S. Effect of methamphetamine or preference for morphine in rats. Folia Pharmacologica Japan 81:459-468, 1983. SWEDBERG, M.D.B., HENNINGFIELD, J.E., GOLDBERG, S.R. Evidence of nicotine dependency from animal studies: Self-administration. Tolerance and withdrawal. In: Russell, M.A.H., Stolerman, I.P., Wannacott, S. (eds.) Nicotine: Actions and Medical Implications. Oxford: Oxford University Press, in press. TAKADA, K., HAGEN, T.J., COOK, J.M., GOLDBERG, S.R., KATZ, J.L. Discrimina- tive stimulus effects of intravenous nicotine in squirrel monkeys. Pharmacology Biochemistry and Behavior 30:243-247, 1988. TAYLOR, P. Cholinergic agonists. In: Gilman, A.G., Goodman, L.S., Rall, T.W., Murad, F. (eds.) Goodman and Gilman's The Pharmacological Basis of Therapeu- tics, Seventh Edition, 1985a, pp. 100-109. TAYLOR, P. Ganglionic stimulating and blocking agents. In: Gilman, A.G., Goodman, L.S., Rall, T.W., Murad, F. (eds.) Goodman and Gilman's The Pharmacological Basis of Therapeutics, Seventh Edition. New York: MacMillan Publishing Compa- ny, 1985b, pp. 215-221. THOMPSON, T., SCHUSTER, CR. Morphine self-administration, food-reinforced and avoidance behaviors in rhesus monkeys. Psychopharmacologia 5:87-94, 1964. THOMPSON, T., SCHUSTER, CR. Behavioral Pharmacology Englewood Cliffs, New Jersey: Prentice-Hall, 1968. THOMPSON, T., UNNA, K.R. (eds.) Predicting Dependence Liability of Stimulant and Depressant Drugs. Baltimore: University Park Press, 1977. TOBACCO INTERNATIONAL. A new form of chewable tobacco: Pinkerton Tobacs. April 17, 1987, p. 26. TOBACCO REPORTER. Papers, filters, tipping. What's new for cigarettes. Tobacco Reporter 112(4):29-34, April 1985. TOBIN, M.J., JENOURI, G., SACKNER, M.A. Subjective and objective measurement of cigarette smoke inhalation. Chest 82(6):696-700, December 1982. TOBIN, M.J., SACKNER, M.A. Monitoring smoking patterns of low and high tar cigarettes with inductive plethysmography. American Review of Respimtoty Disease 126(2):258-264, August 1982. TONNESEN, P., FRYD, V., HANSEN, M., HELSTED, J., GUNNERSEN, A.B., FORCHAMMER, H., STOCKNER, M. Effect of nicotine chewing gum in combina- tion with group counseling on the cessation of smoking. New England Journal of Medicine 318:15-18, 1988. TRAHIR, R.C.S. Giving up cigarettes: 222 case studies. Medical Journal of Austmlia 1(18):929-932, May 6, 1967. ULE'lT, J.A., ITIL, T.M. Quantitative electroencephalogram in smoking and smoking deprivation. Science 164(3882):969-970, May 1969. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse- quences of Smoking: The Changing Cigarette. A Report of the Surgeon General. U.S. Department of Health and Human Services, Public Health Service, Ofiice of the Assistant Secretary for Health, Office on Smoking and Health. DHEW Publication No. (PHS) 81-50156, 1981. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse- quences of Smoking: Cancer. A Report of the Surgeon General. U.S. Department of Health and Human Services, Public Health Service, Office of the Assistant Secretary for Health, Office on Smoking and Health. DHHS Publication No. (PHS) 82-50179, 1982. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse- quences of Involuntary Smoking: Cardiovascular Disease. A Report of the Surgeon General. U.S. Department of Health and Human Services, Public Health Service, Office on Smoking and Health. DHHS Publication No. (PHS) 84-50204, 1983. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse- quences of Smoking. Chronic Obstructioe Lung Disease. A Report of the Surgeon Geneml. U.S. Department of Health and Human Services, Public Health Service, Office on Smoking and Health. DHHS Publication No. (PHS) 8450205, 1984. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse- quences of Smoking. Cancer and Chronic Lung Disease in the Workplace. A Report of the Surgeon General. US. Department of Health and Human Services, Public Health Service, Office on Smoking and Health. DHHS Publication No. (PHS) 85 50207, 1985. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse- quences of Involuntary Smoking. A Report of the Surgeon General. U.S. Depart- ment of Health and Human Services, Public Health Service, Centers for Disease Control, Office on Smoking and Health. DHHS Publication No. (CDC) 87-8398, 1986a. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse- quences of Using Smokeless Tobacco. A Report of the Advisory Committee to the Surgeon General. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health. NIH Publication No. 86-2874, 1986b. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. Adult Use of Tobacco Survey, 1986. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, Office on Smoking and Health, 1966c. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. Drug Abuse and Drug Abuse Research. The Second Triennial Report to Congress from the Secretary. U.S. Department of Health and Human Services, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse. DHHS Publication No. (ADMl 87-1486, 1987a. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. Cigarette smoking in the United States, 1986. Morbidity and Mortality Weekly Report 36f351581-585, September 11, 198% U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE. Smoking and Health. Report of the Advisory Committee to the Surgeon General of the Public Health Service. U.S. Department of Health, Education, and Welfare, Public Health Service. DHEW Publication No. (PHS) 1103, 1964. U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE. Smoking and Health. A Report of the Surgeon Geneml. U.S. Department of Health, Education, and Welfare, Public Health Service, Office of the Assistant Secretary for Health, Office on Smoking and Health. DHEW Publication No. (PHS) 7950066, 1979. U.S. FOOD AND DRUG ADMINISTRATION. Action on Smoking and Health vs. Harris, 1980. U.S. FOOD AND DRUG ADMINISTRATION. Letter to Congressman Waxman, September 29, 1987. 237 WACK, J.T., RODIN, J. Smoking and its effect on body weight and the system of caloric regulation. The American Journal of Clinical Nutrition 35(2):36f%380, February 1982. WARBURTON, D.M., WESNES, K., SHERGOLD, K., JAMES, M. Facilitation of learning and state dependency with nicotine. Psychopharmacology 89(1):55-59, May 1986. WEEKS, J.R. Experimental morphine addiction: Method for automatic intravenous injections in unrestrained rata. Science 138(3537):143-144, October 12, 1962. WESNES, K., WARBURTON, D.M. Smoking, nicotine and human performance. In: BaIfour, D.J.K. (ed.) Nicotine and the Tobacco Smoking Habit. Oxford: Pergamon Press, 1984, pp. 133-152. WEST, R. Use and misuse of craving. British JournuZ of the Addictions 82(1):39-41, 1987. WEST, R.J. Psychology and pharmacology in cigarette withdrawal. Journal of Psychosomatic Research 28(5):37%386, 1984. WEST, R.J., JARVIS, M.J., RUSSELL, M.A.H., CARRUTHERS, M.E., FEYERA- BEND, C. Effects of nicotine replacement on the cigarette withdrawal syndrome. British Journal of Addiction 79(21:2X+219, June 1984. WEST, R.J., RUSSELL, M.A.H. Effects of withdrawal from long-term nicotine gum LW. Psychological Medicine X(4):891-893, November 1985a. WEST, R.J., RUSSELL, M.A.H. Pre-abstinence smoke intake and smoking motivation as predictors of severity of cigarette withdrawal symptoms Psychopharmacology 87(3):334-336, November 1985b. WEST, R.J., RUSSELL, M.A.H. Cardiovascular and subjective effecta of smoking before and after 24 h of abstinence from cigarettes. Wychopharmncology 92:1X?-121, 1987. WEST, R.J., RUSSELL, M.A.H., JARVIS, M.J., FEYERABEND, C. Does switching to an ultra-low nicotine cigarette induce nicotine withdrawal effects? Psychophatma- colony 84(1):126-123, September 1984. WEST, R.J., RUSSELL, M.A.H., JARVIS, M.J., PIZZEY. T., KADAM, B. Urinary adrenaline concentrations during 10 days of smoking abstinence. Psychopharma- cology &1(1):141-142, September 1984. WEST, R.J., SCHNEIDER, N. Craving for cigarettes. British Joumcd of the Addiction 82(4):375-384, April 1987. WEST, R.R., EVANS, D.A. Lifestyle changes in long term survivors of acute myocardial infarction. Journal of Epidemiology and Community Health 40:103- 109, 1986. WEYBREW, B.B., STARK, J.E. PsychoZogical and Physiological Changes Associated with Deprivation from Smoking, U.S. Naval Submarine Medical Center Report No. 490. Bureau of Medicine and Surgery, Navy Department, 1967. WIKLER, A. Conditioning factors in opiate addiction and relapse. In: Wilner, D.M., Kassebaum, G.G. (eds.) Narcotics. New York: McGraw-Hill, 1965, pp. 85-100. WINDHOLZ, M., BUDAVARI, S., STROUMTSOS, L.Y., FERTIG, M.N. The Merck Index. Rahway, New Jersey: Merck and Co., 1976. WISE, R.A., YOKEL, R.A., DEWIT, H. Both positive reinforcement and conditioned aversion from amphetamine and from apomorphine in rata. Science 191:127%1275, March 1976. WOODMAN, G., NEWMAN. S.P., PAVIA, D., CLARKE, S.W. Temperature and calibration corrections to puff volume measurements in cigarette smoking. Physics in Medicine and Biology 29(111:1437-1440, November 1984. WOODMAN, G., NEWMAN, S.P., PAVIA, D., CLARKE, S.W. Inhaled smoke volume, puffing indices and carbon monoxide uptake in asymptomatic cigarette smokers. Clinical Science 71(41:421427, October 1986. 238 WOODMAN, G., NEWMAN, S.P., PAVIA. D., CLARKE, SW. lnhaled smoke volume and puff indices with cigarettes of different tar and nicotine levels European Journal of Respiratory Diseases 70:187-192. 1987. WOODS, J.H., KATZ, J.L., WINGER, G. Abuse liability of benzodiazepines. Pharma- cological Reviews 39:251413. 1987. WYNDER, E.L., KAUFMAN, P.L., LESSER, R.L. A short-term follow-up study on ex- cigarette smokers. American Review of Respiratory Disease 96(4):645-655, October 1967. YANAGITA, T. Brief review on the use of self-administration techniques for predicting drug dependence potential. In: Thompson, T., Unna, K.R. (eds.1 Predicting Dependence Liability of Stimulant and Depressant Drugs. Baltimore: University Park Press, 1977, pp. 231-242. ZACNY, J.P., STITZER, M.L. Effects of smoke deprivation interval on puff topogra- phy. Clinical Pharmacology and Therapeutics 38r 1):109-115, July 1985. ZACNY, J.P., STITZER, M.L. Effect of puff size instructions on puff volume. Addictive Behaviors 11:17-23, 1986. ZACNY, J.P., STITZER, M.L., BROWN, F.J., YINGLING, J.E., GRIFFITHS. R.R. Human cigarette smoking: Effects of puff and inhalation parameters on smoke exposure. Journal ofPharmacology and Experimrntui Therapeutics 240(2):554-564, February 1987. ZACNY, J.P., STITZER, M.L., YINGLING, J.E. Cigarette filter vent blocking: Effects on smoking topography and carbon monoxide exposure. Pharmacology Biochemis- try and Behavior 25(6):1245-1252, December 1986. ZEIDENBERG, P., JAFFE, J.H. KANZLER, M., LEVITT, M.D., LANGONE. J.J., VAN VUNAKIS, H. Nicotine: Cotinine levels in blood during cessation of smoking. Comprehensive Psychiatry 18(1):9.7-101. January-February 1977. 239 CHAPTER V TOBACCO USE COMPARED TO OTHER DRUG DEPENDENCIES 241 CONTENTS Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247 Clinical Characteristics of Drug Dependence ............. .248 Drug Dependence Defined ................................. 248 Diagnostic Criteria for Drug Dependence ............. 249 Features of Drug Dependence., ......................... .250 Highly Controlled or Compulsive Drug Use .. .250 Physical Dependence and Tolerance ............. 251 Harmful Effects ........................................ 252 Course of Drug Dependence.. ...................... 252 Polydrug Dependence and Multiple Psychiat- ric Diagnosis ......................................... 254 Spontaneous Remission .............................. 255 Chemical Detection Measures ............................ 256 Patterns in the Development of Drug Dependence.. . . . .259 Current Use of Cigarettes and Other Drugs . . . . . . . . . 259 Epidemiological Studies of the Progression of Drug Use . , . . . . . . . . . . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .261 Tobacco Use as a Predictor of Other Drug Use.. . .262 Frequency of Use of Cigarettes and Other Drugs.. 263 Initiation of Drug Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264 Vulnerability to Drug Dependence: Individual and Environmental Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265 Pharmacologic Determinants of Drug Dependence ..... .267 How Drugs Control Behavior.. .......................... .267 Dependence Potential Testing: Psychoactive, Rein- forcing, and Related Effects ............................ 269 Effects of Drugs on Mood and Feeling (Psy- choactivity) ........................................... 270 Methods and Results .............................. 272 Drug Discrimination Testing ....................... 274 Methods and Results ............................. .275 Drug Self-Administration ........................... .276 Initiation of Drug Self-Administration ...... .277 Evaluation of Reinforcing Effects ............. 279 Results from Drug Self-Administration Studies .............................................. 281 243 Drug Dose as a Determinant of Drug Intake ............................................... 282 Cost of the Drug as a Determinant of Intake .............................................. ,283 Place Conditioning Studies ........................ .284 Constraints on Dependence Potential Testing. 285 Dependence Potential Testing: Tolerance and Withdrawal ................................................. .286 Tolerance ............................................... .287 Cross-Tolerance .................................... .288 Mechanisms of Tolerance ....................... .288 Constitutional Tolerance ........................ .290 Withdrawal Syndromes ............................. .291 Spontaneous Withdrawal Syndromes ........ .292 Precipitated Withdrawal Syndromes ......... .293 Variability in Withdrawal Syndromes ...... .294 Cravings or Urges ................................ .295 Constraints on Physical Dependence Potential Testing ................................................ .296 Therapeutic or Useful Effects of Dependence-Pro- ducing Drugs .............................................. .298 Adverse and Toxic Drug Effects.. ...................... .298 Identification of Dependence-Producing Drugs ...... .304 Comparison Among Drugs .......................... 305 Environmental Determinants of Drug Dependence In- cluding Behavioral Conditioning ........................... .306 Drug Taking as a Learned Behavior .................. .307 Drug-Associated Stimuli Modulate Drug Seeking .. .308 Conditioned Withdrawal Symptoms May Precipi- tate Drug Seeking ........................................ 310 Relapse to Drug Dependence.. ................................. 311 Definition of Relapse ........................................ 312 Measurement of Relapse ................................... 313 Rates of Relapse.. ............................................ 313 Correlates of Relapse ...................................... .315 Pretreatment Correlates of Relapse ................... .315 Severity of Drug Dependence ...................... 315 Psychiatric Impairment .............................. 316 Demographic Factors ................................. 320 Treatment Correlates of Relapse ........................ 320 Posttreatment Correlates of Relapse ................... 321 Family Support Factors ............................. 321 Drug Use Among Peers ............................. 321 Involvement in Work and Leisure Activities .322 244 Negative Emotional States.. . . . . . . . . . . . . . . . . . . . . . . . . 322 Treatment of Drug Dependence ............................... 324 Goals of Treatment .......................................... 325 Types of Treatment for Drug Dependence .......... .326 Pharmacologic Treatment of Drug Dependence .... .326 Replacement Therapy ............................... .326 Blockade Therapy .................................... .328 Nonspecific Pharmacotherapy or Symptomatic Treatment ............................................. 328 Pharmacologic Deterrents ........................... 329 Behavioral Treatment Strategies ........................ 329 Relapse Prevention Skills ........................... 330 Leisure Activity Skills ............................... 331 Stress Management Skills .......................... 332 Motivation Enhancing Treatments .............. .332 Conclusions .......................................................... 334 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336 245 Introduction The present Chapter compares cigarette smoking and nicotine with other forms of drug dependence and addicting drugs. Other chapters in this Report describe the behavior of cigarette smoking, the known biobehavioral mechanisms and modulators of nicotine's actions, and techniques for achieving abstinence from smoking. As is evident from this Report, cigarette smoking is most usefully ex- plained and characterized as a drug dependence process in which nicotine is the identified drug of dependence. It is also evident that by either the World Health Organization (WHO) definition of "drug addiction" that was issued in the 1950s (WHO 1952) or by the definitions of "drug dependence" issued since the 1960s (WHO 1964, 1969, 1981), nicotine is appropriately categorized. as an addicting or dependence-producing drug. Its designation as a drug is also consis- tent with the definitions provided by the WHO (1981) and the Food and Drug Administration (FDA) (1987). Nicotine-delivering tobacco preparations (which include all currently marketed tobacco prepara- tions) could, therefore, be appropriately categorized as addicting or dependence-producing drugs. In addition to evaluating nicotine with respect to definitions of dependence-producing drugs, it is also useful to compare features of tobacco dependence and the pharmacologic properties of nicotine to other drug addictions and addicting drugs, respectively. This comparison is the purpose of the present Chapter. Two of the most widely studied drug addictions provide standards to which other addictions may be compared. They are the addictions to the opium-derived or related substances ("opioids," e.g., morphine, heroin, methadone, codeine) and to alcohol. For nearly a century, it has been widely accepted that use of these substances could lead to addictive behavior and to adverse effects. Moreover, such conse- quences of use develop in a sufficient number of persons that there have been recurrent regulatory efforts to restrict access and conditions of use. Cocaine and related psychomotor stimulants (e.g., amphetamine) provide an additional important standard by which to judge suspected and known addicting chemicals. These stimulants have been accepted as standards by which to evaluate the addicting potential of other stimulants since the 1950s. It is beyond the scope of the present Chapter to review all aspects of drug dependence in detail. Rather, this Chapter summarizes primarily the pharmacologic aspects of drug dependence. In particu- lar, the Chapter provides information that permits a comparison of the pharmacologic basis of tobacco dependence, as described in the other Chapters, with the pharmacologic basis of other forms of drug dependence. More extensive reviews of the topics to be discussed have emerged from various review panels sponsored by the National Institute on Drug Abuse (NIDA) (Krasnegor 1978,1979a,b,c; Thomp- son and Johanson 1981; Grabowski, Stitzer, Henningfield 1984; 247 Sharp 1984) and the National Academy of Sciences (Levison, Gerstein, Maloff 1983); other reviews have been held under the auspices of professional scientific societies (Goldberg and Hoffmeis- ter 1973; Thompson and Unna 1977; Balster and Harris 1982; Taylor and Taylor 1984; Seiden and Balster 1985). Other important determinants and consequences of drug dependence are more thoroughly described elsewhere (Blaine and Julius 1977; Manatt 1983; Tims and Ludford 1984; Petersen 1978; Bell and Battjes 1985; Richards and Blevens 1977; Dupont, Goldstein, O'Donnell, Brown 1979; Lettieri, Sayers, Pearson 1980; Crowley and Rhine 1985). Clinical Characteristics of Drug Dependence Drug Dependence Defined Before the 1960s it was fairly common to invoke factors such as "criminality, " "character deficit," "immorality," and "weakness of will" in the clinical diagnosis of "drug addiction." In addition, these factors often included various social connotations. In part, it was because these attributes were not objective or scientifically based that the WHO in 1964 recommended that the term "addiction" be replaced with "drug dependence" in an effort to be more precise and descriptive in definition (WHO 1964, 1981). According to current conceptualizations, the central and common element across all forms of drug dependence is that a psychoactive drug has come to control behavior to an extent that is considered detrimental to the individual or society (WHO 1981; APA 19873. Although the precise wording varies, the central concept of drug- dependence definitions refers to the behavior of the individual who has come under the control of a psychoactive drug, and this concept has provided the cornerstone of most definitions of depen- dence/addiction for at least a century (Berridge 1985) and arguably for several centuries (Murray et al. 1933; Austin 1979; Levine 1978). The involvement of a psychoactive drug is the critical feature that distinguishes drug addictions from other habitual behaviors. In principle, the term "drug dependence" might be used to characterize any form of drug ingestion; however, the term is generally reserved for use when the chemical meets criteria as a "psychoactive" drug. These criteria are based on drug-induced changes in brain function; such changes may involve alterations in mood, feeling, thinking, perception, and other behavior. In this Chapter the term "drug dependence" or "drug addiction" refers to self-administration of a psychoactive drug in a manner that demon- strates that the drug controls or strongly influences behavior. In other words, the individual is no longer entirely free to use or not use the substance. Often times, this reduction in the degree to which use TABLE l.-Diagnostic criteria for psychoactive substance dependence A. At least three of the following: Substance often taken in larger amounts or over a longer period than the person intended Persistent desire or one or more unsuccessful efforts to cut down or control substance use A great deal of time spent in activities necessary to get the substance (e.g.. theft), to take the substance (e.g., chain smoking), or to recover from its effects Frequent intoxication or withdrawal symptoms when expected to fulfill major role obligations at work, school, or home (e.g., does not go to work because of hangover, goes to school or work "high," intoxicated while taking care of own children), or when substance `~(se is physically hazardous (e.g., drives when intoxicated) Important social, occupational, or recreational activities given up or reduced because of substance use Continued substance use despite knowledge of having a persistent or recurrent social, psychological, or physical problem that is caused or exacerbated by the use of the substance (e.g., continuing heroin use despite family arguments about it, cocaineinduced depression, or ulcer made worse by drinking Marked tolerance: need for markedly increased amounts of the substance (i.e., at least a 50 percent increase) to achieve intoxication or desired effect, or markedly diminished effect with continued use of the same amount (Note: The following items may not apply to cannabis, hallucinogens. or PCP) Characteristic withdrawal symptoms (see specific withdrawal syndromes under Psychoactwe Substance-Induced Organic Mental Disorders) Substance often taken to relieve or avoid withdrawal symptoms B. Some symptoms of the disturbance persistent for at least 1 month, or occurrent repeatedly over longer period of time SOURCE: American Psychiatric Association (1987). is considered "voluntary" is described as "habitual" or "compulsive" drug use. Diagnostic Criteria for Drug Dependence The Diagnostic and Statistical Manual (DSM-III-R) of the Ameri- can Psychiatric Association (APA 1987) provides a useful example of the objective criteria currently used to define drug dependence. As stated in DSM III-Revised: "The essential feature of this disorder is a cluster of cognitive, behavioral, and physiological symptoms that indicate that the person has impaired control of psychoactive substance use and continues use of the substance despite adverse consequences." Specific diagnostic criteria for psychoactive sub- stance dependence are shown in Table 1. The APA designated 10 classes of psychoactive substance for which use may lead to dependence: alcohol; amphetamine or similarly acting sympathomimetics; cannabis; cocaine; hallucino- 249 gens; inhalants; nicotine; opioids; phencyclidine (PCP) or similarly acting arylcyclohexylamines; and sedatives, hypnotics, or anxiolyt- its. The fact that dependence criteria are the same for all classes of drug use highlights the assumption that dependence processes are functionally similar across substances with different pharmacologic profiles. Features of Drug Dependence Behavior that leads to drug ingestion, as well as the various behavioral and physiological sequelae resulting from the ingestion, are determined by both drug (pharmacologic or agent) and nondrug (behavioral or environmental) factors which will be discussed in this Chapter. The nondrug determinants include characteristics of the individual ("host" characteristics) such as age, genotype, and person- ality. Highly Controlled or Compulsive Drug Use Highly controlled or compulsive drug use indicates that drug- seeking and drug-taking behavior is driven by strong, often irresisti- ble urges. It can persist despite a desire to quit or even repeated attempts to quit. Compulsive drug use may take precedence over other important priorities. The extent to which compulsive behavior is apparent varies across individuals and is most easily detected in extreme cases. For example, to maintain daily drug intake laryngectomized patients may smoke cigaret.tes through their tracheostomy hole, cocaine users may take cocaine at the risk of loss of family and job, and prostitution has been observed to occur in exchange for a variety of drugs for which availability was low or price was high. The drug-seeking behavior itself ranges from the routine and licit procurement of cigarettes or alcohol, to the possibly more extensive behavioral repertoire necessary to obtain prescriptions for certain drugs, to the highly intricate chains of behavior required to procure many illicit drugs. Drug-seeking behavior is not determined entirely by the specific pharmacologic properties of a particular drug, however. For instarce, when alcohol or tobacco has been prohibited, procurement has at times involved as much risk and involvement as the procurement of illicit drugs in the 1980s (Austin 1979; Brecher 1972). A drug may be taken to avoid withdrawal symptoms and other undesirable sequelae of drug abstinence. This factor may contribute to the level of compulsivity which develops. Addicting drugs often provide some therapeutic benefit or otherwise useful effect (Chapter VI); these effects may also contribute to the compulsive nature of drug use. Whether or not such benefits are considered to be more important than the adverse effects of drug taking, this factor is important because it may have been prominent in initial exposure to the drug, it may have strengthened the control of the drug over behavior, and it may constitute a potential cause for relapse. Physical Dependence and Tolerance The observation of a withdrawal syndrome that accompanies abstinence from chronic drug exposure is the primary index of physical dependence induced by the drug (Martin 1965; Kalant 1978). Drug withdrawal syndromes are behavioral and physiological sequelae of abstinence from chronic drug administration. Tolerance refers to the diminished responsiveness to successive administration of a drug; it may occur independently of physical dependence but is a frequent concomitant (Kalant 1978). The magnitude of tolerance and physical dependence is directly related to the frequency and magnitude of the drug-dosing regimen; thus, low or infrequent drug dosing may not produce measurable levels of tolerance or physical dependence. Tolerance may develop in the absence of physical dependence; for example, infrequent dose administration may result in decreased responsiveness even though no measurable withdrawal reaction accompanies drug abstinence. Whereas initial drug exposure may have caused marked behavior- al and physiological disruption, the development of physical depen- dence implies that a relatively normal appearing behavioral and physiological functioning requires continued drug administration and that disruption will occur when the drug is withdrawn. For example, at certain doses, opioids, sedatives (including alcohol), and nicotine can produce marked intoxication in nontolerant individuals. As tolerance develops, these same dose levels may produce no readily observable signs of intoxication, and in the case of opioids and nicotine only extremely high doses or sudden abstinence are accompanied by disruption of ongoing behavior. The development of tolerance to repeated drug exposure and of the onset of a withdrawal syndrome may be observed following a period of repeated drug exposure and drug abstinence, respectively, but these factors do not in themselves define a drug dependence syndrome requiring intervention to prevent relapse to drug use. It is possible to establish tolerance and physical dependence by repeated drug administration even when the animal or human never actually self-administered the drug. In animals, this is often done in experimental studies; human patients requiring pain relief may become tolerant to and physically dependent on opioid analgesics in hospital settings. Such animals and humans do not necessarily exhibit drug-seeking behavior when drug administration is terminat- ed. Another such instance is the fetal opioid syndrome, in which treatment of the withdrawal reaction might be indicated but no 251 drug-seeking behavior would be present for which an intervention would be needed (Weinberger et al. 1986). Although not always essential for the occurrence of addictive drug-seeking behavior, tolerance and withdrawal phenomena are important in principle because they can serve to strengthen the control of the drug over behavior. Specifically, tolerance development can result in increased drug intake in an attempt to maintain the desired drug effects, and the onset of a drug withdrawal syndrome may constitute an aversive state which is alleviated by drug taking. Harmful Effects The concept that some sort of harm or disadvantage to the individual or society is a consequence of drug use is another element in most definitions of drug dependence. This concept is complex and socially determined, however. For example, drug seeking may result in illicit production and trafficking as currently occurs for illicit drugs (Drug Abuse Policy Office 19841, and had occurred for tobacco at various times when it was banned (Austin 1979; see also Warner 1982 for a discussion of recent cigarette-smuggling issues). Adminis- tration of drugs, or abstinence in the physically dependent person, may directly produce adverse behavioral and psychiatric effects ("psychotoxicity"). Finally, toxicity may also be a direct physiological effect of the addicting drug itself (e.g., liver damage caused by alcohol) or to associated toxins (e.g., transmission of the human immunodeficiency virus by needle sharing among i.v. drug users, or carcinogens delivered by tobacco smoke). These forms of drug-associated damage can result in a variety of societal costs such as health care of drug users (including cigarette smokers), lost productivity of the work force (including tobacco-use- associated losses in productivity), and criminal justice system burdens associated with illicit drug use. Such adverse effects of drug use constitute the "liability" of drug use and may also be factors in the determination that drug use constituted "drug abuse"..(Yanagita 1987). These societal aspects of drug dependence frequently invoke debates which pit the "right" to self-damage against the "right" of society to protect itself from the direct damage or costs incurred as a consequence of the individual's behavior. A historical appraisal of psychoactive substance use reveals that societies have often moved cautiously to restrict the use of drugs when there was little assumption of drug-use-associated damage. Course of Drug Dependence The chronic nature of drug ingestion in the severely dependent individual suggests that. drug dependence processes themselves may be long lasting and resistant to termination. In contrast, the direct 252 effects of psychoactive drugs are generally limited to a few hours or days at most. Peak physical withdrawal signs and symptoms from opioids, sedatives, alcohol, and tobacco appear to last for about 1 to 2 weeks. However, at least for the opioids, a secondary stage of withdrawal may last for 1 year or more; this has been termed protracted withdrawal (Martin 1965; Jasinski 1981). As discussed in Chapters III and VI, an analogous protracted abstinence syndrome appears to exist in tobacco dependence and to be of importance for treatment efforts. Therefore, despite the relatively short-term dura- tion of the effects of drug administration or withdrawal, the clinically relevant duration of drug dependence is much longer. A major implication of post-1960s definitions of drug dependence is that drug dependence is not an absolute phenomenon, but rather may vary in degree (Jaffe 1965, 1985; Miller 1979). Often, within an individual the level of severity increases over time ("progressive" characteristic). The course may be quite variable, however. For example, an initially rapidly developed high level of use may be followed by long-term or transient remissions, while some individu- als never progress at all beyond levels of use of a given drug that are sometimes considered safe and acceptable (Vaillant 1970, 1982). Such low or intermittent levels of drug use are sometimes referred to as "occasional," "controlled, " "recreational" or "social" drug use or "chipping"; such use may still be problematic because there may be acute adverse consequences (e.g., auto accidents following drinking), as well as a transition to chronic drug use (as is characteristic following occasional tobacco use) and the possibility that any use involves illicit behavior (e.g., procurement of alcohol and tobacco by minors or possession of marijuana). There are differences among drugs in the relative incidence of occasional users compared to regular daily users who meet criteria for dependence. For example, it is generally estimated that less than 15 percent of those who consume alcoholic beverages are dependent (Miller 1979). Analysis of opioid data are more problematic (Zinberg and Jacobson 1976); however, observations such as those made of Vietnam veterans show that opioid chipping is not only a well- documented phenomenon but may also be common in some social and environmental settings. Robins and colleagues found (1) that opioid chipping was a common occurrence among enlisted men in Vietnam, (2) that 88 percent of heroin-addicted Vietnam veterans used heroin occasionally upon their return to the United States, and (3) that most (approximately 90 percent) were able to avoid readdic- tion (Robins et al. 1977; Robins and Helzer 1975; Robins, Helzer, Davis 1975; Robins, Davis, Goodwin 1974; Robins, Davis, Nurco 1974; see also Zinberg 1972, 1980). In contrast, however, chipping appears relatively rare among tobacco users: the 1985 National Health Interview Survey showed that 10.6 percent of current smokers 253 smoke 5 or fewer cigarettes/day (unpublished data, Office on Smoking and Health; see also Russell 1976 and US DHHS 1987). Polydrug Dependence and Multiple Psychiatric Diagnosis Another feature of drug dependence is the common use of multiple substances, including tobacco, by dependent individuals. In fact, the most consistent feature of such multiple drug use is the high rate of co-occurrence of tobacco dependence along with dependence on opioids, alcohol, stimulants, and even gambling (Taylor and Taylor 1984). In addition, drugs used by individuals may sometimes vary and be interchanged as price and availability vary (e.g., cocaine is preferred by many but individuals may use opioids, or even sedatives, when cocaine is unavailable) (Kliner and Pickens 1982). Several drugs may also be taken simultaneously; for instance, heavy consumption of nicotine, alcohol, and marijuana is common. Finally, most surveys indicate that use of drugs such as cocaine, alcohol, opioids, and marijuana is accompanied (and usually preceded) by use of nicotine (US DHHS 1987). Tobacco use concurrent with other drug dependencies is so prevalent that it is not generally considered to be of diagnostic significance or considered as a basis of multiple drug dependence diagnosis. Recently, the possible interactive nature of codependen- ties to nicotine and other drugs has been given increasing attention in drug treatment programs (Taylor and Taylor 1984; Kozlowski et al. 1984). These data are discussed later in this Chapter, as well as the issue of whether nicotine serves as a "gateway" to the use of illicit drugs. Also of clinical significance is the concurrence of drug dependence and some other psychiatric disorder. This phenomenon is termed multiple or dual diagnosis (Meyer 1986; McLellan, Woody, O'Brien 1979; Allen and Frances 1986; Rounsaville and Kleber 1986; Jaffe and Ciraulo 1986). In general, dependence on opioids, alcohol, cocaine, and nicotine is often associated with elevated rates and levels of antisocial tendencies and extraversion, but such trends are not generally regarded as multiple diagnoses (for a review of several forms of multiple diagnosis, see Taylor and Taylor 1984). The designation of multiple diagnosis is reserved for the concurrent appearance of a clinically significant psychiatric disorder and drug dependence; the most common of such disorders would appear to be depression, anxiety, and antisocial personality (McLellan, Woody, O'Brien 1979; Rounsaville et al. 1982; Woody, McLellan, O'Brien 1984). 254 Spontaneous Remission It is characteristic of drug dependence that some persons discon- tinue use of the drug while not engaged in a formal treatment program (i.e., "on their own") although they may have participated in a treatment program at some earlier point in time (Stall and Biernacki 1986). Spontaneous remission refers to intentional and unintentional cessation of drug use, variously referred to as "natural recovery, " "maturing out," "burning out," or "self-quitting," but most frequently in current literature as "spontaneous remission." Such quitting is sometimes reported to be due to "will power" or "just deciding to quit." However, follow-up studies have revealed that significant environmental events are often associated with such quitting (for example, Vaillant 1970,1982). Such data have suggested to some that the terms such as "self-quitting," "self-help," and "spontaneous remission" are misnomers (Fisher 1986; Fisher et al. 1988); nonetheless, because the term spontaneous remission is extant in the scientific literature, it will be used here. This Section provides a brief summary of available information comparing alcohol, opioids and tobacco with regard to their rates of spontaneous remission and of factors associated with remission from drug use. In studies of spontaneous remission, a minimum criterion for abstinence, such as 1 year, is often imposed. Although the recorded history of drug dependence acknowledges that some people can achieve abstinence without benefit of formal intervention programs, there was little systematic study of spontaneous remission until the 1970s. Major motivations for the current interest in this phenome- non are to determine if the so-called spontaneous remitters differ in behavioral or physiological parameters from other drug-dependent persons, to identify factors which may be systematically applied in treatment settings, and to better understand the process of drug dependence itself. The percentage of such spontaneous remitters reported in any given study appears to vary more as a function of population and study variables than as a function of drug class. For instance, data averaged across 10 studies show that approximately 30 percent of opioiddependent persons spontaneously remit (Anglin et al. 1986) although estimates of remission rates vary from 2 percent to 65 percent (Harrington and Cox 1979; Winick 1962). On the other hand, approximately 90 percent of people who have quit smoking report that they quit without the aid of formal treatment programs or smoking cessation devices (Fiore et al., in press; see discussion of related issues in Fisher et al. 1988). Deriving precise quantitative comparisons of rates of spontaneous remission across the various drug dependencies is problematic due to the differing criteria used to identify those who are spontaneous remitters. For example, in tobacco surveys, rates of spontaneous 255 remission are often estimated by retrospective self-reports from a sample of former smokers, whereas surveys of opioid and alcohol users generally include only those who were dependent enough to be involved in formal treatment programs at some time. The factors which are associated with spontaneous remission appear to be similar across dependencies on alcohol, opioids, and tobacco (Stall and Biernacki 1986). Table 2 is a summary of findings which have been reported on factors related to spontaneous remis- sion. As shown in the Table, influences such as health problems associated with use of the drug and social pressures are frequent precipitants of spontaneous remission among persons who were dependent on alcohol, opioids, or tobacco. Similarly, spontaneous remitters have often learned to better manage their drug "cravings" and to provide contingent reinforcement for quitting to themselves, and may even undergo significant lifestyle changes (Stall and Biernacki 1986). These data regarding spontaneous remission support the conclu- sion, discussed earlier, that it is somewhat misleading to infer that spontaneous remitters are truly spontaneous or that they were not "really dependent" as is sometimes assumed (Fisher 1986; Fisher et al. 1988; US DHHS 1982). Rather, it seems more plausible that spontaneous remitters are largely those who have either learned to deliver effective treatments to themselves or for whom environmen- tal circumstances have fortuitously changed in such a way as to provide a therapeutic situation (Fisher 1986; Stall and Biernacki 1986; Vaillant 1982, 1970). In addition, persons most likely to quit use of tobacco and opioids without benefit of formal intervention do tend to have shorter histories of use and/or be at lower levels of dependence (US DHHS 1987). Such issues, relating specifically to cigarette smoking, have been reviewed in considerable detail in a previous report of the Surgeon General (US DHHS 1982). Chemical Detection Measures Although drug dependence is not reliably diagnosed simply on the basis of amount of drug intake (Crowley and Rhine 1985; Jaffe 19851, it can be useful to determine whether or not a person has ingested a significant amount of a drug. For example, as is discussed later in this Chapter, many treatment programs require objective verifica- tion of drug-free patient status. A potentially useful adjunct for objectively assessing exposure to drugs is to test for the presence of the drug in biological specimens (Walsh and Yohay 1987; Hawks and Chiang 1986). For instance, blood, urine, saliva, expired air, and other biological samples can be assayed for residual drug or drug-specific markers (e.g., metabolites). Such testing aids in determining that presumed drug-related effects were not actually symptoms of some other organic or mental TABLE 2.-Studies concerning spontaneous remission behavior, by drug and commonly mentioned factors important to remission Factor Alcohol Tobacco Heroin Significant others Health problems Cahalan (1970), Goodwin et al. (1971). Knupfer (1972). Lemere (19531, Saunders et al. (19791, Stall (1963), Tuchfeld (1981) Social sanctions Cahalan (1970), Edwards et al. (1977!, Goodwin et al. (1971), Knupfer (1972), Stall (1983), Thorpe and Perret (1959), Tuchfeld (19&U), Vaillant (1982) Edwards et al. (19771, Goodwin et al. (1971), Knupfer (1972), Saunders et al. (19791, Stall (1983). Tuchfeld (1981), Vaillant (1982) Financial problems Cahalan (1970), Saunders et al. (19791, Stall (1983). Thorpe and Perret (1959), Tuchfeld (1981) Significant accidents Knupfer (1972), Stall (1983), Tuchfeld (1981) Management of cravings Stall (1983) Hecht (1978), Pederson and Lefcoe (1976) Perri et al. (1977) DiClemente and Prochaska (1979), Hecht (1978), Pederson and Lefcoe (1976), Perri et al. (1977) Hecht (1978) Perri et al. (1977) Baer et al. (1977), DiClemente and Prochaska (19791, Hecht (1978). Pederson and Lefcoe (1976), Petri et al. (1977) Biemacki (19833 Biemacki (19831, Schasre (19661, Vaillant (1966a.b, 1970) Biernacki (1983). Waldorf and Bicrnacki (1979), Vaillant (1964. 1970) Biernacki (1963) Biernacki (1983), Joquez (1963L Waldorf and Biemacki (1981) Biemacki (19631, Joqua (1983) TABLE 2.--Chntinued Factor Alcohol Tobacco Heroin Positive reinforcement for quitting Edwards et al. (1977). Stall (1983, Internal psychic change/m&v&on Edwards et al. (1977). Knupfer (19721, Saunders et al. (1979). Turhfeld (1981) Change III lifestyle Edwards et al. ,1977). Knupfer (19721. Saunders et al. (1979). Tuchfeld (1961) Baer et al. (19771, DiClemente and Prochaska (1979). Pederwn and Lefcoe (1976) Biernacki (19831 Raw et al. (19771. Hecht (19761 Biernacki (19831, Schasre (19661. Waldorf and Blernacki (19811 DiClemente and Prochaska I 19791, Hacht (19781 Biernackl 11983~. Jorquez ~19831, Schasre r1966). Waldorf and Biernacki (1981 I SOURCE: Mcdrficd Irom Stall and Birrnacki iI disorder. One problem with such verification is that the drug level measured reflects recency as well as amount of drug use and thus may lead to either underestimation or overestimation of the typical level of drug use. Furthermore, absolute level of use does not necessarily determine whether use is pathological or detrimental. Another problem is that biochemical drug tests vary widely in both their specificity (correct drug identification) and sensitivity (mini- mum amount of drug det,ected) (see Grabowski and Lasagna 1987 and Walsh and Yohay 1987 for general reviews of such issues; and Benowitz 1983 and Muranaka et al. 1988 for a tobacco-related review; also see Chapter II). Presently, verification of drug dependence is based largely on the behavioral factors as described below. The most useful application of testing for drug levels in the body remains the verification of compliance with treatment regimens in which drug abstinence is the goal. These and other issues regarding the methodologies and applications of chemical detection measures have been reviewed by a committee of the American Society for Clinical Pharmacology and Therapeutics (in press). Patterns in the Development of Drug Dependence When the relationships among drug dependencies have been studied in major epidemiological surveys (e.g., NIDA's National Household Survey (NHS) (US DHHS 1987)), two findings consistent- ly emerge: persons who use dependence-producing drugs are often cigarette smokers, and cigarette smoking precedes and may be predictive of illicit drug use. Some of the data which have led to these conclusions are summarized in this Section. Current Use of Cigarettes and Other Drugs The association of current use of one drug with current use of other drugs has been studied extensively. One such study is the NHS conducted by NIDA (US DHHS 1987). The Eighth NHS, conducted in 1985, involved personal interviews with 8,038 persons 12 years of age and older, representative of the household population of the conti- nental United States. Questions were asked about the age of respondents when they first tried a cigarette and age when they first started smoking daily. This distinction may be important when comparing cigarette use with the use of other drugs. Persons who do not make the transition from trying cigarettes to daily use may be less likely to use other drugs than those who do make this transition. A similar format was used with alcohol (i.e., age at which respondent first tried alcohol, not including childhood sips, and age of first using alcohol once a month or more). Questions about age at the onset of other drug use were limited to age at first use. In the NHS studies, TABLE 3.-Current use of alcohol, marijuana, and cocaine among "current" cigarette smokers and nonsmokers by age group (percentages) Age group. current drug use "Current" cigarette use - No YES Alcohol 12-17 23.5 74.2 E-25 64.7 82.6 2G34 62.5 81.0 235 52.5 68.6 Marijuana 12-17 lb25 26-34 235 5.8 47.3 13.7 35.4 10.6 26.0 1.7 3.5 12-17 0.4 8.8 lW5 3.9 13.9 2634 4.1 9.2 235 0.4 0.6 NOTE Current use IS any use reported m the 30 days prior to the interwew SOURCE. Natmnal Household Surwy on Drug Abuse. 1985 tin preparatmn, current drug use is defined as any use of the drug during the 30 days preceding the interview. Based on data from the 1985 NHS on Drug Abuse, Table 3 shows associations among use of various psychoactive substances. As shown in the table, rates of current use (i.e., during the past 30 days) of marijuana, alcohol, and cocaine are much higher among "current" cigarette smokers than among others. For example, among 12- to 17- year-olds, almost three-fourths of "current" smokers were current alcohol users compared with less than one-fourth of the youths who were not "current" smokers. Approximately 47 percent of the "current" cigarette smokers report being current marijuana users compared with 5.8 percent of the youths who were not "current" smokers. Differences as large as those shown in Table 3 represent very strong correlations between use of cigarettes and use of other drugs. The strength of the correlation between use of cigarettes and use of other drugs, licit and illicit, suggests the potential importance of directing prevention efforts to the early gateway drugs: cigarettes and alcohol (Kandel and Yamaguchi 1985; Clayton 1986; Clayton and Ritter 1985). Epidemiological Studies of the Progression of Drug Use Tobacco use has been found to play a pivotal role in the development of other drug dependencies. The classic descriptive model for initiation patterns of drug use was developed by Kandel (1975), who first divided drugs into two groups of availability: licit and illicit. Kandel concluded that virtually all persons who ever used illicit drugs such as marijuana and cocaine had previously used licit drugs such as cigarettes and alcohol. Kandel's developmental stages model is based on the assumption that there are relatively invariant patterns of onset of use. The stages are: (1) No Use of Any Drugs (2) Use of Beer or Wine (3) Use of Cigarettes and/or Hard Liquor (4) Use of Marijuana (5) Use of Other Illicit Drugs Although Kandel's model addresses the initiation or onset of drug use, it does not account for patterns of early use (e.g., frequency of occasions or quantity per occasion). Nonetheless, there is general agreement that the model accurately characterizes the drug initia- tion process in the United States as one that begins with use of licit drugs (tobacco and alcohol) and, if progression occurs, involves greater use of these substances (Kandel, Marguilies, Davies 1978; Huba, Wingard, Bentler 1981; O'Donnell and Clayton 1982). This pattern has also been observed in France and Israel (Adler and Kandel 1981). In a longitudinal study of the progression of drug use, Yamaguchi and Kandel (1984a) gathered baseline data in 1971 from subjects in the 10th and 11th grade in New York State. This representative sample was followed up in 1981 when the average age was 24.7 years. The order of onset identified by Yamaguchi and Kandel(1984a) was alcohol, cigarettes, marijuana, illicit use of psychoactive or prescrip tive drugs, and other illicit drugs. Among persons who had used both alcohol and cigarettes 10 times or more, alcohol use preceded cigarette use in 70 percent of the cases for males and 55 percent of the cases for females. Among persons who had used cigarettes and marijuana 10 or more times, 67 percent of the males and 72 percent of the females reported using cigarettes first. Using a sophisticated statistical analysis, Yamaguchi and Kandel (1984a) derived several additional conclusions including the follow- ing: (1) For men, the pattern of progression was one in which the use of alcohol preceded marijuana; alcohol and marijuana preced- ed other illicit drugs; and alcohol, cigarettes, and marijuana preceded the illicit use of other psychoactive drugs. Eighty- seven percent of the men were characterized by this pattern. 261 (2) For women, the pattern of progression was one in which either alcohol or cigarettes preceded marijuana; alcohol, cigarettes, and marijuana preceded other illicit drugs; and alcohol and either cigarettes or marijuana preceded the illicit use of psychoactive drugs. Eighty-six percent of women shared this pattern. Tobacco Use as a Predictor of Other Drug Use In an analysis of nationwide data from the high school senior class of 1980, Clayton and Ritter (1985) found that alcohol drinking and cigarette smoking were the most powerful predictors of the extent of marijuana use for both males and females. Cigarette use was a stronger predictor of marijuana use among females. Moreover, this role of cigarette smoking was especially pronounced when it had been initiated at age 17 or earlier. Similarly, data from the longitudinal study by Yamaguchi and Kandel (1984a,b) revealed that, among persons with some history of alcohol use, cigarette smoking was a powerful predictor of marijuana use. Consistent with the above described findings regarding cigarette smoking, smokeless tobacco use has also been shown to be a predictor of other drug use, including cigarette smoking (Ary, Lichtenstein, Severson 1987). More than 3,000 male adolescents were interviewed twice, at an approximately g-month interval, to determine their rates and levels of use of various psychoactive substances. The main findings were that (1) users of smokeless tobacco were significantly more likely to use cigarettes, marijuana, or alcohol than nonusers; (2) users of smokeless tobacco were significantly more likely to take up use of cigarettes, marijuana, or alcohol than nonusers; (3) smokeless tobacco users who were using these other substances at the time of the first interview showed substantially greater increases in levels of use of these other substances over the 6-month interval than did nonusers of smokeless tobacco; and (4) 71 percent of those who had been using smokeless tobacco at the first interview remained users at the second interview. Cigarette smoking is also a predictor of cocaine use. White and colleagues (US DHHS 1987) began with a large sample of 12-, 15-, and 18-year-old adolescents in New Jersey and reinterviewed them at 3-year intervals. As reported in NIDA's Triennial Report to Congress (US DHHS 19871, White and coworkers found that there were several predictors of cocaine use in 18-year-olds who had been interviewed 3 years earlier: prior use of cigarettes, alcohol, and marijuana. Furthermore, at the time of the second interview (of the l&year-olds), the cocaine users used cigarettes, alcohol, marijuana, and other drugs more often than did nonusers of cocaine. Although alcohol use frequently precedes tobacco use, the use of alcohol only progresses to dependence (alcoholism) in about 10 to 15 262 percent of all drinkers (Miller 1979). Use of cigarettes, by contrast, almost inevitably escalates to a level characterized as dependent use (Russell 1976; US DHHS 1987). This is consistent with the observa- tion that although some use of alcohol may precede tobacco use, it is prior use of tobacco and not alcohol that emerges in the above-cited studies as the stronger predictor of illict drug use. The 1985 High School Senior Survey by NIDA (US DHHS 1987) showed that the first dependence-producing drug tried among users of alcohol and illicit drugs was often tobacco. For example, among all respondents 12 years of age and older, first use of tobacco and alcohol occurred in the same year for 18 percent of the sample; cigarettes were used first by 62 percent of the sample, and alcohol was used first by 20 percent. Among those who tried both cigarettes and marijuana, 14 percent first tried these drugs in the same year, 75 percent tried cigarettes first, and 11 percent tried marijuana first. Among those who tried both cigarettes and cocaine, 95 percent used cigarettes first, 3 percent used them first the same year, and only 2 percent used cocaine before cigarettes. These observations show that when cigarettes and another of these dependence-producing drugs have been used by the same individual, cigarette use usually is the first of the two drugs used. One difference between cigarette smoking and the use of other common substances (e.g., milk, sugar, or aspirin) that may also precede the use of illicit drugs is that nicotine itself is a drug that produces the tolerance, physical dependence, and drug- seeking behavior that meet the criteria of a drug-dependence syndrome. Frequency of Use of Cigarettes and Other Drugs Measures of frequency of drug use also yield important findings. The data presented in Table 4 show the percentage of persons in three groups (never smoked, tried cigarettes but never used them daily, used cigarettes on a daily basis) who report use of alcohol, marijuana, and cocaine. The criterion for alcohol use is 5 or more consecutive drinks during at least 1 day in the past 30 days; criteria for marijuana and cocaine use involve previous use of these drugs more than 10 times during the respondent's lifetime. These criteria were used to eliminate those who merely tried the drug on a few occasions ("experimental" use). The percentages are presented separately for four age groups. The main finding shown in Table 4 is that those who become daily cigarette smokers are considerably more likely than others to report use of these other drugs, regardless of age group. For example, among the 12- to 17-year-olds, less than 0.5 percent of the never smokers report using marijuana more than 10 times compared with 3.3 percent of those who tried but never used cigarettes daily and 22.7 percent of those who have used cigarettes daily. These data TABLE 4.-Use of alcohol, marijuana, and cocaine among "never" cigarette smokers, "occasional" cigarette smokers, and daily cigarette smokers, by age group (percentages) Cigarette use pattern Age group. Never Tried, never Smoked drug use smoked used daily daily 12-17 2.7 15.9 38.5 18-25 12.3 31.9 49.6 x%34 9.8 23.0 41.3 235 5.6 9.2 20.1 Marijuana' 12-li la-25 2634 235 0.2 3.3 22.7 3.3 8.3 37.4 2.8 12.9 30.3 0.6 1.8 3.8 12-17 0.2 0.a 6.4 lP25 1.3 4.5 14.2 2634 1.8 7.2 15.6 235 0.2 0.3 1.9 extend those presented in Table 3: associations exist between cigarette smoking and other drug use when considering "current" use (any use in the past 30 days) (Table 3) or measures of frequency of drug use (Table 4). Similarly, a study of alcohol drinking and cigarette smoking among students in grades 7 to 12 in New York State showed a positive correlation between the frequency of consuming alcoholic beverages and both the likelihood of smoking cigarettes and daily cigarette consumption (Welte and Barnes 1987). Initiation of Drug Use Initiation of drug use often occurs through social contacts, independent of the pharmacologic actions of the drug. Drug seeking is then sustained and modulated through combined social and pharmacologic factors. With the possible exception of stimulants such as cocaine and amphetamine, initial exposure to many psy- choactive drugs (including opioids, alcohol, and nicotine) is often associated with aversive consequences (Haertzen, Hooks, Ross 1981; Haertzen, Kocher, Miyasato 1983). For example, opioids may pro- duce nausea; alcohol and nicotine not only produce nausea but may 264 produce initially aversive sensory effects in some preparations (e.g., high-concentration alcoholic beverages may taste "bad" and ciga- rette smoke may be "harsh"). As a consequence, lengthy periods of occasional ("experimental" or %ocial'? drug use frequently precede the development of daily drug use. These observations imply that nondrug factors are important in the initiation and maintenance of drug intake until dependence upon the drug itself develops (Crowley and Rhine 1985; Vaillant 1970, 1982; Marlatt and Baer 1988; Brown and Mills 1987). As discussed elsewhere in this Chapter, such factors can also modulate level of drug use as well as influence the frequency of quitting attempts and their likelihood of success (see also Chapters IV and VII in this volume and earlier Reports of the Surgeon General). The specific factors that have been identified and accepted as prominent in helping to establish initial exposure to drugs (Crowley and Rhine 1985) include availability of the drug, cost of the drug, social acceptability of the drug, and other environmental sources of pressure to use drugs. The acceptability of the drug preparation itself can be manipulat- ed by controlling the dose of the drug and increasing its sensory palatability. For example, the utility of some of the newer smokeless tobacco formulations as "starter" products for youth is held to be due in part to the lower concentrations of nicotine, formulations that facilitate use (e.g., snuff in pouches), as well as nontobacco flavorings (e.g., mint or cinnamon) (Henningfield and Nemeth-Coslett 1988; US DHHS 1986, 1987; Connolly et al. 1986). Such strategies of "starter product" manipulation are analogous to those used to initiate drug seeking in laboratory animals, described later in this Chapter. Such product acceptability factors, combined with the ready availability, peer pressure to use, perceptions that the products were safe, and marketing strategies aimed at increasing the social desirability of smokeless tobacco use, appear to have been largely responsible for the marked rise in use of smokeless tobacco by youth in the 1970s (Ary, Lichtenstein, Severson 1987; Christen and Glover 1987; Con- nolly et al. 1986; Connolly, Blum, Richards 1987; Glover et al. 1986; Guggenheimer et al. 1987; Kirn 1987; Kozlowski et al. 1982; Marty et al. 1986; Negin 1985; Silvis and Perry 1987; US DHHS 1979; Appendix A). Vulnerability to Drug Dependence: Individual and Environmental Factors Despite the complexity of the issues, it is useful to identify factors that differentiate individuals who appear more susceptible to drug dependence. These factors may collectively be termed vulnerability factors. Vulnerability factors are diverse, varying among individuals and within individuals at different times (Radouco-Thomas et al. 1980; Marlatt and Baer 1988; Brown and Mills 1987). Vulnerability may arise from genetic variation or from environmental sources including learning (Jones and Battjes 19851. Vulnerability factors are such that they do not necessarily compel a person to use a drug; in fact, they might be undetected in a person never exposed to a dependence-producing drug. Nonetheless, the presence of several vulnerability factors can increase the likelihood of the development of drug dependence, including cigarette smoking. The concept of a predisposition to drug dependence arose from the observation that not all people are equally prone to becoming behaviorally dependent. upon drugs (Mann et al. 1985; Radouco- Thomas et al. 1980; Jaffe 1985; M.N. Hesselbrock 1986; V.M. Hesselbrock 1986; Mirin, Weiss, Michael 1986). The multiple sources of differences in predisposition or vulnerability to drug dependence are not mutually exclusive. One is a genetic predisposition, shared by family members by virtue of their common biological heritage. Another is an experiential predisposition, shared by family members by virtue of their shared life experiences. For instance, children with parents who are dependent on drugs are at elevated risk of becoming dependent (Hawkins, Lishner, Catalan0 1986; Begletier et al. 1984; Kumpfer 1987). For tobacco, the magnitude of the effect is greater when both parents smoke than when only one parent smokes (Borland and Rudolf 1975; Green 1979). Other types of vulnerability factors are physiologic (e.g., pain, sleep deprivation) and psychiatric (e.g., anxiety, depression) conditions that may constitute undesirable states for which relief is sought by use of a drug (Crowley and Rhine 1985). Finally, as discussed earlier in this Chapter, a variety of nonpharmacologic factors are important in the initiation and development of drug dependence (e.g., price, availability); such factors may be considered vulnerability factors in their own right. A recent area under active investigation is the identification of specific vulnerability factors in youth (Brown and Mills 1987). For example, cigarette smoking has long been associated with juvenile behavior problems (Armstrong-Jones 1927; Welte and Barnes 1987; Kumpfer 1987); more recently, scientific data have confirmed the statistical association of increased rates of cigarette smoking among juveniles with a conduct disorder diagnosis (i.e., adolescent deviance) (Sutker 1984). A related observation is that children with conduct disorders are at elevated risk of using opioids, cocaine, alcohol, tobacco, and other psychoactive drugs (Baumrind 1985). In fact, Kellam, Ensminger, and Simon (1980) found that certain indices of mental health identified in first graders were highly predictive of the use of various psychoactive drugs (including alcohol, opioids, marijuana, and nicotine) when the children were restudied in their teenage years. These studies do not directly address the degree to which juvenile behavior problems are causes or consequences of drug use. It is plausible that either drug use or other behavior problems can exacerbate each other, possibly alternately contributing to a gradual escalation of drug use, behavior problems, or both. These observations suggest that it is especially important to prevent initiation of drug use among individuals who appear to be at increased risk (vulnerability) to developing drug dependencies. Pharmacologic Determinants of Drug Dependence As discussed earlier in this Chapter and in Chapter I, it is the involvement of a dependence-producing drug that sets drug addic- tions apart from the so-called "addictions" to other substances (e.g., food) and activities (e.g., gambling). There are scientific methods to determine if use of a substance involves a dependence-producing drug. These methods, how they are applied to study drugs such as morphine, cocaine, and nicotine, and some of the main findings from such work are reviewed in this Section. A wide range of drugs can be used to modify behavior (e.g., as used in psychiatric treatment); however, the term drug dependence is generally reserved for dependencies which involve drugs that can sustain repetitive drug self-administration by virtue of their tran- sient effects on mood, feeling, and behavior. Drugs that exert such effects via alteration of functioning of the brain or central nervous system (CNS) are generally termed "psychoactive" (WHO 1981). When the psychoactivity of a given drug is frequently pleasant, it is referred to as a "euphoriant," as "reinforcing," or as an "abusable" drug, although these terms are not precisely interchangeable. This framework is consistent with that described by Lewin (1931); namely, that these drugs are chemicals which are "taken for the sole purpose of producing for a certain time a feeling of contentment, ease, and comfort." Drugs which produce such effects effectively control the behavior of a wide range of species, including humans. How Drugs Control Behavior Drugs cause addiction by controlling the behavior of users; that is, addicting drugs come to influence behavior leading to their own ingestion. The behavioral and pharmacologic mechanisms of such control have been reviewed elsewhere (Thompson 1984) and will only be briefly summarized in this Section. Behavior, including drug taking, is biologically mediated by the electrical and chemical stimuli which arise from the nervous system. These stimuli may originate within the body and brain of the individual, but they may also arise from environmental events and be detected by sensory processes such as vision and audition. Dependence-producing drugs control behavior by activating, inhibiting, or mimicking the existing chemical circuits of the nervous system. Dependence-producing 267 drugs are those that readily exert control over behavior by virtue of their stimulus properties. It is useful to distinguish among four kinds of stimulus effects produced by dependence-producing drugs. (1) Drugs can produce interoceptiue or discriminatiue effects that a person or animal can distinguish from the nondrug state. These effects may set the occasion for the occurrence of particular behaviors. For example, the taste of alcohol or the smell of tobacco smoke can set the occasion for social interactions, and the "priming" effects of a single dose of a drug can lead to subsequent drug seeking and relapse in animals or humans with a history of use (Griffiths, Bigelow, Henningfield 1980; Colpaert 1986). (2) Drugs may serve as positive reinforcers or rewards which directly strengthen behavior leading to their administration. The reinforcing efficacy may be related to effects termed either "stimu- lating, " "relaxing," "pleasant," Xseful," "therapeutic," or "euphori- ant" or may be related to providing relief of withdrawal symptoms or other undesirable states. (3) Drug administration or abstinence can also function as "punishers" or aversive stimuli. For example, high-dose levels of most psychoactive drugs serve as an upper boundary level of intake; analogously, decreasing drug levels can also function as aversive stimuli contributing to the strength of drug taking as a means to avoid such aversive effects (Downs and Woods 1974; Goldberg et al. 1971; Henningfield and Goldberg 1983b; Kozlowski and Herman 1984). Aversive stimuli may function as negative reinforcers by strengthening behavior that removes the stimuli (Skinner 1953). Thus, drug withdrawal symptoms are sometimes referred to as negative reinforcers that increase drug seeking. (4) Drug administration, or abstinence following a period of chronic administration, can serve as unconditioned stimuli, in which case they may directly elicit various responses, e.g., vomiting at high- dose levels of opioid administration or during opioid withdrawal, light-headedness produced by rapid smoking, and a strong urge to use a drug. As will be discussed later in this Chapter, repetition of such phenomena can lead to their elicitation by drug-associated stimuli, e.g., the sight or smell of drug-associated stimuli (O'Brien, Ehrman, Ternes 1986; Wikler 1965; Wikler and Pescor 19671. All of these processes may occur whether or not the person has correctly identified their source, i.e., is "aware" of how the drug led to the behavior (Fisher 1986). Furthermore, the biological power and generality of these processes are evidenced by the findings that they also occur in animals (Young and Herling 1986; Spealman and Goldberg 1978; Johanson and Schuster 19811. Drugs differ widely in their potential to control behavior via such mechanisms. Dependence-producing drugs usually readily control behavior in all of the above capacities. Quantification of such characteristics is the cornerstone of testing for the likelihood that use of a drug will lead to addiction. Observers in the 19th and early 20th centuries (e.g., Lewin 1931) had correctly determined that it was the psychological (behavioral) effects (sometimes termed "psych- ic" or "mental" effects) of substances that led to their habitual use. Practical methods for evaluating the behavior-modifying properties of drugs did not emerge until the behavioral sciences themselves had become sufficiently sophisticated in the 1930s and 1940s. Prior to this time, dependence-producing drugs were identified on the basis of retrospective observations of their effects. Since the 194Os, however, drug testing has grown increasingly reliable at identifying ("screen- ing") drugs for their potential to produce dependence prior to observations of dependence outside the laboratory. In fact, highly reliable information can now be obtained on the basis of animal testing alone (Martin 1971; Thompson and Unna 1977; Brady and Lukas 1984; Bozarth 1987b). Methods for evaluating the behavior-modifying properties of drugs were largely developed beginning in the 1940s in studies with morphine-like opioids and cocaine-like stimulants, and have only recently been systematically used to evaluate nicotine. The methods will be described in the remainder of this Section, along with a comparison between the behavioral-pharmacologic actions of nic- otine and those of other drugs. Dependence Potential Testing: Psychoactive, Reinforcing, and Related Effects To scientifically determine if a chemical is dependence producing, a series of scientific tests may be done. These tests are jointly termed dependence potential tests. In this Chapter, Dependence Potential Testing refers to laboratory tests which measure the behavioral and physiological responses of animals and humans to drug administra- tion and to termination of chronic drug administration. Taken together, the results of these tests can be used to objectively predict whether a drug lends itself to self-administration by persons who are exposed. The focus of the present Section is on how the methods are applied to evaluate the potential of drugs to control behavior and to produce transient alterations in mood or feeling that are predictive of self-administration. Such effects have essentially defined the dependence-producing drugs and have set them apart from other medicinals and food; drugs with such effects are sometimes termed "psychotropic" or "behaviorally active" but most commonly as "psychoactive" (President's Advisory Commission 1963; WHO 1981). Not all psychoactive drugs lead to dependence; many drugs used to treat behavioral and psychiatric disorders are considered to have minimal dependence potential (for example, tricyclic antidepres- sants) or may actually produce effects that substantially impair long- 269 term compliance with therapeutic regimens (for example, major tranquilizers). How dependence-producing drugs are distinguished from other psychoactive drugs will be described in this Section. The next Section will discuss methods used to measure test drugs for their potential to produce tolerance and physical dependence. In reviews and proceedings from various expert committees, the procedures to be described have been referred to as testing for "Abuse Liability," " Psychic Dependence," "Abuse Potential," "Ad- diction Liability," " Behavioral Dependence," and "Dependence Po- tential" (Brady and Lukas 1984; Goldberg and Hoffmeister 1973; Thompson and Unna 1977; Seiden and Balster 1985; Thompson and Johanson 1981; Bozarth 1987b; WHO 1981). Whereas there are differences in focus that are evident when these methods are compared, the general goals and strategies are consistent. These will be briefly described in this Section. Detailed descriptions of these methods have been provided by an expert subcommittee of the Committee on Problems of Drug Dependence (Brady and Lukas 1984) and in numerous conferences involving world experts on such procedures (Goldberg and Hoffmeister 1973; Thompson and Unna 1977; Seiden and Balster 1985; Thompson and Johanson 1981; Bozarth 198713). The results of the methods are also considered in the process of reviewing the national and international regulatory status of various drugs either known or suspected to be addicting by the FDA, the Drug Enforcement Agency (DEA), and the WHO (WHO 1981, 1987). Effects of Drugs on Mood and Feeling (Psychoactivity) Dependence-producing drugs can change the way a person thinks, feels, and behaves. The effects may be very subtle (e.g., feelings of relaxation), or they may be profound (e.g., intoxication and impaired cognitive abilities). The scientific assessment of the effects of drugs on mood and feeling (also referred to as "psychoactive," "psychologi- cal," "interoceptive," "subjective," "psychic," or "self-reported" effects) was essentially an extension of the methods developed to assess physiological actions of drugs. By the late 194Os, several drug dependence researchers had concluded that physical dependence potential testing was of limited value in predicting whether drug- seeking behavior would develop following exposure to a given drug (Isbell 1948; Isbell and Vogel 1948). These researchers used observa- tional techniques to measure interoceptive drug effects. Later, the reliability and general applicability of the techniques were substan- tially enhanced by incorporation of the methods developed by Rao (1952) for assessing changes in subjective state and the methods developed by Beecher (1959) for the measurement of pain and analgesia in humans. 270 These methods contributed to the development of what are generally considered the first objective questionnaires for assessing addictive drug effects by Fraser and his colleagues (Fraser and Isbell 1960; Fraser et al. 1961). A prominent feature of the questionnaires was a series of scales to evaluate the ability to feel or discriminate a drug effect, to rate the liking of the drug effect, and to identify the drug that was given from a list of widely used and abused drugs. The next major advance in the quantification of subjective drug effects was the development of the Addiction Research Center Inventory (ARCI) by Haertzen and his colleagues (Haertzen, Hill, Belleville 1963; Haertzen 1966, 1974: Haertzen and Hooks 1969; Haertzen and Hickey 1987). The ARC1 contained scales that were empirically derived to be sensitive to the effects of specific drugs and drug classes (e.g., sedatives, stimulants, hallucinogens). One of the most useful scales was developed to measure the effects of morphine and benzedrine (a prototypical opioid and stimulant, respectively); this scale was subsequently referred to as the "Morphine Benzedrine Group" or "MBG" or "Euphoriant" scale, because morphine-like and benzedrine-like drugs increased the scale scores while simultaneous- ly producing feelings often reported as pleasurable (Haertzen, Hill, Belleville 1963; Haertzen 1974). Scores on the MBG scale are also elevated by most other addicting drugs (Jasinski 1977; Jasinski, Johnson, Henningfield 1984; Henningfield 1984). More recently, the highly specific drug discrimination testing procedures (described below) have been added to the human drug dependence potential testing armamentarium (Chait, Uhlenhuth, Johanson 1984, 1985). To the extent to which certain common features are identified using tests such as the above, they may be categorized together, e.g., as dependence-producing or addicting drugs. This is referred to as determining "pharmacologic" equivalence. Conversely, to the extent to which these same drugs differ in certain respects, they may also be subcategorized as, for instance, analgesics, sedatives, or stimu- lants. Such categorization must be viewed with caution, however, because overemphasis on any particular feature of a drug can be misleading. For instance, morphine,. alcohol, and amphetamine can all produce behavioral and physiological effects that are stimulant- like as well as effects that are sedative-like (Gilman et al. 1985; Dews and Wenger 1977). Nicotine has been viewed as both a stimulant ("excitant") (Lewin 1931) and a sedative (Armstrong-Jones 1927). Most commonly nicotine is now categorized as more stimulant-like than sedative-like, but with an appreciation of its diverse range of potential effects, which depend upon the dose given and the measure used (Gilman et al. 1985). Methods and Results Assessment of the psychoactivity of drugs in humans essentially entails giving either drug or placebo to volunteers and then asking them to report the nature of effects produced. Replicability and objectivity are increased by using standardized questionnaires such as those described above (e.g., "liking" scales, ARCI). In practice, several procedural variations are used to further enhance the reliability and validity of the results. The dose of the drug is varied to assess the nature of the dose-effect relationships; for all depen- dence-producing drugs, ratings of dose strength or the percentage of accurate drug identifications is directly related to the dose given. Subjects with histories of use of a variety of drugs can be asked to report which, if any, of those drugs the test drug feels like; such testing is useful to determine the extent to which the test drug produces any effects on mood and feeling that resemble those of previously studied drugs. Subjects with histories of use of a variety of drugs and who report "liking" the effects of a range of drugs can be used to help assess the dependence potential of the test drug by rating how desirable they find it to be. Incorporation of several of these methods can add considerably to the strength of conclusions which can be drawn. For example, morphine-like opioids, pentobarbital-like barbiturates, amphet- amine-like stimulants (including cocaine), alcohol, and nicotine all produce rapidly onsetting and offsetting discriminative effects; the magnitude and duration of these effects are directly related to dose; all elevate scores on the liking and MBG scales; the effects of ail are directly (though complexly) related to pharmacokinetic factors such as rate of systemic absorption; all produce discriminative effects that correspond to certain physiological changes; all produce effects that can be accurately identified by an observer; all are identified as known addicting drugs by subjects with a history of use of such drugs; pretreatment with antagonists may block these effects (only opioids and nicotine have been systematically studied on this dimension). Such orderly and consistent kinds of effects across drugs confirm that they are appropriately categorized together as addict- ing drugs. The selectivity and sensitivity of such procedures are illustrated in Figure 1. As shown in the Figure, when persons with multiple drug dependence histories were given drugs under double-blind condi- tions, they rated placebo (unconnected data point on each graph) and the nonaddicting zomepirac at a minimal level of "liking" (Jasinski, Johnson, Henningfield 1984). As a direct function of dose, however, the known addicting drugs were rated with greater liking scores. As also illustrated in Figure 1, nicotine produced comparable dose- related increases in drug liking scores as did amphetamine, mor- phine, and pentobarbital. Studies with human volunteers have also 272 MORPHINE (SC) BUPRENORPHINE w t d-AMPHETAMINE (SC) NICOTINE (IV) z 5 PENTOBARBITOL PO) 1 / I k o o ??? CHLORDIAZEPOXIDE (PO) t . L- 4 o o? ?????? PENTAZOCINE W) DS-THC PO) c L / . o ? ?? o? ZOMEPIRAC Drug dose (mg) FIGURE l.-Liking scale scores of the single-dose questionnaire NOTE: Sample size ranges from 6 ipentobarbxtal and chlordiazepoxide) to 13 (d-amphetaminei The high dose of each drug (except wmepirac) produced significant (p 20 cigarettes/day) had body weights approaching that of nonsmokers. Two studies (Bjelke 1971; Kopczyn- ski 1972) reported no relationship between level of smoking and weight. The effect of age on the smoking/body weight relationship was examined in six investigations. Five of six studies (86 percent) (Albanes et al. 1987; Bjelke 1971; Hjermann et al. 1976; Jacobs and 415 TABLE %-Cross-sectional evaluations of smoking and body weight Study Design and sample Major results Moderator variables Limitations Albanes et al. 12.103 me" and women. Smokers weighed 5.95 lb less Age: current smokers gained Smoking self-report ( 1987) NHANES II Survey than nonsmokers, controlled for less after age 25 than either age, sex; smokers taller and nonsmokers or exsmokers leaner than nonsmokers, based Smoking duration: body mass on skinfold index decreased with smoking duration increase Smoking rate: moderate smokers leaner than low or high rate smokers Andrew and All 18,831 pregnant women, Across all heights, smoking Pregnant women only; McGarry Cardiff, Wales, 1985-1988 mothers lighter than nonsmokers birth survey record (1972) data; actual weight changes not presented Biener 274 (174 men, 100 women) ex- 49% women, 39% men gained Retrospective w81) smokers, worksite setting weight following cessation; quitter postcessation gain self- approximate average gain: women report; no nonsmoker 11 lb, men 15 lb control group Blair et al. 183 white male, 284 white female Smokers 2.647.5 lb lighter than Small sample size; (1980) insurance company employees; nonsmokers, 0.88-15.21 lb lighter white office workers average age 34 than ex-smokers; smaller only skinfolds for smokers of both sexes than nonsmokers TABLE 2.-Continued Study Design and sample Major results Moderator variables Limitations Bjelke (1971) 8,638 male, 10,331 female respondents. mail survey, Norway general population "systematic sample" Used "bulk index" (weight/height'); both sexes current smokers less bulky than quitters and never smokers Fehily et al. (1984) 211 nonsmoking, 282 smoking men, aged 45-59, heart disease study Smokers weighed 7.5-10.3 lb less than nonsmokers. 6.6-9.4 lb less than ex-smoken: pipe/cigar smokers weighed 2.4 lb more than nonsmokers; weight/height' index results similar Smoking rate: not related to weight Age: older respondents greater smoker/nonsmoker bulk differences Sex: women greater smoker/nonsmoker bulk differences Self-report by mail; no weights, no statistical analyses presented - Small, all white. restricted sample; smoking self-report Fisher and Gordon (19851 15% random sample, 10 U.S., Canadian clinics; 2,269 male, 2,105 female whites, aged 20-59, LRC Prevalence Study Men: smoking nondrinkers weighed 6.6 lb less than nonsmoking nondrinkers; smoking drinkers weighed 2.2 lb less than nonsmoking drinkers Women: smoking nondrinkers weighed 2.2 lb less than nonsmoking nondrinkers; smoking drinkers weighed 4.4 lb less than nonsmoking drinkers All white population; smoking self-report Friedman et al. (1981r 38 smoking-discordant monozygotic twin pairs, average age 40 years Smokers weighed 5.07 lb lass than nonsmokers Self-report by mail; small restricted sample e TABLE 2.4hntinued Study Design and sample Major results Moderator variables Limitations Garn et al. (1978bI 17,649 pregnant women, national health survey Smoking mothers prepregnancy weight less than nonsmoking mothers; difference: whites 2.43 lb. blacks 3.53 lb SEIS and race: no smoking/weight relationship influence Pregnant women only; self-reports Garrison et al. (1983) Framingham study participants; zL6xx.d 194!+1952 Nonsmokers 55% of highest weight group; smokers 80% of lowest weight group Goldbourt and Medalie (1977) - Gyntelberg and Meyer (1974) 10,059 male government workers, aged 40-65 ______ 5,249 employed men. aged 40-59, Denmark Current smokers l/4 inch taller, 2.35 lb less than nonsmokers; ex- smokers in between: leaner skinfolds for smokers than ex- smokers and nonsmokers Nondrinking smokers 1.5 percentile points lighter than nondrinking nonsmokers: light drinking smokers 2.9 percentile points lighter; heavy drinking smokers 5.9 percentile points lighter than drinking nonsmokers Sample sire. weights not given; no statistical evaluation Limited age range. employment group; smoking self-report All-male sample. one city; smoking self- report Hjermann et al. ( 1976) Approximately 18,090 male participants, aged 40-49, coronary risk factor screening, Oslo Aged 45-49 smokers body weight 3.09 lb less than nonsmokers; aged 40-44 difference not significant; no group weight/height* index differences Smoking rate: heavy smoker ( > 20/day) body weights higher than lighter smoker Age: older smokers (45-491 weighed less than nonsmokers; younger smokers (40-44) no effect Smoking self-report: limited age range; one city; all men TABLE S.--Continued Study Design and sample Major results Moderator variables Limitations Holcomb and Meigs (1972) 226 manufacturing company male hourly employees, aged 56-59 Mild to moderate smokers 14 lb lighter than never smokers, ex- smokers, and heavy smokers Smoking rate: heavy smokers (> 1 pack/day) heavier than lighter smokers, equivalent to nonsmokers Smoking self-report; limited age, incomes; all men Huston and Stenson (1974) 184 men, British Field Regiment 5 10 mm subscapular skinfold men averaged 22 cigarettes/day; 2 15 mm subscapular skinfold men averaged 12 cigarettes/day Limited male sample; smoking self-report; nq separate smoker/ nonsmoker data Jacobs and Gottenborg (1981) 3,291 white men and women, aged 29-59, no cardiovascular disease or elevated risk factors; randomly selected middleclass suburb census tract blacks Smokers lighter than never smokers and quitters Smoking rate: male moderate Smoking self-renort: I . smokers (14-29 cigarettes/day) restricted population 6.39 lb lighter than nonsmokers, 2.65-9.93 lb lighter than light and heavy smokers; female moderate smokers 5.07 lb lighter than never smokers, 1.54-8.38 lb lighter than heavy smokers Age: moderate/never smoker weight difference increased with ak?P Khosla and Lowe (1971, 10,482 male steel workers, Wales Per weight/height* index, smokers lighter than nonsmokers Smoking rate: heavy smokers (> 35 cigarettes/day) heavier than moderate smokers (15-34) Age: group weight differences increased after age 35 Smoking self-report; restricted population Kittel et al. 8,284 male factory workers, (1978) Belgium Relative weights significantly lower for cigarette smokers than never smokers, ex-smokers, and pipe/cigar smokers Limited population, risk factor Rx program - is TABLE 2.-Cmtinued Study Design and sample MJor results Moderator variables Limitations Kopcsynski (1972) 3.059 random selectees, pulmonary disease study, Poland Nonsmokers heavier than smokers, except 26year-old men Sex. age. smokii rate: no smoking/weight relationship influence Smoking self-report; weights not reported Lincoln (1970) 3,220 male household heads, aged 41-70, acroea United States Smokers weighed 3-14 lb less than nonsmokers SES smoker/nonsmoker weight difference increased as income decreased Smoking rate: heavy smokers (221 cigarettes/day) weighed 4 lb more, moderate smokers (11-20 cigarettes/day) 4 lb less than all-smoker average Restricted population; men Matsuya (1982) 90 telephone employees, Japan Examokera weighed 5.29 lb more than nonsmokers; light smokers 2.87 lb leas, heavy smokers 0.44 lb less than ex-smokers Small, nonrepresentative sample; data self-report Nemery et al. (1963) 210 steelworkers. aged 4555. 2 10 years' service, FJelgium Smokers weighed 12.13 lb less than never smokers, 14.33 lb less than ex-smokers Restricted population; smoking self-report Stamford et al. (1984al 164 (56 smokers, 108 nonsmokers) premenopausal women; smokers: 220 cigarettes/day, 25 years, inhale Smokers weighed 11.96 lb less, had lower average Quetelet Index than nonsmokers Small sample size; premenopausal women only; data self-report Stamford et al. (1964b) 269 adult men, fitness center SCWd"ed; smokers: 2 20 cigarettes/day, 2 5 Smokers weighed 14.99 lb leas. had 12% leas body fat than nonsmokers years, inhale Select sample. exercising men; smoking self-report; heavy smokers TABLE t.-Continued Study D&i and sample Major results Moderator variables Limitations Stephens and Pedemon (1933) 15.518 persons aged >lo; questionnaire, anthropometry Smokers weighed less than nonsmokera; female smokers weighed 1.32 lb more to 5.73 lb less than female nonsmokers; men weighed 3.09-7.7 lb less; smokers averaged 3.445 lb less than nonsmokers White women self- report. smoking self- report; no statistical significance tests Sutherland et al. (1960) Random sample, 175 men and women, rural town, New Zealand Weight/height* index and &infolds significantly higher in nonsmoking than smoking women; higher for nonsmoking men, but not signiftcant Wailer and Brooks (1972) 2,169 health exhibit visitors "Little weight difference" among current smokers, nonsmokers, and ex-smokers Sax: male smokers not significantly leaner than nonsmokers; smoking women lighter than nonsmoking women Smoking self-report: small sample size Smoking self-report; bathroom scale weight; healthconscious population; high % cigar/pipe smokers; no statistical evaluations Zeiner-Henriksen ( 1976) Approximately 15,0(x) randomly s&cted Norwegians Current smokers average and relative weight lower than nonsmokers or exsmokers Smoking and weight self-report, questionnaire is TABLE S.-Longitudinal evaluations of smoking and body weight Study Design and sample Major results Moderator variables Limitations Blitzer et al. (19771 `57,032 women, aged 20-59, self- help weight loss groups Bosse et al. (198th 1,749 adult men, Normative Aging Study, as=cssed over 5 years Burse et al. (19821 4 paid volunteers; llday baseline, 2lday quit period, 26 day resumption period Quitters gained 7.0-10.2 lb more than continuing smokers Average &year gains: never smokers 1.81 lb, former smokers 1.87 lb; current smokers 2.00 lb; ex-smokers who quit 6.34 lb Smoking rate: weight Smoking and weight gain/previous smoking rate self-reports; all women proportional trying to lose weight Age: younger quitters gained more Adiposity: fatter quitters gained more Smoking self-reports; all men; actual weights not presented Tar rate: higher pretest tar rate smokers gained most Anxiety: high related to higher gain 3 of 4 gained weight; 1.98 lb increase during cessation: 1.76 lb loss on resumption Very small sample, paid volunteers; short- term evaluation Cambien et al. (1981) 1,097 Paris civil servants, aged 25-35, screened, randomly assigned, cardiovascular risk factor reduction intervention or control groups; a-year followup evaluation Treatment group quitters gained 4.85 lb, control group quitters 7.50 lb; nonsmokers and no change smokers gained 1.54 lb in treatment group, 2.2 lb in control Smoking self-report; risk factor reduction program participants Carney and Goldberg 09841 13 women, 5 men, aged 28-67, smoked 2 20 cigarettes/day. 2 5 years; 12 male controls; 15 smokers abstained 2 weeks Quitters weight change range: -3.09 to +9.0 lb Smoking rate/duration: no weight change relationship Biological variables: weight gain positively related to lipoprotein lioase activitv in adiwse tissue Smoking self-report; controls weight changes not reported; short-term evaluation TABLE 3.-Continued Study Design and sample Major results Moderator variables Limitations Coates and Li (1983) 373 male asbestosexposed smokers, aged 242; 87% white, mean education 12.8 years; 12 months assessment after cessation effort Continuous quitters gained 5.15 lb; continuous smokerv gained 0.35 lb Smoking self-report; all male, nonrandom sample Cornstock and Stone (1972) 502 male telephone workers, aged 40-59. mostly white; 2 assessments 5 years apart 5.year followup average gains: never smokers 2.43 lb, ex- smokers 5.07 lb, continuing smokers 2.42 lb; quitters 11.24 lb and showed greatest skinfold increases Smoking rate: increasing quitter weight gain with heavier prequit smokmg Smoking self-report; men only Dallosso and James (19841 16 (8 men, 8 women) antismoking clinic participants; mean age, men 47.1, women 35.4; assessed before and 6 weeks after clinic 10 quitters gained 3.06 lb; 5 continuing smokers lost 0.99 B Small sample sire; smoking self-report; limded followup Emont and Cummings I1987J 125 stop-smoking clinic participants; pretreatment and l- month followup assessments 76% quitters and shppers ( 5 5 cigarettes/day) averaged 5.8 lb gain Nicotine gum. gain/gum use reliable negative correlation for heavy smokers: gain not related to age. sex. marital status, baseline body weight Weight gain. smoking self-report. confounded by gum use; limited followup: incomplete data Fagrrstrom llY87) 28 nicotine gum users; abstinent at 6 months Infrequent gum users gained 6.83 lb, frequent users 1.98 lb Nicotine gum: frequent users gained less weight Small sample sire; measures unclear Friedman snd Siegclaub (19801 Multiphasic health checkup patients; smoked, then quit 12-18 months later (N=3,825) or continued (N=9,3921 Quitters gained 2-3 lb more than continuing smokers Smoking rate: higher initial smoking rate related to greater weight gain after cessation Smokmg self-report; whites only data !s TABLE 3.-Continued Study Design and sample Major results Moderator variables Limitations Cam et al. 6,979 women followed through (1978b) 2 2 pregnancies Higher prepregnancy weights for habitual nonsmokers than habitual smokers: whites 3.4 lb, blacks 4.1 lb; lower habitual smoker gains between pregnancies for both races Race: no weight/smoking relationship influence Smoking self-reports; restricted population Garvey et al. (1974) 670 white male veterans. aging study, asaeswd 4-l years after initial assessment Smoking/weight change significantly related; recent quitters (55 years) gained 4.19 lb more than smokers, nonsmokers, former smokers Age: 4W quitter weight increase greatest Smoking self-report; exact quit date unknown Glauser et al. (1970) Cordon et al. (1975) I male smokers, cessation program; assessed preprogram. 1 month postprogram 4,798 Framingham study participants: 1,498 male smokers, 492 male nonsmokers, 1,634 female nonsmokers, 1.174 female smokers; examined short-term changes after biennial exam 1. long-term effects between biennial exams 4, 10 At l-month followup, participants gained 6.4 lb At entry, male smokers weighed 8.0 lb less than nonsmokers; short-term male quitters gained 3.8 lb, nonsmokers 0.5 lb, continuing smokers 0.3 lb; new smokers lost 9 lb; too few female quitters to evaluate Smoking self-report; exact quit date unknown Smoking self-report; change analysis, men only Gormican et al. (1960) 301 pregnancy obstetrics records, women, aged 17-35 Smoker, nonsmoker prepregnancy weight similar; no last 2 trimester weight gain difference (nonsmokers 24.6 lb, smokers 22.6 lb) Clinic record data; pregnancy weight gain data only TABLE 3.-bntinued Study De&n and sample Major results Moderator variables Limitations Grinstead (1981) 45 subjects (38 women, 7 men), average age 40; evaluated 6 months after cessation treatment; saliva thiocyanate verification During program, 63% subjects averaged 2.86 lb increase, 34% averaged 2.46 lb decrease; at followup, 37% averaged 6.97 lb gain, 43% averaged 3.27 lb lees Questionnaire, phone interview data Grits et al. (in press) 554 selfquitters (245 men. 309 women), mean age 41.4, 85% Caucasian, 9% black, 4% Asian, 1% Asian-American, 1% Native American; l-year followup 35% previous quitters gained. 3% last; at 1 year, abstainers averaged 6.1 lb gain; relapsers gained 2.71 lb while abstinent, lost 1.3 lb upon relapse; continuous smokers gained 0.3 lb Questionnaire, phone interview data Grassarth-Maticek et al. (1983) 1,353 subjects, Yugoslavian village of 14,ooO, every 2d household oldest member; evaluated 1965-1966. 1969 Smoking reduction/weight increase relationship (regression coefficient -0.30) Smoking self-report; weights. weight changes not reported Gunn and Shapiro (1985) 89 cessation clinic participants; all quit at initial evaluation: 3 month followup assessment 43 of 54 030%) quitters gained Z-30 lb Smoking, height, weight self-report: inadequate statistical evaluation Hall et al. (1986) 255 smoker participants (122 men, 133 women), 2 smoking treatment trials; 6, 1Zmonth followups; biochemical verification Abstainers gained more than smokers at 1 year Smoking rate: pretest smoking levellpostcessation weight gain positively related Chronic dieting: chronic diet subjects gained most Multiple Rx (e.g., nicotine gum) participant data included Hataukami et al. (1964) 27 smokers hospitalized 7 days; 20 subjects smoked 3 days, then quit 4 days; 7 control group subjecte smoked throughout Quitters gained 1.76 lb in 4 days Small sample size; inpatient environment E TABLE 3.-Continued Study Design and sample Major results Moderator variables Limitations Haworth et al. t1990) 536 women (2.74 nonsmokers, 302 smokers) interviewed last prenatal visit (18%) or within day after delivery (82%1 No smoker/nonsmoker pregnancy weight gain difference Hickey and 150 men 1124 smokers); Bmonth. Mulcahy 2.year followups after myocardial (1973) infarction Quitter, reducer, continuing smoker differences not signilicant Smoking self-report: pregnancy weight gain data only Smoking self-report; postmyocardial infarction may motivate heahhy behavior Iiolme et al. (1985) 16,202 Oslo men, aged 4049, screening program; 1,232 (elevated cholesterol or upper quartile coronary risk score) randomly assigned diet/smoking intervention or control: &year fOlLOWID 17% controls, 24% intervention quit; l- to 2.yearquitter weight increased more than controls, then decreased to below prequit level Smoking self-report; confounded by high cardiovascular disease risk health intervention; weights not reported Howell (1971) Retrospective, 1,121 men, aged 40-54; 15 to 20year weight gain examinations Light smokers (~20 cigarettes/day) gained 1.9 lb less than heavy smokers, 3.1 lb less than ex-smokers, 3.6 lb less than never smokers Smoking rate: lower rate related to less weight gain Retrospective report Hughes and Hutchinson (1963) 37 smokers and 19 ex-smokers with pulmonary emphysema followed 23 years Smokers lost 0.32 lb/yr, ex- smokers gained 1.17 lb/yr; significant difference Smoking self-report; pulmonary emphysema population TABLE 3.-Continued Study Design and sample Major results Moderator variables Limitations Jenkins et al. ( 1973) 2,318 men (546 never smokers, 359 previous quitters, 547 light smokers, 666 heavy smokers), aged 39-49, 11 California corporations in Western Collaborative Group Study; changes asses& since age 25; 1960-1969 studv Weight loss more likely for light and heavy smokers than never smokers and quitters Smoking self-report; weights not presented Kramer ( 1982) 175 subjects, commercial cessation prcgram (41 nonparticipants or nonlocated, 59 quitters. 75 continuing smokers) 2 l-year followup 76% nonsmokers, 56% smokers gained weight: these smokers mean gain 1.7 lb, these nonsmokers mean gain 3.0 lb All date self-report; high attrition. data loss; presentation incomplete Lund-Larsen and Tretli (1992, 12,329 men and women, aged 2049. cardiovascular disease project; 2 screenings 3 years apart Stpokers mean and relative weight less than nonsmokers; female quitters gained 5.95 lb, male quitters 7.64 lb; smoking- starter men lost 1.96 lb, women 5.5 lb; smokers and nonsmokers little/no change Sex: men. women weight change/smoking cessation and initiation similar Self-report Manley and Roland (1963) 39 male, 55 female smokers, cessation program; randomly assigned, 1 of 3 4-week treatments or attention placebo control; Bmonth followup; CC verification 31% abstinent at followup: abstainers averaged 10.93 lb gain, relapsers 6.92 lb Relapser definition unclear TABLE 3.-Continued Study Design and sample M.?+ar zwults Moderator variables Limitations Noppa and Rengtsmn (1980) 1,362 Swedish women, aged 38-W Current smokers leaner than nonsmokers; At 6 years, quitters gained 7.72 lb; smoking-starters lost 1.54 lb, nonchangers gained 3.09 lb Smoking self-report Pincherle (19711 222 upper-class male quitters; followup 2 1 year after first visit 28% gained weight; 22% last Smoking self-report; limited population; incomplete report; no weights presented Powell and McCann (1981) 29 women, 22 men, 5day cessation project; 2- and 6month followup At 2 months, 54% gained weight, range 3-20 lb. mean 8.96 lb; all subjects mean 4.69 lb Smoking self-report; no separate abstainer, smoker data; small sample sire Puddey et al. (1985) 66 cessation program volunteers, pair-matched by age, sex, body mass index; randomly assigned experimental, control groups; 2- week baseline, &weak treatment, 6week followup; thiocyanate, Co verification 14 quitters gained 3.97 lb; controls 0.44 lb Small sample sire Rabkin (1964) 40 male, 67 female smokers, assigned to 3 cessation groups; followup 3 weeks w&completion; 67.3% gained weight, average 1.76 lb; skinfold increase 6.6 mm bicchet&l verification No age. age at smoking start, rate. relative weight, anxiety correlation to male or female weight change Small sample size; weight self-report TABLE 3.-Continued Study Design and sample Major results Moderator variables Limitations Rantakallio and 12.068 pregnant women. n. No smoking/nonsmoking Pregnant women only; Hartikainen-Sorrin Finland, 1966, 15% smokers pregnancy weight gain difference smoking self-report; (1981) (smoked after 2 months pregnancy weight gain pregnant); nonsmoking controls data only matched for age. parity, place of residence, marital status Rush 162 low-income urban pregnant Mean pregnancy weight gain Smoking rate: higher rate Pregnant women only; (1974) women, no known medical lower for smokers (0.73 lb/wk) related to lower pregnancy smoking self-report; problems, < 140 lb preconception than nonsmokers (0.90 lb/wk) weight gain pregnancy weight gain weight; had borne low data only birthweight infant; randomized controlled nutritional supplementation trial Schoenenberger 4,421 male MRFIT volunteers, With MRFIT intervention, Smoking self-report; (1982) aged 35-57, good health but significant body weight decrease confounded by risk upper lO-15% coronary risk in smokers (mean 4.6 lb). factor reduction factor score; randomly assigned nonsmokers (mean 5.6 lb), program participation; to intervention or control groups; reducers (mean 3.75 lb); quitters restricted population followup 3 annual visits average weight change minimal (mean 0.55 lb) Seltzer 794 adult white male veterans, At admission, ex-smokem 5.9 lb White veterans; (1974) average age 45, Normative Aging heavier than nonsmokers, 8.1 lb smoking self-report Study; screened for "high" health heavier than currant smokers; at level, geographic stability; 214 5 years, quitters gained 8.0 lb, screened at 5 years continuing smokers 3.5 lb TABLE 3.-Continued Study Design and sample Major results Moderator variables Limitations Stamford et al. (1966) 13 sedentary women, 48day su-ful quitters; l-year follow"p At 48 days, weight increased 4.85 lb; at 1 year, quitters increased 18.07 lb; 3 relapsers reduced weight to baseline levels; per hydrostatic weighing, gain was 96% fat Small female sample; smoking self-report Tuomilehto et al. (198.5) 10,940 cardiovascular disease prevention program participants. aged 25-59, random sample. e. Finland; selectees with high blood pressure or hypertensive medicine asses& 5 years apart; smoking data from 2,264 Quitters body nmss increased 2.31 lb/m*; starting smokers decreased 1.46 lb/m' Smoking self-report; hypertensives Vandenbroucke et al. (1984) 3,091 Netherlands civil servants, spouses (1,583 men. 1,508 women), aged 40-65, general health exam: 25year followup 76.6% lean, 65.1% obese men smoked; 22.1% lean, 11.3% obese women smoked Smoking self-report; restricted population Gottenborg 1981; Khosla and Lowe 1971) documented increasing weight differences between smokers and nonsmokers with advancing age. Typically, aging smokers failed to gain as much weight as aging nonsmokers. Three evaluations systematically compared males with females (Bjelke 1971; Kopczynski 1972; Sutherland et al. 1980). Two of the three (Bjelke 1971; Sutherland et al. 1980) reported the differences in body weight between smokers and nonsmokers to be greater in females than in males. Longitudinal Evaluations of Smoking and Body Weight Table 3 presents the results of 43 longitudinal evaluations of the effects of smoking on body weight. Consistent with the cross-section- al evaluations, the overwhelming majority (86 percent, 37 of 43) present evidence that smokers who quit smoking gain weight, that people who quit smoking gain more weight than nonsmokers, and that people who initiate smoking lose weight relative to nonsmokers. Of the six studies that did not find these relationships, three limited their examination to smoking and weight changes in pregnant women (Gormican, Valentine, Satter 1980; Haworth et al. 1980; Rantakallio and Hartikainen-Sorri 1981). two relied on participants making broad cardiovascular risk factor reduction efforts in subjects at high risk for cardiovascular disease (Hickey and Mulcahy 1973; Holme et al. 19851, and the remaining study supplied incomplete reports of the data (Kramer 1982). Of those studies on the effects of smoking cessation on weight, the length of followup ranged from 4 days to 7 years. According to these investigations, those who quit smoking gained an average of 6.16 lb (range: 1.76 to 18.07) during the year after cessation. Daily cigarette consumption was the only moderator variable that received sufficient attention in this group of studies reaching specific conclusions. Seven of nine studies (78 percent) (Blitzer, Rimm, Giefer 1977; Bosse, Garvey, Costa 1980; Comstock and Stone 1972; Fried- man and Siegelaub 1980; Hall, Ginsberg, Jones 1986; Howell 1971; Rush 1974) reported a positive relationship between cigarette consumption and weight change; that is, as pretest cigarette consumption increased, postcessation weight gains also increased. Two studies (Carney and Goldberg 1984; Rabkin 1984) did not find a relationship between cigarette consumption and postcessation weight gain. In summary, there is substantial evidence of an inverse relation- ship between cigarette smoking and body weight. Of 71 studies reported since 1970, 62 (87 percent) collectively indicate that smokers weigh less than nonsmokers and that people who quit smoking gain weight. Older smokers, females, and those smoking approximately one pack of cigarettes/day may experience the 431 largest weight control effects of cigarette smoking. Smokers who smoke heavily tend to gain the most weight following smoking cessation. These generalizations are consistent with reviews based on other studies reported since 1880 (Grunberg 1986a). Not all smokers who quit smoking gain weight. Further, for ex-smokers who do gain weight, the amount of weight infrequently poses a serious health risk. The Role of Nicotine Animal studies indicate that nicotine administration results in weight loss or decreased weight gains and that cessation of nicotine results in body weight gains greater than those of controls (Bowen, Eury, Grunberg 1986; Grunberg 1982, 1985, 198613; Grunberg, Bowen, Morse 1984; Grunberg, Bowen, Winders 1986; Grunberg, Winders, Popp 1987; McNair and Bryson 1983; Morgan and Ellison 1987; Schechter and Cook 1976; Wager-Srdar et al. 1984; Wellman et al. 1986). Most of these studies report inverse dose-response relation- ships between nicotine and body weight. Becent research on nicotine polacrilex gum with humans corrobo- rates the role of nicotine in body weight effects. Fagerstriim (1987) reported that subjects who quit smoking were much less likely to gain weight when they consistently used nicotine polacrilex gum. Abstinent subjects who regularly used the gum gained less than 2 lb at a 6month followup. In contrast, the infrequent gum users gained almost 7 lb (p< 0.05). Emont and Cummings (1987) reported a significant negative relationship (r=-O.37) between the number of pieces of nicotine polacrilex gum chewed per day and weight gain for heavy smokers ( > 26 cigarettes/day). No such relationship between gum use and weight gain was observed for lighter smokers (< 26 cigarettes/day). Mechanisms Underlying The Relationship Between Smoking and Rody Weight The inverse relationship between smoking and body weight may result from changes in energy intake, changes in energy expendi- ture, or both. Energy intake involves dietary intake. Energy expenditure is affected by behavioral factors (physical activity1 and biological factors (e.g., metabolism). These potential mechanisms are examined below. Dietary Intake Several prospective investigations have evaluated dietary intake changes following smoking cessation in humans. Hatsukami and coworkers (1984) hospitalized 27 smokers for a 7day period. After a 3day baseline, 20 of the subjects were deprived of smoking for 4 days 432 while the remaining 7 served as a control group. During this I-day period of abstinence, caloric intake increased significantly (from 1,397 to 1,651 kcal), which corresponded with a significant 1.76lb increase in weight. In the most comprehensive study to date, Stamford and coworkers (1986) evaluated changes in dietary intake, physical activity, and resting metabolic rate in 13 sedentary females who quit smoking for a 48day period. Following smoking cessation, mean daily caloric consumption increased by 227 kcal, which accounted for 69 percent of the variance in postcessation weight gain (4.85 lb). Robinson and York (1986) followed 11 smokers who quit for 7 days. Mean dietary intake significantly increased, but changes in resting metabolic rate were not observed. Dallosso and James (1984) followed 10 subjects for 6 weeks after they participated in a stop smoking clinic. There was a 4percent drop in resting metabolic rate in smokers who quit, a drop which was reliable when the data were expressed per kilogram of body weight. The average dietary intake increased by 6.5 percent, but this difference did not reach statistical significance. Preliminary results of a recent investigation indicate gender differences in the effects of short-term smoking cessation on body weight and food intake (Klesges, Meyers et al. 1987). Female smokers who quit for 1 week increased their body weight and dietary intake significantly more than male smokers who quit. This sex difference is consistent with animal studies (Grunberg, Bowen, Winders 1986; Grunberg, Winders, Popp 1987). Given females' marked concerns regarding postcessation weight gain (Klesges and Klesges, in press), future studies will need to investigate possible gender differences in response to smoking cessation. Several studies indicate that smokers may differ from nonsmokers in their intake of sweet-tasting simple carbohydrates (sugar) in particular. In a human laboratory study, Grunberg (1982) observed that smokers who were allowed to smoke ate less sweet food than smokers who were not allowed to smoke or nonsmokers. Smokers not allowed to smoke also reported the greatest preference for sweet foods. There were no differences among the three subject groups in consumption of other types of foods. Rodin (1987) conducted a prospective study in which food intake after smoking cessation was carefully evaluated. Smokers who gained weight after quitting smoking increased their sugar consumption in particular. Further, smokers increase consumption of sweet snack foods when they are deprived of cigarette smoking (Duffy and Hall, in press; Perlick 1977). On the other hand, two early investigations (Bennett, Doll, Howell 1970; Richardson 1972) found higher sugar consumption in smokers relative to nonsmokers. However, Richardson (1972) found that this difference was because of low-sugar intake in ex-smokers, while Bennett, Doll, and Howell (1970) argued that the differences 433 were largely due to increased added sugar intake because of hot beverage consumption. These two studies, which are inconsistent with the more recent studies, did not carefully measure all food intake and did not assess intentional changes in food intake to control body weight. Several animal experiments have documented that food intake decreases during nicotine administration and increases after admin- istration has ceased and that these changes in food intake corre- spond with changes in body weight (Bowen, Eury, Grunberg 1986; Grunberg 1982; Grunberg, Bowen, Winders 1986; Levin et al. 1987; McNair and Bryson 1983; Wager-Srdar et al. 1984). Consumption of sweet foods by male rats is particulary affected by nicotine (Grun- berg 1982; Grunberg et al. 1985). However, nicotine also reduces bland food intake in female rats and has a greater effect on body weight of female rats than of male rats (Grunberg, Winders, Popp 1987; Grunberg, Bowen, Winders 1986; Levin et al. 1987). Several investigations have reported that changes in body weight in animals also occur without observing decreases in food intake as the result of nicotine administration (Grunberg, Bowen, Morse 1984; Schechter and Cook 1976; Wellman et al. 1986). In one investigation, chronic exposure to cigarette smoke reduced body weight and food intake in rata; however, hamsters exposed to cigarette smoke decreased body weight without reducing food intake (Wager-&&r et al. 1984). Several methodological factors complicate these results, including the use of different strains of animals, different routes of administration and dosages of nicotine, and whether acute versus chronic effects of nicotine were reported. However, these results indicate that more than the mechanism of food intake was involved in producing nicotine- and smoking-related weight changes. Data from short-term human studies and several animal experi- ments indicate that dietary intake is involved with smoking-related energy imbalance. Based on self-reported cross-sectional surveys, it has been reported that smokers' dietary intake is the same as (Albanes et al. 1987; Fehily, Phillips, Yarnell 1984; Fisher and Gordon 1985; Matsuya 1982) or significantly higher than (Picone et al. 1982; Stamford et al. 1984a,b) that of nonsmokers while the smokers simultaneously maintained a lower body weight. Assuming that smokers are not consistently biased in their reports of dietary intake, it appears that either differences in physical activity or metabolic rate are maintaining the body weight differences between smokers and nonsmokers. Physical Activity The data available from cross-sectional investigations, short-term prospective studies, and animal investigations seem to indicate that changes in physical activity do not play a role in either differences in 434 body weight between smokers and nonsmokers or the weight gain associated with smoking cessation. Some cross-sectional investiga- tions have found that smokers have lower levels of physical activity compared with nonsmokers (Karmas 1981). Others have not found differences in physical activity and physical fitness between smokers and nonsmokers (Gyntelberg and Meyer 1974; Stamford et al. 1984b; Stephens and Pederson 1983). A recent review (Blair, Jacobs, Powell 1985) that addressed the relationships among exercise, physical activity, and smoking concluded that smoking and physical activity are negatively associated; however, the relationship was extremely weak and variable. Animal studies on the relationship between nicotine and physical activity have generally found that physical activity plays a small role or fails to correspond to decreases in weight during nicotine administration (Bowen, Eury, Grunberg 1986; Cronan, Conrad, Bryson 1985; Grunberg and Bowen 1985b). One study found that decreases in physical activity after cessation of nicotine appeared to contribute to postdrug body weight increases (Grunberg and Bowen 1985b), but this effect was quite small and occurred only in males. A few prospective human investigations have evaluated physical activity changes following smoking cessation (Hatsukami et al. 1984; Hofstetter et al. 1986; Klesges, Brown et al. 1987; Rodin 1987; Stamford et al. 1986). These investigations found no changes in physical activity as a result of smoking cessation. Metabolic Rate Metabolic rate is an important consideration in energy imbalances associated with smoking cessation because approximately 75 percent of total energy expenditure is in the form of metabolism (Bernstein et al. 1983; Ravussin et al. 1982). Metabolism increases as the result of acute nicotine administration and immediate effects of smoking (Ghanem 1973; Ilebekk, Miller, Mjos 1975; Robinson and York 1986; Schievelbein et al. 1978; Wennmalm 1982). The major question, however, is whether these effects persist long enough to have a direct impact on body weight. Given that (1) smokers do not have higher levels of physical activity compared with nonsmokers (Blair, Jacobs, Powell 1985). (2) some studies report smokers' dietary intakes are the same as or higher than those of nonsmokers (Picone et al. 1982; Stamford et al. 1984a,b), and (3) smokers maintain lower body weights than nonsmokers, it is reasonable to postulate that changes in metabolism contribute to the relationship between smoking and body weight. Additionally, there are several reports in the literature on animals that have documented nicotine-induced reductions in body weight without a concomitant reduction in food intake (Grun- berg, Bowen, Morse 1984; Schechter and Cook 1976; Wellman et al. 1986). 435 Direct evidence supporting a chronic metabolic mechanism that modulates the smoking/body weight relationship is beginning to emerge. Metabolic rate was chronically measured in a study of rat and hamster exposure to cigarette smoke (Wager-Srdar et al. 1984). Higher resting metabolic rates were observed on only one of the test days compared with the pretest in the rat investigation, while no significant differences were observed in the hamster study. Another recent investigation (Wellman et. al. 1986) evaluated brown adipose tissue (BAT) thermogenesis at different levels of nicotine and caffeine injections. No differences in BAT thermogenesis were observed in response to either nicotine or caffeine. The group that received a combination of caffeine and nicotine showed a 63 percent increase in BAT thermogenesis. The few studies that have evaluated metabolic rate changes in response to smoking cessation in humans have produced inconclu- sive results. Three investigations found metabolic changes after cessation in human smokers. An early report (Glauser et al. 1970) found decreases in oxygen consumption for seven male subjects who quit smoking for 1 month (neither food intake nor physical activity was monitored). A more recent investigation found a 4-percent drop in metabolic rate (reliable when data were expressed per kilogram of body weight) and no significant increase in dietary intake for 10 subjects who quit smoking for 6 weeks (Dallosso and James 1984). In the only study that used a respiration chamber, Hofstetter and others (1986) reported that total energy expenditure was 10 percent higher during a 24-hr period of smoking versus a 24-hr period of abstinence in eight smokers. No changes were observed in physical activity or mean basal (sleeping) metabolic rate (dietary intake was held constant). However, this difference in energy expenditure disappeared after 24 hr. Three investigations did not find a change in metabolic rate as the result of smoking cessation. Burse and associates (1982, 1975) did not observe changes in resting metabolism in a sample of four smokers who quit for 3 weeks. This investigation did find reliable increases in desire for food, however. In another study, 11 smokers were studied after a `I-day period of smoking abstinence (Robinson and York 1986). Total energy expenditure following a meal did not change during the cessation period. Stamford and colleagues (1986) failed to fmd changes in oxygen consumption in 13 subjects who quit smoking for 48 days. This investigation did find marked dietary intake changes that accounted for 69 percent of the variance of postcessation weight gain. There are several possible explanations for the inconsistency observed in the literature on metabolic rate. Different investigators have used different criteria (e.g., resting oxygen consumption, BAT thermogenesis) for operationalizing metabolism. It is possible that 436 previous dieting history (Brownell et al. 1986) and the use of nicotine polacrilex gum (Fagerstrom 1987) may directly impact the metabolic response to smoking cessation. It is not clear what the metabolic response to nicotine with added agents is likely to be. For example, one study found that while neither nicotine nor caffeine alone produced a change in BAT thermogenesis, the two combined increased thermogenesis by 63 percent (Wellman et al. 1986). This finding is particularly interesting given that smokers may be more likely to drink caffeinated beverages than nonsmokers (Blair et al. 1980). Finally, the available literature on human studies used very small subject groups, making it impossible to detect subtle but potentially meaningful changes in resting metabolic rate. The small sample sizes do not allow for an evaluation of variables that may potentially moderate the metabolic response to smoking cessation. Summary of Mechanisms Literature Changes in dietary intake appear to be involved in weight gains after cessation of smoking or cessation of nicotine administration. Physical activity plays little or no role in the relationship between smoking and body weight. The data on metabolic contributions to postcessation weight gain are suggestive, but further research is needed. Unfortunately, much of the relevant human research literature is characterized by small sample sizes, short followup evaluations, and inadequate evaluations of energy balance following smoking cessation. To date, only one investigation has comprehen- sively evaluated (i.e., simultaneous assessment of dietary intake, physical activity, and metabolic rate) energy balance changes as the result of smoking cessation. This was a sample of 13 sedentary females followed for 48 days (Stamford et al. 1986). Comprehensive, prospective evaluations of energy balance changes in response to smoking cessation are needed. Additionally, no study has evaluated possible long-term changes in dietary intake, physical activity, and metabolic rate as a result of smoking cessation. The longest followup period reported in the literature to date is 2 months (Dallosso and James 1984). Finally, evaluation of potential moderator variables of dietary intake, physical activity, and metabolic rate as the result of cessation is needed. Gender (Grunberg, Winders, Popp 1987; Klesges, Meyers et al. 1987), previous dieting history (Brownell et al. 1986; Hall, Ginsberg, Jones 1986). pretest levels of lipoprotein lipase (Carney and Goldberg 1984), and the use of nicotine polacrilex gum (Fagerstrom 1987) appear to be important variables influencing weight gain and need further investigation. Does the Relationship Between Smoking and Weight Promote Either the Initiation or Maintenance of Smoking Behavior? Some research attention has been given to body weight as a potential moderator of smoking initiation, maintenance, and cessa- tion. Unfortunately, many investigations do not report weight- related issues (Borkon, Baird, Siff 1983; Eiser et al. 1985; Pederson and Lefcoe 1976; Perri, Richards, Schultheis 1977). The investiga- tions that have evaluated these issues consistently report relation- ships between body weight and smoking initiation (Charlton 1984a) and maintenance (Klesges and Klesges, in press). A survey of 16,000 school children (Charlton 1984a) in England found that the heaviest regular smokers were the most likely to agree that smoking controls weight (42.2 percent) compared with those students who never smoked (16.6 percent). Agreement in- creased with increased levels of smoking. More girls than boys agreed with this statement, and girls were also more likely to be regular smokers. Charlton (1984b) also reported that among the perceived effects of smoking, smokers viewed "calming the nerves" as the most popular reason (72 percent) followed by "smoking keeps your weight down" (39 percent). Other investigations are consistent with the Charlton (1984a,b) report. In a recent study of 1,000 adolescents in Canada (Feldman, Hodgson, Corber 1985), significantly more girls than boys were concerned about becoming overweight (36 vs. 14 percent, p, or with behavior modification or health education interven- tions (Rabkin et al. 1984). Most studies have found hypnosis to be superior to no-treatment control groups, although Lambe, Osier, and Franks (1986) found no such difference. Followup abstinence rates reported for hypnosis in recent studies have ranged from less than 4 percent (Perry, Gelfand, Marcovitch 1979) to 60 percent (Javel 1980), with a mean of approximately 28 percent. These figures may be spuriously high because several studies reported less than 6 months of followup and most relied exclusively on subject self-report. There is little evidence that hypnotic induction per se facilitates smoking cessation and maintenance above and beyond the effects of other treatment components (including the posthypnotic suggestions themselves) (Holroyd 1980; Katz 1980). Acupuncture Acupuncture involves the use of needles or staple-like attachments and commonly is given at the ear either by press needle or staple puncture. Acupuncture has gained popularity over the past 10 years (Schwartz 1987). There are few carefully controlled evaluations of 504 this procedure for smoking cessation. Many published reports have suffered from serious methodological shortcomings (e.g., lack of control conditions, short or nonexistent followup periods, failure to include data from all treated subjects). Six studies have compared acupuncture at the "correct" site for smoking cessation against an "incorrect" or sham site. In only one study (MacHovec and Mann 1978) was the correct site significantly superior to the sham site. As with hypnosis, most evaluations of acupuncture have relied exclu- sively on self-reports. At this point, there is little evidence that acupuncture relieves withdrawal symptoms or promotes smoking cessation. A combination of acupuncture and supportive counseling or skills training may be more effective (Schwartz 1987). Treatment of Special Smoker Populations Recognition of smoking as a dependence-producing behavior leads to important implications in treating several populations of smokers including women, blacks, and Hispanics. Current trends (Appendix A) indicate that the burdens of smoking in the future may be disproportionately felt by lower socioeconomic and minority popula- tion groups. For treatment to have optimal impact, it must meet the needs of smokers from diverse circumstances. Presently, the vast majority of those who avail themselves of formal intervention are white and are from relatively advantaged socioeconomic back- grounds. It is not obvious that interventions for special populations should differ substantially from those that are currently available. There are indications based on smoking patterns and environmental and social factors that suggest the importance of tailored intervention. A great deal more research is needed, however. At this point, for example, it is unclear whether self-help treatment manuals oriented to specific target groups are preferable to more general manuals. Currently there are almost no materials or programs prepared especially for blacks or Hispanics. If the needs of lower SES and minority smokers are not met, the trend for smoking to be disproportionately concentrated among these groups is likely to continue. Considerations of treatment for the dependent smoker are not complete without substantial attention to issues of application and dissemination, especially to smokers not being served by current interventions. Applying Smoking Interventions to Women Sex Differences in Cessation and Relapse Rates Trends in cigarette smoking among men and women in this century have followed roughly similar curves, except that increases and decreases in smoking prevalence among women have lagged 15 to 30 years behind rates for men (Harris 1983; US DHEW 1980, Appendix A). Recent declines in overall smoking prevalence are attributed to lower initiation rates among teenage males and higher cessation rates among adult males Remington et al. 1985). The percentage of former smokers in the male population has increased more dramatically than the percentage of former smokers in the female population (Appendix A). Jarvis (1984) adjusted cigarette cessation rates in Britain and in the United States to reflect the proportion of males who switched from smoking cigarettes to smoking pipes and cigars. After this adjustment, sex differences in cigarette cessation rates disappeared for individuals under age 50. Several recent, well-controlled prospective evaluations of cigarette cessation programs found no differences in the proportions of women and men who achieved initial cessation and/or long-term mainte- nance (Curry 1986; Gritz 1982; Hall, Ginsberg, Jones 1986). The question of whether previously observed gender differences in cessation and relapse rates (the magnitude of which is often small) reflect real and stable sex differences, historical effects true only in older smokers, or statistical artifacts due to analytical limitations is not resolved, Motivation to quit. In one of the few studies addressing gender differences in motivation to quit, Curry (1986) found that successful male and female abstainers did not differ in their overall reasons for quitting (e.g., "Smoking is inconsistent with my commitment to good health"). However, women in Curry's (1986) study differed signifi- cantly from men on questions related to four more specific subdimen- sions of motivation: self-determination (,`I will like myself better"), reinforcement ("My hair and clothes won't smell"), influence of significant others (,*I can get praise from people I am close to [for quittingr'), and social consequences ("Smoking is less socially acceptable"). Perhaps these more specific reasons for quitting should be considered in tailoring the content of smoking treatments to female subjects. Education. The personalization (perception of the personal rele- vance) of abstract information has been shown to be an important aspect of behavioral change in general (Mahoney 1974) and of health-related behavioral change in particular (Ben-Sira 1982; Schinke and Gilchrist 1984). Available evidence suggests that many women may not fully be aware of some important gender-specific health consequences of smoking (Shiffman 1986b; Sorensen and Pechacek 1987). Adolescent women in particular often either are not well informed or choose to ignore information on the harmful effects of smoking during pregnancy (Simms and Smith 1983; Stewart and Dunkley 1985). It may be useful to develop educational campaigns that publicize the gender-specific risks of smoking. Information that might be used in such educational campaigns comes from studies of important adverse interactions between smoking and female physiology, especially estrogen-related pro- cesses. Several studies have found a positive association between cigarette smoking and early menopause (Baron 1984; Willett et al. 19831, estrogen-related postmenopausal osteoporosis and associated fractures (Daniel1 1976; Paganini-Hill et al. 1981), and invasive cervical cancer (Brinton et al. 1986). Social values and beliefs. Cigarette smoking is a multidetermined behavior shaped by both personal and environmental variables (Chassin, Presson, Sherman 1985; Jones and Battjes 1985). The bulk of research on smoking has assumed that the developmental pathways leading to cigarette use and later dependence are the same for males and females. Several lines of recent research suggest that this assumption is overly simplistic (Barton et al. 1982; Baumrind 1985; Ensminger, Brown, Kellam 1982; Gritz 1982; Yamaguchi and Kandel 1984). The developmental and social dynamics that propel female adolescents into smoking may differ from those operating on young males. Several studies suggest that female smokers appear attracted to cigarette smoking by a need to identify with a particular social image (Gritz 1982, 1984; Jacobson 1982, Mausner and Brand- Spiegel 1985). Studies of advertising influence show that women, more than men, choose cigarette brands for image reasons (Bergler 1981; Fisher and Magnus 1981). Cigarette smoking today is often associated in the media with independent women who are not only sexually desirable (and slender) but also successful in traditionally male activities (Baker, Dearborn et al. 1984; Godley, Lutzker, Lamazor, Martin 1984). Reliance on cigarettes for bolstering an important, self-selected social image may make some women resis- tant to educational messages on the health consequences of smoking. Another factor bearing on women's use of cigarettes for social image reasons involves body size and weight control (Gritz 1985; Jacobson 1982; US DHEW 1980). Data from junior high students suggest that even at young ages females more than males are interested in cigarettes as a weight control aid (Charlton 1984; Chapter VI). Achieving Abstinence Weight gain. Women's fear of weight gain has been widely observed (US DHEW 1980). Some animal data (Grunberg, Bowen, Winders 1986; Grunberg, Winders, Popp 1987; Levin et al. 1987) as well as preliminary results from a study with human subjects (Klesges, Meyers et al. 1987) suggest that females are more likely than males to gain weight following removal of nicotine. In contrast, Hall, Ginsberg, and Jones (1986) found that although all subjects gained weight after achieving abstinence, weight gain was no more 507 likely to cause female subjects than male subjects to relapse (Chapter VI). More studies are needed to determine whether fear of weight gain in the early stages of cessation is a more powerful obstacle for women than is actual weight gain later in the cessation process. Stress manogenent. Social, psychological, and epidemiological studies consistently report the greater importance of cognitive appraisal processes and monitoring of internal states and feelings on the part of females compared with males (Blechman 1984). Several studies have characterized women as negative-affect smokers-i.e., individuals who smoke in response to emotional discomfort and for purposes of tension reduction (Brunswick and Messeri 1984; Christen and Glover 1983; Dembroski 1984; Livson 1985; Mitic, McGuire, Neumann 1985; Rust and Lloyd 1982; US DHEW 1980). Other researchers have found that negative-affect smokers grow more reliant on cigarettes than do smokers who respond to social or external stimuli (Ockene et al. 1981; Pomerleau, Adkins, Pertschuk 1978). In current cessation studies, female subjects, compared with male subjects, have reported more stress during the quit process (Abrams et al. 1987) and more concern about finding alternatives to cigarettes for coping with stress (Abrams et al. 1987; Moreton and East 1983; Sorensen and Pechacek 1987; Chapter VI). Social support. Women, more often than men, report a preference for interacting and learning in settings that involve close, informal, personal, dyadic, or small-group interactions (Brady 1987; Glynn, Pearson, Sayers 1983; Grady, Brannon, Pleck 1979; Linehan 1984). Both the quantity and the quality of women's participation increase in groups composed solely of women (Burden and Gottlieb 1987; Linehan and Egan 1979; Gambrill and Richey 1986). Grits (1982) concluded that women are more successful in programs that provide social support and individualized therapist-client contact, and less successful in programs in which such support is absent or when external environmental supports are lacking. Data continue to indicate the importance of social support (and partner support in particular) for maintenance of smoking cessation among women (Coppotelli and Orleans 1985; Sorensen and Pechacek 1987). Smoking Cessation Initiatives for Black Americans Black Americans constitute the Nation's largest minority group, making up 12 percent of the population, and have the highest smoking rate of the major U.S. ethnic/racial groups; 34.8 percent of all black American adults smoke, compared with 29.7 percent of non- Hispanic whites and 25.7 percent of Hispanic adults (Appendix A). Blacks also suffer the Nation's highest rates of mortality and morbidity from cardiovascular diseases and cancer, including core- nary heart disease and lung cancer (Cooper and Simmons 1985; US DHHS 1985, 1986). Moreover, smoking represents an especially 508 serious health risk for blacks, given the disproportionate incidence of infant mortality and low birth weight, hypertension, diabetes, and hazardous occupational exposures within the U.S. black population (US DHHS 1985). To date, relatively little research has been done to clarify smoking/quitting patterns and determinants among black Americans or to test smoking cessation interventions in black populations. The 1985 Cancer Prevention Awareness Survey (US DHHS 1987) found that blacks were less likely than the general public to report hearing or reading about cancer prevention in the preceding 6 months, and were less likely to view tobacco use as a cancer risk. There is also evidence that blacks have less belief in personal control over health outcomes and disease, particularly cancer (Deniston 1981; Snow 1983; US DHHS 1987). Sociodemographic Factors The so&demographic correlates of smoking status among black Americans are similar to those for the U.S. population as a whole: these include lower income, lower education levels, lower occupa- tional status, unemployment, being male, and being unmarried (never married, separated, or divorced) (Eisinger 1971; Marcus and Crane 1987; Orleans et al. 1987; US DHHS 1985; Warneke et al. 1978). Restricted Health Care Access More limited access to health care, particularly to preventive health services, may also play a role in the higher black smoking rate (Eisinger 1971; Green 1975; Rogers and Shoemaker 1971; US DHHS 1985; Warneke et al. 1978). Fewer blacks (54 percent) than whites (70 percent) report a physician's office as their regular source of care, and twice as many blacks as whites say they receive their regular care from hospital outpatient clinics and emergency rooms or public health clinics (where continuous care and preventive health services are less likely) (US DHHS 1985). Therefore, it is not surprising that the 1985 National Health Interview Survey (NHIS) found fewer adult black smokers (33 percent men, 43 percent women) than white smokers (40 percent men, 47 percent women) reporting medical advice to quit smoking (Marcus and Crane 198'7). Social Norms and Advertising Influences Peer and family modeling appears to play the usual role in the initiation and maintenance of smoking as well as in smoking cessation (Orleans et al. 1987; Warneke et al. 1978). However, the combination of a higher smoking rate among blacks and a pervasive, well-financed, black-focused tobacco advertising campaign may lead 509 to stronger smoking norms within the black community (Cooper and Simmons 1985; Cummings, Giovino, Mendicino 1987; Davis 1987). Determinants of Quitting Motivation and Success Among Black Smokers Factors influencing quitting motivation and success among black smokers appear to be similar to those among smokers in general, including beliefs in smoking-related health harms and quitting benefits; personal relevance of the health threat; a greater number of sources of support and communication about smoking health risks and quitting; the extent to which family, friends, and health professionals provide personal information about smoking risks; personal medical advice to quit; self-mastery motivation; past efforts to quit or cut, down; degree of tobacco dependence; and primary group social supports for quitting and nonsmoking (Eisinger 1971; McDill 1975; Orleans et al. 1987; Pechacek and Danaher 1979; Prochaska and DiClemente 1983; Warneke et al. 1978). Again, however, considerably more research is needed. Smoking and Quitting Patterns Among Black Americans Although black smokers smoke fewer cigarettes per day than white smokers, they smoke brands with higher tar/nicotine yields, especially menthol brands (Friedman, Sidney, Polen 1986; Appendix A). The 1981 NHIS showed that 65 percent of black smokers smoked brands with 1.1 mg or more of nicotine, in contrast to only 35 percent of white smokers, and that 67 percent of black smokers smoked menthol cigarettes, in contrast to only 26 percent of white smokers, In fact, it has been estimated that three high-nicotine menthol brands account for more than 60 percent of cigarettes purchased by blacks (Cummings, Giovino, Mendicino 1987). Menthol additives may pose additional health risks (Cummings, Giovino, Mendicino 1987); these additives could conceivably influence puffing patterns (e.g., by reducing the perceived "harshness" of the tobacco) so as to heighten nicotine delivery or smoking risks (e.g., by enabling the smoker to tolerate inhaling more often or more deeply or to smoke the cigarette to a shorter length). However, to date no studies that address this issue have been published. National survey data (US DID-IS 1985) suggest that black smokers attempt to quit at the same rate that white smokers do. However, blacks appear to be less likely to remain abstinent (Appendix A). Quitting barriers faced more often by blacks include the same so&demographic factors that explain their higher smoking rate, including the greater life stress and more limited resources associated with lower SES. 510 Quit-Smoking Treatments Quitting methods. A recent survey of black ex-smokers showed that like U.S. ex-smokers as a whole, the vast majority had quit "on their own": 9 in 10 said they relied on "willpower," and only 1 in 10 reported using formal treatment programs, self-help guides or aids, or nicotine polacrilex gum (Orleans et al. 1987). There are, to date, no published data on the extent to which black and white U.S. smokers differ specifically in their access to, or use of, quit-smoking services and resources. Sources/treatment agents. Physicians and other health care provid- ers are powerful sources of quit-smoking assistance (Orleans 1985) and may be especially important sources for black Americans. In the 1985 Cancer Prevention Awareness Survey (US DHHS 19871, blacks reported more often than the general population that they would be very likely to follow a doctor's advice about ways to reduce cancer risks (US DHHS 1987). Messages/methods. It is currently unclear whether black smokers would benefit any more or less than other groups from generally effective quit-smoking strategies and treatments. When outreach has assured equal black-white access to treatments and information (broadly defined in terms of recruitment efforts, location, affordabili- ty, appeal, and readability), outcomes for black and white smokers have been similar. For instance, Windsor and colleagues (1985) offered clearly worded pregnancy-focused self-help materials on quitting to women in public health maternity clinics and found no differences in quit rates between black and white participants of similar SES. High-coronary-risk black men assigned to the Special Intervention of the Multiple Risk Factor Intervention Trial (MRFIT) achieved 6-year quit rates (43 percent) essentially comparable to those of white participants (46 percent) despite lower SES (Connett and Stamler 1984). On the other hand, preliminary unpublished results from several ongoing trials suggest that interventions developed for the general population may not be appropriate for or acceptable to lower SES minority smokers. Channels/delivery modes. Church groups, fraternal organizations, and other groups within the black community have a unique role to play in bringing effective programs and resources to the attention of smokers and to provide support needed for compliance (Eng, Hatch, Callan 1985; Orleans et al. 1987). Besides improving treatment accessibility, these organizations have the potential to provide ongoing assistance and support for quitting efforts and nonsmoking maintenance. Eng, Hatch, and Callan (19851, for instance, describe working through black churches in rural North Carolina to offer smoking cessation, weight control, diet modification, and stress management health education and behavioral change programs. Lay health advisers were recruited to work with local professionals to 511 organize church-based health fairs and to provide screening and referral on an individual basis. Interventions for Smoking Cessation Among Hispanics As the most rapidly growing ethnic group in the United States, Hispanics have caught the attention of demographers, social scien- tists, and health planners, yet relatively little is known of their smoking behaviors or responses to various intervention and treat- ment approaches. There is recent evidence (Davis 1987) that cigarette advertising is increasingly targeted to specific groups and that Hispanics have become a major focus of sophisticated marketing approaches. Prevalence Smoking prevalence among Hispanic males is comparable to that amcng white males and considerably less than that among blacks. Smoking among Hispanic women, in contrast, is considerably lower than smoking among either white or black women (Marcus and Crane 1985). Hispanics consume considerably fewer cigarettes per day than do whites. Heavy smoking among Hispanics is relatively infrequent (Marcus and Crane 1985,1987; Samet et al. 1982; Stem et al. 1975). Data from the 1985 Current Population Survey indicate substan- tial differences in smoking status by Hispanic subgroup. More Puerto Ricans reported smoking than did other subgroups (Mexican- Americans, Cubans, and Central and South Americans). Caution is needed in interpreting these data as they are based on limited numbers of respondents. Marcus and Crane (1985) reported that the pattern of high smoking prevalence among Hispanic men and relatively low prevalence among Hispanic women held true across a number of Hispanic subgroups. Overall, the data suggest consider- able ethnic diversity within the Hispanic population. Diversity in smoking prevalence among Hispanics also has been found in the Hispanic Health and Nutrition Examination Survey (HHANES) conducted between 1982 and 1984 (Appendix A). Cultural differences among divergent Hispanic groups may need to be considered in the design and content of treatment programs. Smoking Antecedents Markides, Coreil, and Ray (1987) used data from a three-genera- tional study and found that smoking behavior among younger Mexican-Americans was positively correlated with that of their middle-aged parents. This association was stronger for women. In a study of Mexican-American high school students who were identified as potential school dropouts, Bruno and Doscher (1984) found more 512 smokers in this group than among other students. These researchers found that 56 percent of their survey population of 78 potential dropouts had increased their cigarette consumption in the previous year. Otero-Sabogal and colleagues (1986) reported that "positive social presentation" as a consequence of smoking was mentioned by Hispanics in their study group. Castro and coworkers (in press) state that smoking and other habitual behaviors do not occur in isolation, but are part of a lifestyle. Smoking has been identified by these authors and others as a "core unhealthy behavior" that is associated with other such behaviors as use of illicit drugs, alcohol abuse, driving while intoxicated, nonuse of seat belts, and a pattern of little aerobic exercise. However, on a test of knowledge about the health consequences of smoking, moderate-to-heavy cigarette smokers were the highest scorers, suggesting an intellectual awareness of the risks involved in their behavior. Smoking Interventions The only available study that specifically targeted Hispanics was reported by Wittenberg (1983). During a market survey for the "Healthy Mothers, Healthy Babies" campaign, focus groups were organized to gather information from minority women. Researchers held sessions with eight groups of black women and seven groups of Mexican-American women. The results of these sessions suggested that the women involved largely ignored health advice, including advice to quit smoking, believing that the negative consequences would affect the mother and not the baby. Wittenberg (1983) found that the physician was considered the most credible source of health information but that family and friends were also important sources of information, which sometimes was in conflict with professional advice. Mexican-American women cited a paucity of Spanish-speak- ing health providers, and both minority groups stressed the need for such providers to have a better understanding of dietary preferences and traditional cultural patterns to more adequately serve pregnant minority women. The roles of the family, the Catholic Church, and the Spanish language have been said to be at the heart of the cultural identity of Hispanics in the United States (Guernica and Kasperuk 1982; Perez-Stable 1987). These influences have not been systematically assessed or harnessed in the design of smoking intervention programs for Hispanics. Research addressing other ethnic groups is virtually nonexistent. Methodological Issues in Treatment Study Design and Evaluation Since the late 1970s researchers and theoreticians have made progress in developing theoretical comparison strategies in evaluat- ing pharmacologic and behavioral treatment interventions. This has 513 gradually resulted in the use of more sophisticated analytic compari- sons in at least a few studies (Brandon, Tiffany, Baker 1987; Hall, Rugg et al. 1984; Harackiewicz et al. 1987; Raw and Russell 1980; Tiffany, Martin, Baker 1986). The development of specific measures and investigator adoption of theory-driven analytic strategies (A- brams et al. 1987; Davis and Glaros 1986; Erickson et al. 1983; Hall, Rugg et al. 1984; Harackiewicz et al. 1987; Mermelstein, Lichten- stein, McIntyre 1983; Shiffman and Jarvik 1976; Tiffany, Martin, Baker 1986) should result over the next 10 years in a clearer understanding of therapeutic change processes. Integrated theoreti- cal approaches in which treatment, subject, and context factors are considered simultaneously may prove especially fruitful. A second major methodological concern is the typical smoking intervention study design. Most researchers, when they do use control or comparison treatments, merely pit one treatment against another, often with no clear theoretical basis. Some investigators systematically remove or add treatment elements largely on prag- matic grounds. Unfortunately, such experimental designs permit only weak inferences concerning the specific effective elements of treatment (McFall 1978). Earlier reviews (Pechacek 1979) noted that the principal problem plaguing smoking treatment evaluation was that clinical outcomes were typically inferred from data of suspect validity. Previously, most long-term outcome data were based on client self-reports of smoking status, possibly supported by informant reports. Both self- and informant reports are vulnerable to biases that make them inadequate in research settings as sole measures of outcome (Glynn, Gruder, Jegerski 1986; Li et al. 1984; Murray et al. 1987). Fortunate- ly, over the last 9 years biochemical verification of self-reports has become a more common practice, although it is by no means universal. Carboxyhemoglobin estimates from breath samples and measure- ments of thiocyanate in urine, saliva, or plasma and of cotinine in saliva and serum have been used most frequently to assess smoking status. Carboxyhemoglobin has a relatively brief half-life and is affected by ambient CO, activity level, and some drugs (Ringold et al. 1962; Henningfield, Stitzer, Griffiths 1980). However, this measure is inexpensive and can provide subjects immediate feedback on an important health risk factor. Thiocyanate may remain elevated for up to 12 to 14 days after smoking cessation (BarylkoPikielna and Pangborn 1968; Pettigrew and Fell 1973). Thiocyanate levels may be quite variable within individuals (Barylko-Pikielna and Pangborn 1968). Assays of thiocyanate are insensitive to low levels of smoking (Vogt et al. 1977) and are often poorly correlated with self-reported smoking rates or actual measures of puffing patterns (Abueg, Colletti, Rizzo 1986; Burling et al. 1985; Vogt et al. 1977). Further- 514 more, thiocyanate levels may be considerably affected by consump tion of common foods (e.g., almonds, tapioca, cabbage, broccoli, and cauliflower; Bliss and O'Connell 1984). For these reasons, cotinine is a generally preferred assay. Cotinine, a major metabolite of nicotine, is detected above nonsmoker levels for up to 48 hr after a single cigarette is smoked (Zeidenberg et al. 1977). Cotinine levels may persist for up to 7 days after cessation of habitual smoking (Benowitz et al. 1983). Cotinine assays tend to be expensive, limiting their usefulness. Readings will not accurately reflect smoking in individu- als who use nicotine polacrilex gum. Immediate feedback to subjects is not possible with thiocyanate and cotinine measures. Biochemical assays do not provide complete information concern- ing posttreatment smoking status. Self-report, although not ade- quate when used alone, is a necessary measure. Also, when subjects are aware of the use of biochemical assays, their self-reports of abstinence agree well with assay results (Hall, Rugg et al. 1984; Hall, Sachs et al. 1984; Glynn, Gruder, Jegerski 1986; Raw and Russell 1980). However, other studies have found no improvement in the accuracy of reporting with the use of physiological measures (Bliss and O'Connell 1984). Insufficient attention has been devoted to length and intensity of treatment as determinants of outcome (Chapter V). As noted previously, the vast majority of individuals who have quit to date have done so in the absence of formal intervention. Spontaneous remission among chronic drug users has been observed not only for tobacco but for opioids and alcohol as well (Chapter V). However, evidence of spontaneous remission does not justify a failure to treat chronic smokers who are (or who perceive themselves to be) unable to achieve abstinence on their own. Changing social norms appear to be extremely significant in the recent decline in smoking prevalence (Appendix A). Public health approaches have the potential of reaching far larger numbers of smokers than do intensive clinical treatments, yet some individuals obviously are resistant to these normative influences. Many tobacco users do not appear responsive to minimal contact or community interventions. Sachs (1986) has argued that highly intensive clinical procedures may be cost-effective for certain populations of high-risk smokers (e.g., those who already have suffered myocardial infarc- tions). Some individuals persist in their tobacco use despite the presence of immediate life-threatening health problems related to their dependence. Other issues with which the field still struggles are definitional, e.g., the operational definitions of abstinence and relapse. Studies that report abstinence rates during followup split on whether they require continuous abstinence from the end of treatment or merely abstinence at the point of followup. Abstinence levels can differ 515 substantially depending on which measure is used. Failure to follow a common practice in reporting outcome (or to provide sufficient information to allow independent calculations) substantially in- creases the difficulty of comparing success rates across studies (Bigelow and GssipKlein 1986). The National Interagency Council on Smoking and Health formu- lated stringent standards for the evaluation of smoking cessation programs. Complete cessation including total abstinence from tobac- co in all forms for a period of 1 year was defined as the primary criterion for success. Several major health agencies (the American Cancer Society, the American Heart Association, and the American Lung Association) have endorsed these standards. Biochemical validation of self-reported abstinence is not required in these guidelines. The guidelines fail to distinguish between an isolated "slip" and actual relapse in the definition of successful quitting (GssipKlein et al. 1986). Many studies still fail to include enough subjects to permit adequate statistical power and to promote generalixability of results. Few cessation studies have used validity checks to determine the extent to which treatment manipulations actually were implement- ed effectively. This is especially important when counseling strate- gies are being compared (Hall, Rugg et al. 1984; Tiffany, Martin, Baker 1986). Counseling manipulations and therapist training and experience should be adequately described, and validity checks of counseling differences should be incorporated into the assessment plan. Selection of subjects represents another important issue (e.g., type of smoker, cigarette consumption, prior history of failures). Treatment outcome may be influenced substantially by the charac- teristics of the smokers assigned to intervention. In sum, cessation research has made methodologically notable strides in that, in the best studies, outcomes are verified with multiple assays (including biochemical ones), the design and evalu- ations of treatments are now theory driven, improved therapy process measures are used, and a variety of specific pragmatic problems such as subject attrition have been reduced. These im- provements are recent, however, and characterize a relatively few published studies. Conclusions Smoking treatment research has been marked by considerable progress since it was reviewed in the 1979 Report of the Surgeon General (US DHEW 19791, both in methodological sophistication and to a lesser extent in the consistency of success achieved by the best multicomponent cessation programs. In contrast to the generally positive outcomes of multicomponent treatments, there is mounting evidence that no single intervention 516 constitutes a generally effective method. In the case of multicompo- nent treatment interventions, individual components should comple- ment one another. Interventions that hold promise and deserve additional attention are low-aversion directed-smoking strategies, skill-training treatments, interventions that enhance the self-attri- bution of treatment success, and interventions that train individuals to obtain and use social support resources. Low-aversion smoking treatments are important because of their acceptability, ease of administration, and generally promising results when used with other treatment elements. Research on skills training should explore the extent to which enhanced clinical outcomes depend on the acquisition and actual use of specific smoking-relevant skills. Thera- peutic manipulations that enhance self-attributions of success or self-efficacy estimates could have wide treatment applicability. The combination of increased knowledge and skills, self-efficacy, and social support should enhance treatment outcomes. Investigators should make more explicit the relationship between theory and therapeutic manipulations, valid assessments should be tailored to tap processes implicated by theory in behavioral change, and greater sample sixes should be included in treatment evaluation studies. Individual differences may be important in assigning smokers to combined pharmacologic and behavioral treatment (Hughes 1986). Some smokers appear to resist pharmacologic inter- vention. Smokers who attribute their success to pharmacologic agents may be at increased risk for relapse when these agents are withdrawn (Davison and Valins 1969). Conversely, some smokers accept pharmacologic treatment but refuse behavioral approaches. Many of these refusals stem from required time commitments that the smokers view as excessive. Dissemination of effective treatment strategies is critically need- ed. Considering the vast body of treatment literature that has accumulated, surprisingly little systematic transfer to community settings has occurred. Many treatment programs that are available (e.g., proprietary, public service) have not been subjected to rigorous evaluation. Furthermore, these programs often do not reflect recent laboratory findings. This is especially true for pharmacologic ap- proaches. Very few applied programs adequately address nicotine replacement therapies or other potentially relevant pharmacologic adjuncts to treatment. Dissemination is especially lacking for minority and lower SES populations, which may have the greatest need for these types of services. Relapse As in many areas of clinical practice, therapeutic interventions have been developed and implemented in the absence of a complete 517 understanding of the processes being treated. Future development of smoking cessation treatments designed to maintain abstinence in the face of high relapse prevalence should benefit greatly from an expanded knowledge base that is being accumulated concerning the correlates and determinants of smoking relapse. Research has shown that smoking cessation is a process involving several discrete stages. These stages include precontemplation, contemplation, decision, action, and maintenance (Prochaska and DiClemente 1983, 1985, 1986; DiClemente and Prochaska 1985; Prochaska et al. 1985; Velicer et al. 1985; Wilcox et al. 1985). This Section considers recent research on factors related to successful maintenance of nonsmoking once initial cessation has been achieved during the action stage. Studies of long-term outcomes in smoking cessation indicate that relapse, rather than maintenance, is the most prevalent outcome during this stage. Hunt and his colleagues (Hunt, Barnett, Branch 1971; Hunt and Matarazzo 1973) showed that over a wide range of treatments, relapse rates of 75 to 80 percent could be expected among smokers who achieved initial cessation (Figure 2, Chapter V). These findings have been replicated many times in recent treatment outcome studies (Schwartz 1987). It should be noted, however, that these relapse rates are based on single quit attempts. Cumulative long-term abstinence rates covering multiple quit attempts may be considerably better (Schachter 1982). Defining Relapse Given that relapse depends on the achievement of initial cessation, definitions of relapse must include a definition of cessation. In addition, many investigators distinguish between a "slip" or smoking one's first cigarette and a "relapse" or return to regular smoking (Brownell et al. 1986). The National Working Conference on Smok- ing Relapse recommended a duration of 24 hr of continuous tobacco abstinence to define initial cessation. A slip was defined as a "period of not more than 6 consecutive days of smoking following at least 24 hr of abstinence" (Ossip-Klein et al. 1986). Smoking beyond 6 consecutive days was then defined as a relapse. These definitions of quit episode, slip, and relapse are somewhat lenient. Many investiga- tors require a longer period of initial abstinence (e.g., 48 hr or 1 week) for a quit episode and regard even a few smoking occasions as a relapse rather than a slip. Considerable data indicate that an initial slip is highly predictive of subsequent relapse (Brandon, Tiffany, Baker 1986; OssipKlein et al. 1986). Conceptual Frameworks Research on the relapse process has focused on two general areas: (1) identifying factors that predispose individuals to relapse or to successful maintenance and (2) identifying factors that precipitate or 518 immediately precede the return to smoking following initial success (Shiffman et al. 1986). Predisposing factors include characteristics of individuals and their environments that make them more or less vulnerable to relapse as they begin the maintenance process. Precipitating factors relate to the circumstances surrounding a specific relapse situation or smoking the first cigarette following a period of abstinence. Social learning theory has provided a useful framework for much of the research on predisposing factors (Bandura 1977b; Brownell et al. 1986; Leventhal and Clear-y 1980; Shiffman et al. 1986). From this perspective, the effects of environmental or behavioral elements on maintenance of nonsmoking are mediated by individual factors such as prior experience with smoking cessation and beliefs about the cessation process. In addition to personal demographic characteris- tics, predisposing, variables examined that are consistent with this framework include smoking and quitting history, social factors (social support and the presence of smoking cues in the social environment), stress, and cognitive factors such as self-efficacy, outcome attributions, and perceptions about the consequences of quitting smoking (Chapter VI). Marlatt and Gordon's model of the relapse process (Marlatt and Gordon 1980, 1985) has provided the foundation for much of the research on the circumstances associated with initial slips and suggests specific hypotheses regarding factors that mediate the transition from an initial slip to a full-blown relapse. This model proposes that initial smoking following a period of abstinence is likely to occur in certain types of high-risk situations. As suggested by the types of predisposing factors listed above, high-risk situations could include intrapersonal factors such as negative affect and severe withdrawal symptoms following a long history of heavy smoking. The first determinant of whether smoking occurs in a high- risk situation is whether the individual uses specific strategies to cope with the situation. Successful coping is assumed to lead to increased confidence in one's ability to maintain abstinence, thereby decreasing the probability of relapse. Failure to cope in the situation coupled with positive expectations about the effects of smoking can lead to an initial slip. The Abstinence Violation Effect (AVE) is proposed as the major mediating factor between an initial slip and a full-blown relapse. Defined as an attributional construct (Curry, Marlatt, Gordon 1987; Marlatt and Gordon 19851, the AVE is characterized by internal, stable, and global causal attributions for smoking the initial cigarette. Research on specific factors within these conceptual frameworks is reviewed below. 519 Predisposing Factors Demographics To the extent that demographic factors are related to initial cessation, the population of individuals who achieve cessation and are "eligible" for relapse is relatively homogeneous. It is not surprising, therefore, that the majority of studies that examined these variables have not found differences in relapse rates by socioeconomic status (Campbell 1983; Eisinger 1971; Evans and Lane 1981; Garvey, Heinold, Rosner, in press; Hirvonen 1983; Horwitz, Hindi-Alexander, Wagner 1985; Jacobs et al. 19711, age (Coppotelli and Orleans 1985; Cummings et al. 1985; Evans and Lane 1981; Hirvonen 1983; Horwitz, Hindi-Alexander, Wagner 1985; Jacobs et al. 1971), or gender (Eisinger 1971; Evans and Lane 1981; Shapiro and Gunn 1985; Horwitz, Hindi-Alexander, Wagner 1985). Excep tions to the findings for age include one study that found an inverse relationship (Garvey, Heinold, Rosner, in press) and two studies reporting a positive relationship between age and long-term success (Campbell 1983; Eisinger 1971). One study did report that males were more successful than were females at long-term maintenance (Hirvonen 1983). Although women and men may be equally likely to relapse, data suggest that their return to smoking is precipitated by different factors. Hirvonen (1983) reports that men more frequently cited alcohol consumption and strong cravings as causes of relapse, whereas women more often cited the influence of other smokers and negative affect. In a prospective study, Swan and colleagues (in press) found that craving predicted relapse for women and not for men, while psychological withdrawal symptoms predicted relapse among men but not women. Studies that have analyzed reports of specific relapse episodes (Shiffman 1982, 1986a) have found no gender differences. The large study by Swan and coworkers (in press) of treated smokers suggests that sex differences in factors associated with relapse may be pervasive. They found almost no overlap between men and women in the factors that predicted relapse. The following factors predicted relapse among women, but not men: the machine- rated nicotine delivery of cigarettes, employment status, rated likelihood of success, and lower work strain. Among men, relapse was predicted by greater stress (hassles) and higher work strain. Campbell (1983) also reports sex differences in predictors of outcome, some of which contradict Swan's findings, and Guilford (1967) reports sex differences on almost all aspects of cessation and maintenance. Although it may be premature to draw conclusions about the causes of relapse among males and females, clearly sex differences must be examined in future work. 520 Smoking and Quitting History Smoking History Most studies indicate that the length of a person's smoking history influences the process of initial cessation (Pomerleau, Adkins, Pertschuk 1978) but is unrelated to relapse (Ashenberg 1983; Carl 1980; Coppotelli and Orleans 1985; Cummings et al. 1985; Evans and Lane 1981; Garvey, Heinold, Rosner, in press; Hirvonen 1983; Horwitz, Hindi-Alexander, Wagner 1985; Jacobs et al. 1971; Pomer- leau, Adkins, Pertschuk 1978; Swan et al., in press). The two studies that report relationships between length of smoking history and relapse are contradictory, with one reporting that smoking longer increased reiapse risk (Graham and Gibson 1971) and the other reporting an inverse relationship between the duration of smoking and the risk of relapse (Eisinger 1971). Conflicting findings have been reported for the number of ciga- rettes smoked per day. Although there are some positive findings (Ockene et al. 1982; Shapiro and Gunn 1985). most studies suggest that the number of cigarettes smoked is not a good predictor of relapse (Campbell 1983; Coppotelli and Orleans 1985; Cummings et al. 1985; Eisinger 1971; Evans and Lane 1981; Graham and Gibson 1971; Hirvonen 1983; Horwitz, Hind&Alexander, Wagner 1985; Jacobs et al. 1971; Pomerleau, Adkins, Pertschuk 1978; Swan et al., in press). A few studies do find an effect of the number of cigarettes smoked on initial cessation (Hirvonen 1983). Precessation cigarette consumption has been positively associated with the length of time between having an initial lapse and a return to regular smoking (Brandon, Tiffany, Baker 1986). It should be noted, however, that number of cigarettes is only a rough indicator of actual intake, particularly for levels above 20 cigarettes/day. Kabat and Wynder (1987) reported that the time between waking up and smoking the first cigarette was a good predictor of outcome. This variable represents one item on the Fagerstriim Tolerance Questionnaire (Fagerstrom 1978) and appears to be strongly related to physical dependence. Smoking Typologies Although their predictive value has been questioned (Joffe, Lowe, Fisher 19811, smoking typologies have been widely used in an attempt to classify smokers or smoking situations (e.g., smoking for stimulation, handling, relaxation; Ikard, Green, Horn 1969). The strongest evidence for the relationship of type of smoking to relapse has been found with people who smoke to control negative affect. In a widely cited study, Pomerleau, Adkins, and Pertschuk (1978) reported that people who said they smoked when experiencing negative affect were more likely to relapse. Similarly, Campbell 521 (1983) reported that smokers who experience craving when emotion- ally upset were more likely to relapse. These findings are diluted, however, by those of other studies showing no relationship between negative-affect smoking and relapse (Coppotelli and Orleans 1985; Eisinger 1971; Garvey, Heinold, Rosner, in press; Jacobs et al. 1971). Quitting History Several studies have found a positive relationship between number of previous quit attempts and success in quitting smoking (Brandon, Zelman, Baker, in press; Tiffany, Martin, Baker 1986). However, other studies report no relationship between the number of prior quit attempts and relapse (Swan et al., in press; Horwitz, Hindi- Alexander, Wagner 1985; Cummings et al. 1985; Coppotelli and Orleans 1985; Ockene, Benfari et al. 1982). Some studies in fact report that subjects with fewer previous quit attempts are more successful in maintenance (Horwitz, Hind&Alexander, Wagner 1985; Graham and Gibson 1971; Garvey, Heinold, Rosner, in press). Garvey and Hitchcock (1987) found that among recidivists, smokers with more past experience in quitting showed a slower rate of progression to regular smoking. Gottlieb and coworkers (1981) and Hirvonen (1983) also report data that suggest a positive relationship between duration of the longest previous cessation effort and successful maintenance. Clearer descriptions of quitting history with respect to both number of previous quit attempts and duration of abstinent periods would be helpful in evaluating the relationship between quit attempts and outcome. Withdrawal and Dependence Withdrawal symptoms, whether elicited by acute deprivation or by conditioned stimuli, are hypothesized to be the link between dependence and relapse (Baker, Morse, Sherman 1987; Shiffman 1979; Wikler 1965). The tobacco withdrawal syndrome consists of a cluster of symptoms that are typically experienced after even brief or partial tobacco deprivation (Hughes and Hatsukami 1986, Ameri- can Psychiatric Association 1980,1987; Chapter IV). The symptoms include craving for cigarettes, irritability, anxiety, difficulty in concentrating, restlessness, and increased appetite (American Psy- chiatric Association 1987). Some physical signs are also commonly reported, but with the possible exception of bradycardia, these appear to be less consistent (Shiffman 1979; Hughes and Hatsukami 1986). Especially significant is the fact that the syndrome has a rapid onset and generally declines within 2 weeks (Shiffman 1979; Shiffman and Jarvik 1976; Cummings et al. 1985; Gottlieb 1985). Several studies have examined the role of withdrawal symptoms as predisposing factors for relapse. In a retrospective study, Burns 522 (1969) reported that recidivists cited withdrawal symptoms as the most common reason for relapse. Other retrospective studies at least partially support this finding (Garvey, Heinold, Rosner, in press; though see Evans and Lane 1981). Gottlieb (1985) found that both physical and psychological withdrawal symptoms predicted early relapse in a group of treated smokers; symptoms accounted for 14 percent of the variance in smoking after 2 weeks. Other investigators have also found that mood disturbance, a possible withdrawal symptom, predicts relapse (Hall et al. 1984; Hirvonen 1983; Manley and Boland 1983). Manley and Boland (1983) found that mood disturbance characterized relapsers even before they quit and after they resumed smoking. The literature also includes negative find- ings (Garvey, Heinold, Rosner, in press; Hughes and Hatsukami 1986; Swan and Denk, in press; Swan et al., in press). Although craving is difficult to define precisely (Kozlowski and Wilkinson 19871, a number of studies have reported relationships between craving and relapse (Campbell 1983; Garvey, Heinold, Rosner, in press; Gottlieb 1985; Hirvonen 1983). The effect appears to be more marked among female smokers, with several studies reporting that it is a significant predictor of relapse only among women (Guilford 1967; Gunn 1986; Swan et al., in press). Cognitive Factors Concern About Weight Gain Quitting smoking often results in weight gain (Grunberg 1986; Chapter IV). Multiple factors may contribute to postcessation weight gain, including decreased metabolism, increased food consumption, and increased preference for sweet-tasting, high-caloric foods (Grun- berg 1982). Highly dependent smokers and those who tend to eat in response to specific emotional and environmental cues appear to be at greatest risk of gaining weight following smoking cessation (Emont and Cummings 1987; Hall, Ginsberg, Jones 1986; Chapter VI). The data relating concern about weight gain to relapse are inconsistent. Klesges and Klesges (in press) found that women were more likely to report relapse for weight-related reasons. Other studies have found that concern about weight gain was not a major detirminant of relapse (Fuller 1982; Greaves, Barnes, Vulcan0 1983; Hirvonen 1983; Shapiro and Gunn 1985). Though there are excep tions (DiClemente 19811, studies typically report that recidivists experience less weight gain than successful abstainers (Manley and Boland 1983; Hall, Ginsberg, Jones 1986). In at least some of these studies, this cannot be confounded by the effects of continued abstinence, because the studies used prospective designs in which weight gain was assessed prior to relapse (Hall, Ginsberg, Jones 1986). Even so, the possibility remains that relapsers are more weight conscious in the first place and exert greater efforts to curtail initial weight gain (Hall, Ginsberg, Jones 1986; Herman and Polivy 1975). Smoker perceptions concerning weight gain may be critical. For some individuals, a gain of only 2 or 3 pounds may be viewed as a cause for great concern. Other individuals may be essentially indifferent to weight gains of 15 to 20 pounds. Self-Efficacy Bandura (1977a, 1982) proposed a common mechanism underlying behavioral change achieved by different procedures: successful psychological interventions all function by creating and strengthen- ing expectations of personal mastery or efficacy. An efficacy expectation is the conviction that one can execute the behaviors necessary to achieve a desired outcome. Such expectations are assumed to affect the initiation of coping behavior, the amount of effort that will be expended to maintain coping behavior, and the persistence of coping behavior in the face of external and internal obstacles. Self-efficacy is an important construct in Marlatt's theory of relapse. Marlatt's theory specifies that people's ability to resist the use of a substance (e.g., cigarettes) in a high-risk situation depends on, among other factors, their self-efficacy level (Marlatt and Gordon 1980). If people have expectations that they can cope with a smoking urge without smoking, they are less likely to relapse. Moreover, people who successfully resist temptation should experience an increase in self-efficacy. The theory also states that selfefficacy is a determinant of whether people who experience an initial lapse are able to prevent escalation to full relapse. Various scales assumed to measure selfefficacy have predicted smoking status at followup (Coelho 1984; DiClemente 1981; Killen et al. 1984; McIntyre, Lichtenstein, Mermelstein 1983; Ockene et al. 1982; Yates and Thain 1985) and latency from treatment end to relapse (Brandon, Tiffany, Baker 1986, Brandon, Zelman, Baker, in press; Erickson et al. 1983; Tiffany, Martin, Baker 1986). Efficacy ratings have also predicted smoking intake after a controlled-smok- ing intervention (Godding and Glasgow 1985) and have differentiated joiners from nonjoiners of a smoking treatment program (Brad and Hall 1984). Important qualifications, however, relate to the timing of the relapse assessment and the subject sample observed. Studies predict+ ing relapse that are based on all treatment subjects (including those who never achieve abstinence) will achieve higher correlations with outcome than will studies assessing only abstinent subjects. Self- efficacy is a less useful predictor when measured shortly after 524 cessation rather than after 1 or 2 months of abstinence (Baer, Holt, Lichtenstein 1986). Condiotte and Lichtenstein (1981) reported seven distinguishable clusters of smoking situations and found a congruence between the situation clusters for which subjects indicated low self-efficacy and the clusters that comprised their actual relapse situations. However, a conceptual replication of the use of efficacy subscales has not demonstrated utility (Baer, Holt, Lichtenstein 1986). Thus, at this point situation-specific selfefficacy assessments have not proved to be of value. Self-effrcacy may reflect the influence of diverse treatments or smoking history variables related to cessation success. Skills train- ing, for example, might be effective to the extent that it enhances smokers' beliefs that they can cope with temptation. Aversion therapy might be effective to the extent that smokers attribute their self-punishment to their high motivation to quit and their ability to use available resources to help stay abstinent. Self-efficacy may in fact be confounded with Bandura's (1977a) concept of outcome expectancy. Rather than measuring subjects' convictions that they could execute specific coping behaviors, most of the studies simply assess& subjects' confidence that they would resist the urge to smoke in the future. The global construct of self-efficacy is somewhat ambiguous. Self- efficacy may include not only response effectiveness, but also motivation to quit and judgment of skills necessary to undertake the quitting program. Selfefficacy as a global predictor can be useful. However, it may be more important to assess what skills individuals learn from different treatment components. A better understanding of the process of acquiring competency in quitting is needed. Knowledge of the specific treatment components that enhance self- efficacy could be significant in developing and refining effective interventions. Outcome Attributions Attribution theory suggests that individuals who attribute their behavioral change to internal factors are more likely to successfully maintain their change (Davison and Valins 1969). This hypothesis was supported in a study by Harackiewicz et al. (1987) which found that, for individuals participating in intrinsically oriented treatment programs (a self-help manual emphasizing individual cessation efforts either with or without nicotine polacrilex gum), internal attributions for initial success were significantly related to longer maintenance of nonsmoking. Contrary to the hypothesis, however, these investigators found that external attributions were positively related to long-term maintenance for individuals participating in extrinsically oriented treatment (nicotine polacrilex gum with a self- help manual emphasizing a doctor's prescribed program). These findings suggest that the degree of consistency between attributions for initial success and the orientation of the cessation approach can affect the probability of relapse. Social Factors Smoking Cues Most exposure to smoking-specific cues is socially mediated-e.g., watching others smoke. Such exposures have been labeled "social contagion" (Shiffman and Jarvik 1987). Few studies have 888e88ed social contagion directly. Many studies have, however, examined the effect of having a spouse, friends, or coworkers who smoke. The literature on the effect of spouse smoking status is surprising- ly contradictory. Several studies report moderate-to-large increases in the probability of relapse among subjects with a smoking spouse (Campbell 1983; Graham and Gibson 1971; McIntyre-Kingsolver, Lichtenstein, Mermelstein 1986; Tongas, Patterson, Goodkind 1976). Some studies, though, report no effect of spousal smoking (Horwitz, Hind&Alexander, Wagner 1985; Garvey, Heinold, Rosner, in press; Swan et al., in press). One possible explanation for the inconsistent findings is that the influence of spousal smoking is so strong that it often prevents initial cessation. This would cause the effect to be only sporadically observed in maintenance. The effects of spouse smoking status may also be complicated by interactions with social support. The risk incurred by having a smoking spouse may be reduced or eliminated if the spouse is supportive (Mermelstein, Lichtenstein, McIntyre 1983). This may be especially true if the spouse refrains from smoking in the presence of the subject, thereby resulting in fewer exposures to smoking cues. The data on friend smoking are clearer. Several studies find that subjects who have more smokers among their friends are more likely to relapse (Eisinger 1971; Garvey, Heinold, Rosner, in press; Ockene et al. 1982; Gottlieb et al. 1981; Goldstein 1981). One study failed to replicate this effect (Swan et al., in press). Brandon, Tiffany, and Baker (1986) found that smokers having a lapse cigarette in the presence of other smokers progressed to regular smoking more quickly than did other lapsers. The most parsimonious explanations of these social contagion effects are that people with many smoking friends tend to experience more exposure to smoking cues and that cigarettes are likely to be more readily available to them. Social Support Social support can serve as a buffer to reduce the negative psychological effects of stressors (Cobb 1976; Cohen, Sherrod, Clark 526 1986; Cohen and Wills 1985; Dean and Lin 1977). Correlational studies have found that the level of perceived social support is related to smoking cessation and maintenance. Coppotelli and Orleans (1985), for example, examined the determinants of mainte- nance among women who recently quit smoking. They found that a measure of "partner facilitation" (problem solving, rewarding quit- ting, understanding, listening, and facilitating coping responses) accounted for 32 percent of the outcome variance at 6 to 8 week postcessation. General social support from spouses, as well as smoking-specific spousal support, has been related to smoking treatment outcome (Horwitz, Hindi-Alexander, Wagner 1985; Mer- melstein et al. 1986; Mermelstein, Lichtenstein, McIntyre 1983; although see Glasgow et al. 1985). Global Support Global support has usually been assessed as perceived support. Using the Interpersonal Support Evaluation List (ISEL; Cohen and Hoberman 1983) to measure support, Mermelstein and coworkers (1986) found that greater perceived support (having someone to talk to about personal matters) predicted maintenance at a 3-month followup. However, the ISEL was unrelated to smoking status at 6 or 12 months, and the 3-month findings were not replicated in a second study by the same investigators (Mermelstein et al. 1986). As noted above, Coppotelli and Orleans (1985) found that women who reported receiving greater support from their husbands were more likely to maintain abstinence. There was no comparison group of male subjects. Smoking-Specific Support Several studies have examined the role of social support directed at smoking cessation. The most thorough investigations of specific support have been conducted by researchers at the University of Oregon, who developed the Partner Interaction Questionnaire (PIQ; Mermelstein, Lichtenstein, McIntyre 1983) to assess perceived helper behaviors. These investigators found that perceived help fulness of partner behaviors was related to cessation and mainte- nance. The actual number of partner behaviors was not related to outcome; however, a measure of the character of the interactions was related. A cluster of partner behaviors labeled "Support and Encouragement" (e.g., expressing understanding or pride) was related to maintenance of abstinence. In contrast, a cluster of behaviors involving "Nagging and Policing" (Mermelstein, Lichten- stein, McIntyre 1983) predicted relapse. Subsequent studies using the PIQ have only partially replicated these findings (Lichtenstein, 527 Glasgow, Abrams, in press; Malott et al. 1984; McIntyre-Kingsolver, Lichtenstein, Mermelstein 19861. Other studies using other measures have also yielded mixed results. In a large prospective study, Prochaska, DiClemente, and colleagues (Prochaska and DiClemente 1983; DiClemente and Pro- chaska 1985; Prochaska et al. 19851 reported that social support predicted continuing abstinence. However, several other research groups have failed to find evidence that smoking-specific support aids maintenance (Evans and Lane 1981; Ockene et al. 1982; Garvey, Heinold, Rosner, in press). stress Some studies have used the life events approach to the assessment of stress (Holmes and Rahe 1967). This technique asks subjects about major life events that have occurred since the subjects stopped smoking. Most studies have found little or no relationship between life stress events and relapse (Shapiro and Gunn 1985; Shiffman, Read, Jarvik 1985). This may be because life stress events are relatively uncommon. Recent research on stress has begun to focus on more frequent and smaller-scale stressors, which Lazarus and colleagues (1981) and DeLongis and coworkers (1982) have called "Hassles." The Hassles Scale assesses the frequency and perceived severity of everyday stressors, such as having difficulties with coworkers or not having enough time for recreation. Swan and colleagues (Swan and Denk, in press; Swan et al., in press) found that hassles during the second month of abstinence only weakly predicted outcomes at 1 year. The effect of hassles was more reliable for men than for women. A somewhat different approach to examining background stress was taken by Cohen and his colleagues, who developed and used the Perceived Stress Scale (PSS). The PSS measures perceived stress and demoralization without reference to particular events or sources of stress. Cohen and colleagues found that PSS scores did predict relapse and that they were strongly associated with daily cigarette consumption among recidivists. Stress and coping theories of smoking imply that deficiencies in personal resources for coping with stress may enhance the risk of relapse (Wills and Shiffman 1985). Using the Ways of Coping checklist, Ashenberg (1983) assessed how subjects who had quit smoking coped with stress in situations that are often associated with relapse. There were no differences between relapsers and abstainers in the kinds of coping reported, but abstainers reported using fewer coping strategies. The meaning of this finding is unclear. Abstainers could have experienced less severe stress or less severe threats to abstinence, and therefore needed fewer coping responses. Conversely, abstainer coping responses could have been more 528 effective, therefore mitigating the need for more coping. Also, when Ashenberg examined recidivists, stressful situations associated with coping were found to be less likely to lead to relapse than those not associated with coping. Precipitating Factors High-Risk Situations A number of studies support the theory that initial smoking following cessation tends to occur in specific t.ypes of high-risk situations. Work by Marlatt and his associates (Marlatt and Gordon 1980, 1985) has identified craving/withdrawal, intrapersonal nega- tive emotional states (e.g., frustration, boredom, and anxiety), interpersonal conflict situations, and social pressure, both direct and indirect, as common types of high-risk situations. Shiffman (1986c) and Baer and Lichtenstein (in press) clustered data on the precipi- tants of relapse crises and lapses. Data from studies of relapee episodes confirm that smoking cues are often involved in smoking relapse. Several studies report the smoking of others in the immediate environment in one-half to three-quarters of all relapse episodes (Brandon, Tiffany, Baker 1986; Colletti, Supnick, Rizzo 1981; Baer and Lichtenstein, in press; Shiffman 1982, 1986c; Cummings, Jaen, Giovino 1985). Many of these same studies report that specific smoking stimuli (usually seeing someone smoking) are responsible for precipitating 24 to 32 percent of all relapses (Shiffman 1982,1986c; GssipKlein et al. 1986; Shapiro, OssipKlein, Stiggins 1983). Studies also report that relapse crises in which someone else is smoking are more likely to result in a smoking episode and in a shorter interval between the initial slip and relapse (Brandon, Tiffany, Baker 1986; C&p-Klein et al. 1986; Shiffman 1982). Abrams and his colleagues (Abrams et al., in press; Chapter III) have recently published data suggesting that individual differences in reactivity to smoking cues may influence cessation and relapse. In retrospective and prospective studies, these researchers found that recidivists responded more strongly than successful quitters to verbally presented smoking situations or to observations of another smoking. Recidivists displayed more anxiety and showed greater heart rats responses. It may be that responses elicited by smoking stimuli (Saumet and Dittmar 1985) reflect conditioned responses to nicotine effects. Other smokers serve not only as cues for smoking but as sources of cigarettes. In half of all relapse episodes, another smoker provides the cigarettes that are smoked (Colletti, Supnick, Rizzo 1981; Baer and Lichtenstein, in press; Cummings, Jaen, Giovino 1985). This does not imply that the smokers exert social pressure to smoke; in most 529 cases, the ex-smoker specifically asks for a cigarette (Brandon, Tiffany, Baker 1986). Data on relapse episodes suggest that relapse also can be cued by other stimuli or activities that have become associated with smoking through contiguity, for instance, food, drink, or relaxation (Baer and Lichtenstein, in press; Brandon, Tiffany, Baker 1986; OssipKlein et al. 1986; Shiffman 1986b). Studies of specific relapse episodes consistently suggest that stress and negative affect play major roles in relapse. Findings from many studies encompassing diverse samples reveal that the majority of relapse episodes are preceded by negative affect (Brandon, Tiffany, Baker 1986; Shiffman 1982, 198613; Marlatt and Gordon 1980; Cummings, Marlatt, Gordon 1980; O'Connell and Martin 1987; Gregory 1984; Baer and Lichtenstein, in press; O&p-Klein et al. 1986; Shapiro, OssipKlein, Stiggins 1983; Giovino et al. 1986; Shapiro 1984). In some studies, as many as 9 out of 10 subjects report negative affect (Coppotelli and Orleans 1985). The most frequently reported emotion is anxiety, but boredom, depression, and anger are also common. Data suggest that the more severe the stress surrounding a temptation to smoke, the higher the likelihood of smoking. Shiffman, Bead, and Jarvik (1985) report a significant linear relationship between stress and smoking in relapse crises. There are contradicb ry data as to whether lapses associated with negative affect are particularly likely to progress to full relapse (Brandon, Tiffany, Baker 1986; O'Connell and Martin 1987). In sum, momentary stress and distress are major factors in relapse episodes. It should be noted, however, that these studies involve retrospective accounts of relapse episodes. The role of negative affect in relapse may change over time. Cummings, Jaen, and Giovino (1985) report that early relapse episodes are more likely to be precipitated by stress; later in abstinence, alcohol and other appetitive cues become more promi- nent. Coping Strategies Coping strategies can be used both to prevent (anticipatory coping) and to directly respond to (immediate coping) high-risk situations. In either case, the strategies used can be behavioral, consisting of responses that are outwardly visible (e.g., leaving a party where others are smoking, engaging in physical activities), or cognitive, consisting of internal responses such as thoughts or images. One of the most commonly used and studied anticipatory coping strategies is stimulus control-the avoidance of stimuli associated with smoking. Research on this strategy shows mixed outcomes, yielding no definitive conclusions (Evans and Lane 1981; Horwitx, 530 Hind&Alexander, Wagner 1985; Prochaska and DiClemente 1983; DiClemente and Prochaska 1985). Data on the relative efficacy of cognitive and behavioral strategies weakly support the superiority of cognitive strategies. Evans and Lane (1981) report weak indications that successful maintainers were more likely to use cognitive techniques rather than behavioral ones. Immediate coping has been assessed in studies that examined situations in which an ex-smoker was tempted to smoke. Studies of immediate coping with the temptation to smoke typically compare episodes in which smoking was averted with episodes in which relapse occurred. Shiffman (1982, 1984b, 1985) found that failure to perform any coping response was the single best predictor of smoking in a tempting situation, accounting for nearly a quarter of the variance in the outcomes of high-risk situations. This finding has been directly and indirectly supported in several other studies (Curry, Marlatt, Gordon 1987; OssipKlein et al. 1986; Shapiro, Ossip Klein, Stiggins 1983; Sjoberg and Johnson 1978; Sjoberg and Samsonowitz 1978). These studies consistently show immediate coping to be effective in preventing smoking in a relapse-promoting situation. One problem with all of these studies, however, is retrospective bias. Subjects may introduce a self-justifying slant into their responses. Unfortunately, it may be virtually impossible to obtain prospective data on immediate coping. Although there is no evidence that greater numbers of coping responses are more effective, there is evidence that it is better to use both cognitive and behavioral coping strategies when faced with a risk situation (Curry, Marlatt, Gordon 1987; Shiffman 1982, 1984b). Cognitive and behavioral coping are rather broad categories of responses. The relative efficacy of specific responses within those categories has also been examined in an attempt to identify effective and ineffective coping responses. Shiffman (1984b) examined the effectiveness of seven behavioral and eight cognitive coping strate- gies. Only one type of coping was not more effective than no coping: subjects who reported using self-punitive cognitions (berating oneself for being tempted to smoke) to cope were as likely to relapse as subjects who made no cognitive coping response. (See Glasgow et al. 1985, for parallel findings on cessation.) Self-punitive cognitions may diminish self-efficacy and engender negative affect, which in turn promotes smoking. Another finding from these comparative analyses was that subjects who reported "willpower" as a means of cognitive coping were significantly more likely to relapse (nearly half re- lapsed) than subjects who used other cognitive coping responses. Nevertheless, subjects who reported willpower fared better than subjects who made no cognitive coping response at all. These two distinctions notwithstanding, the effectiveness of vari- ous coping responses was surprisingly uniform: 13 of the 15 531 responses were better than no response, but there were no signifi- cant differences among these 13 responses. Curry, Marlatt, and Gordon (1987) conducted a very similar set of analyses and arrived at a similar conclusion. Several studies have examined whether individual differences in coping skill are associated with maintenance. The studies used similar analog methods to assess coping skill: subjects were present- ed with situations known to elicit desire to smoke, and their responses to these situations were rated. These studies used both retrospective and prospective analyses and had subjects respond either to written or role-played coping scenarios (Abrams et al. 1987, in press; Davis 1983; Davis and Glaros 1986; Shiffman, Maltese, Jarvik 1982). Results of retrospective analyses showed that 6month abstainers did not differ in coping skill from recidivists (Abrams et al. 1987; Shiffman et al. 1985). Prospective studies also yielded little evidence that coping skill protects against relapse. Such studies have found no relationship between skill level and relapse likelihood, although there was evidence that high-skill subjects took longer to relapse (Abrams et al. 1987, in press; Davis 1983; Davis and Glaros 1986). Also, Davis and Glaros (1986) showed that a skill-based treatment increased the level of smoker coping skills asses& immediately posttreatment but did not enhance smoker followup performance. Abstinence Violation Effect Marlatt and Gordon (1980, 1985) define the Abstinence Violation Effect (AVE) as an attributional construct that mediates the transition from an initial lapse to a full-blown relapse. Curry, Marlatt, and Gordon (1987) found that individuals who smoked but did not return to regular smoking ("slippers") reported significantly greater AVEs than those who relapsed following an initial slip. Brandon, Tiffany, and Baker (1986) reported that only one-third of their subjects (N= 72) used any coping response after a lapse and that the occurrence of coping was unrelated to relapse probability or speed of relapse. Summary and Conclusions 1. Tobacco dependence can be treated successfully. 2. Effective interventions include behavioral approaches and behavioral approaches with adjunctive `pharmacologic treat- ment. 3. Behavioral interventions are most effective when they include multiple components (procedures such as aversive smoking, skills training, group support, and self-reward). Inclusion of too 532 many treatment procedures can lead to a less successful outcome. 4. Nicotine replacement can reduce tobacco withdrawal symp tams and may enhance the efficacy of behavioral treatment. 533 References ABRAM& D.B. Roles of psychosocial stress, smoking cues and coping in smoking- relapse prevention. Health Psychology MSupplement):91-92, 1986. ABRAM& D., MONT& P., CAREY, K., PINTO, P., JACOBUS, S. Reactivity to smoking cues and relapse: Two studies of discriminant validity. Behauiour Research and Therapy, in press. ABRAMS, D.B., MONTI, P.M., PINTO, R.P., ELDER, J.P., BROWN, R.A., JACOBUS, S.I. Psychosocial stress and coping in smokers who relapse or quit. Health Psychology 6(4):269-363, 1987. ABUEG, F.R., COLLEITI, G., RIZZO, A.A. The saliva thiocyanate analysis: A methodological extension and its relationship to CO and self-report in moderate smokers. Addictive Behaviors 11:55-58, 1966. AITKEN, P.P. Peer group pressures, parental controls and cigarette smoking among 10 to 14 year olds. British Journal ofSocial and Clinical Psychology 19(2):141-146, 1980. AMERICAN HOSPITAL FORMULARY SERVICE. Miscellaneous autonomic drugs: Nicotine polacrilex. In: Drug Information. Bethesda, Maryland American Society of Hospital Pharmacists, 1987, pp. 716-715. AMERICAN PSYCHIATRIC ASSOCIATION. Diagnostic and StatisticaI Manual of MentaZ Disorders. Washington, DC.: American Psychiatric Association, 1980. AMERICAN PSYCHIATRIC ASSOCIATION. Diagnostic and Statistical Manual of MentaZ Disorders, Third Edition, Revised. Washington, D.C.: American Psychiatric Association, 1987. ASHENBERG, Z.S. Smoking recidivism: The role of stress and coping. Doctoral Dissertation. Washington University, St. Louis, Missouri. Ann Arbor, University Microfilms International, Thesis No. 84-62189, 1983. ASHLEY, M.J. Smoking and women. In: Forbes, W.F., Frecker, R.C., Nostbakken, D. (eds.) Proceedings of the Fifth World Co n erence on Smoking and Health, Volume 1. f Winnipeg, Canada: Canadian Council on Smoking and Health, 1983, pp. 7-24. BAER, D.S., McCLEARN, G.E., WILSON, J.R. Effecta of chronic administration of tobacco smoke to mice: Behavioral and metabolic measures. Psychopharmacology 67(2):131-137, 1980. BAER, J.S., HOLT, C.S., LICHTENSTEIN, E. Self-efficacy and smoking reexamined: Construct validity and clinical utility. Journal of Consulting and Clinical Psychology 54(6WG-652, December 1986. BAER, J.S., LICHTENSTEIN, E. Classification and prediction of smoking relapse episodes: An exploration of individual differences. Journal of Consulting and Clinical Psychology, in press. BAER, J.S., LICHTENSTEIN, E. Cognitive assessment in smoking cessation. In: Marlatt, G.A., Donovan, D.M. (ads.) Assessment of Addictive Behaviors. New York: Guilford Press, in press. BAKER, L.J., DEARBORN, M., HASTINGS, J.E., HAMBERGER, K. Type A behavior in women: A review. Health Psychology $533477-497, 1964. BAKER, T.B., CANNON, D.S., TIFFANY, S.T., GINO, A. Cardiac response as an index of the effect of aversion theory. Behaviour Research and Thempy 22:403411,1984. BAKER, T.B.. MORSE, E., SHERMAN, J.E. The motivation to take drugs: A psychobiological analysis of urges. In: Rivers, C. (ed.1 Nebraska Symposium on Motivation. Lincoln, Nebraska: University of Nebraska Press, 1987, pp. 257-323. BALFOUR, D.J.K. The effects of nicotine on brain neurotransmitter systems. In: Balfour, D.J.K. (ed.1 Nicotine and the Tobacco Smoking Habit. Oxford: Pergamon Press, 1984, pp. 61-74. BANDURA, A. Selfefficacy: Toward a unifying theory of behavioral change. Psychological Review 84:191-215, 1977a. BANDURA, A. Social Learning Theory. Englewood Cliffs, New Jersey: Prentice-Hall, 1977b. 534 BANDURA, A. Self-efficacy mechanism in human agency. American Psychologist 37(2):122-147, February 1982. BANKS, M.H., BEWLEY, B.R., BLAND, J.M. Adolescent attitudes to smoking: Their influence on behavior. International Journal of Health Education 2q039-44, 1981. BARON, J.A. Smoking and estrogen-related disease. American Journal of Epidemiolo- gy 119(1):9-22, 1984. BARTON, J., CHASSIN, L., PRESSON, CC., SHERMAN, S.J. Social image factors as motivators of smoking initiation in early and middle adolescence. Child L&uelop- ment X+(6):1499-1511, December 1982. BARYLKO-PIKIELNA, N., PANGBORN, R.M. Effect of cigarette smoking on urinary and salivary thiocyanates. Archives of Environmental Health 17:739-745, Novem- ber 1968. BAUGH, J.G., HUNTER, S.M., WEBBER, L.S., BERENSON, G.S. Developmental trends of first smoking experience of children: The Bogalusa Heart Study. American Journal of Plrblic Health 71:5969, 1982. BAUMRIND, D. Familial antecedents of adolescent drug use: A developmental perspective. In: Jones, C.L., Battjes, R.J. (eds.) Etiology of Drug Abuse: Implications for Prevention, NIDA Research Monograph 56. US. Department of Health and Human Services, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse, 1985, pp. 13-44. BEAVER, C., BROWN, R.A., LICHTENSTEIN, E. Effects of monitored nicotine fading and anxiety management training on smoking reduction. Addictive Behaviors 6(4):301-365, 1981. BENOWITZ. N.L., JACOB, P. III, KOZLGWSKI, L.T., YU, L. Influence of smoking fewer cigarettes on exposure to tar, nicotine, and carbon monoxide. New England Journal of Medicine 31X21):1310-1313, November 20, 1986. BENOWITZ, N.L., HALL, SM., HERNING, R.I., JACOB, P. III, JONES, R.T., OSMAN, A.-L. Smokers of low-yield cigarettes do not consume less nicotine. New England Journal of Medicine 309(3):129-142, July 21, 1983. BENOWITZ, N.L., JACOB, P. III, SAVANAPRIDI, C. Determinants of nicotine intake while chewing nicotine polacrilex gum. Clinical Pharmacology and Therapeutics 41:467-473, 1987. BEN-SIRA, Z. Health promoting function of mass media and reference groups: Motivating or reinforcing of behavior change. Social Science and Medicine 16(7):825834, 1982. BERGLER, R. Advertising and Cigarette Smoking. A Psychological Study. Vienna: Hans Huber Publishers, 1981. BERKOWITZ, B., ROSSTOWNSEND, A., KOHBERGER, R. Hypnotic treatment of smoking: The single-treatment method revisited. American Journal of Psychiatry 136(1):83-65, January 1979. BEST, J.A., FLAY, B.R., TOWSON, S.M.J., RYAN, K.B., PERRY, C.L., BROWN, K.S., KERSELL, M.W., D'AVERNAS, J.R. Smoking prevention and the concept of risk. Journal of Applied Social Psychology 14(3):257-273, 1984. BEST, J.A., OWEN, L.E., TRENTADUE, L. Comparison of satiation and rapid smoking in self-managed smoking cessation. Addictive Behaviors 3(2):71-78, 1978. BEWLEY, B.R., BLAND, J.M., HARRIS, R. Factors associated with the starting of cigarette smoking by primary school children. British Journal of Prevention and Social Medicine 28f037-44, February 1974. BIGELOW, G., OSSIP-KLEIN, D.J. (eds.) Classification and assessment of smoking behavior. Health Psychology 5 (Supplement):3-11, 1986. BIGELOW, G.E., STITZER, M.L., LIEBSON, J.A. Substance abuse. In: Hersen, M. ted.) . Pharmacological and Behavioral Treatment: An Integrative Approach. New York: John Wiley and Sons, 1986, pp. 289-311. 535 BIGLAN, A., LICHTENSTEIN, E. A behavior-analytic approach to smoking acquisi- tion: Some recent findings. Journal of Applied Social Psychology 14(3):207-223, 1984. BLECHMAN, E.A. (sd.) Behavior Modifkation with Women. New York: Guilford, 1984. BLISS, R.E., O'CONNELL, K.A. Problems with thiocyanate as an index of smoking status: A critical review with suggestions for improving the usefulness of biochemical measures in smoking cessation research. Health psrChology 3(6):563581, 1984. BOTVIN, G.J., ENG, A., WILLIAMS, CL. Preventing the onset of cigarette smoking through life skills training. I+euentiue Medicine 9(11:135-143, January 1980. BOTVIN, G.J., WILLS, T. Personal and social skills training: Cognitive-behavioral approaches to substance abuse prevention. In: Bell, C.S., Battjes, R. (eda.) Prevention Research: Deterring Drug Abuse Among Children and Adoleecente, NIDA Research Monograph 63. U.S. Department of Health and Human Services, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse, 1985. BOWERS, T.G., WINEIT, R.A., FREDERIKSEN, L.W. Nicotine fading, behavioral contracting, and extended treatment: Effects on smoking cessation. Addictive Behauionr 12181-184, 1987. BRANDON, T.H., TIFFANY, S.T., BAKER, T.B. The process of smoking relapse. In: Tims, FM., Leukefeld, C.G. teds.1 ReZapse and Recovery in Drug Abuse, NIDA Research Monograph 72. U.S. Department of Health and Human Services, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, Nation- al Institute on Drug Abuse. DHHS Publication No. (ADM) 861473, 1986. BRANDON, T.H., ZELMAN, D.C., BAKER, T.B. Effects of maintenance sessions on smoking relapse: Delaying the inevitable? Journal of Consulting and Clinical W~hology, in press. BRANTMARK, B., OHLIN, P., WESTLING, H. Nicotine containing chewing gum as an anti-smoking aid. Psychopharmacolqia 31(3):191-200, 1973. BRINTON, L.A., SCHAIRER, C., HAENSZEL, W., STGLLEY, P., LEHMAN, H.F., LEVINE, R., SAVITZ, D.A. Cigarette smoking and invasive cervical cancer. Journal of the American Medical Association 255(23):3265-3269, June 26, 1986. BRITISH THORACIC SOCIETY. Comparison of four methods of smoking withdrawal in patients with smoking related diseases. British Medical Journal 286@366):595-597, February 19, 1983. BROD, M., HALL, SM. Joiners and non-joiners in smoking treatment: A comparison of psychosocial variables. Addictive Behauion, X2):217-221, 1984. BRODY, C.M. Women's Thempy Groups: Pamdigms of Feminist Treatment. New York: Springer, 1987. BROWN, R.A., LICHTENSTEIN, E., MCINTYRE, K.O., HARRINGTON-KOSTUR, J. Effects of nicotine fading and relapse prevention on smoking cessation. Journal of Consulting and Clinical Psychology 52(2):307308, 1984. BROWNELL, K.D., MARLAll', G.A., LICHTENSTEIN, E., WILSON, G.T. Under- standing and preventing relapse. American &choZogist 41(7):765-782, July 1986. BRUNO, J.E., DOSCHER, L. Patterns of drug use among Mexican-American potential school dropouts. In: Eiseman, S., Wingard, J.A., Huba, G.J. (eds.) Drug Abuse: Foundations for a Psychosocial Approach. Farmingdale, New York: Baywood Publishing Company, 1984, pp. 152-161. BRUNSWICK, A.G., MESSERI, P.A. Gender differences in the processes leading to cigarette smoking. Journal of Psychosocial Oncology 249-69, 1984. BURDEN, D.S., GO'M'LIEB, N. Women's socialization and feminist groups. In: Brody, C.M. @I.) Women's Therapy Groups: Paradigms of Feminist Treatment. New York: Springer, 1987, pp. 24-39. 536 BURLING, T.A., STITZER, M.L., BIGELOW, G.E., MEAD, A.M. Smoking topography and carbon monoxide levels in smokers. Addictive Behaviors 10~319-323, 1985. BURNS, B.H. Chronic chest disease, personality, and success in stopping cigarette smoking. British Journal of Preventive and Social Medicine 2323-37, 1969. CAMPBELL, LA. Predictive factors for smoking withdrawal in patients. In: Forbes, W.F., Frecker, R.C., Nostbakken, D. teds.) Proceedings of the Fifth World Conference on Smoking and Health. Winnipeg, Canada: Canadian Council on Smoking and Health, 1983, pp. 165-169. CAMPBELL, I.A., LYONS, E., PRESCO'IT, R.J. Stopping smoking: Do nicotine chewing gum and postal encouragement add to doctors' advice? Practitioner 231:114-117, 1987. CANNON, D.S., BAKER, T.B., GINO, A., NATHAN, P.E. Alcohol-aversion therapy: Relation between strength of aversion and abstinence. Journal of Consulting and Clinical Psychology 54(6):825-830, December 1986. CARL, L.S. Self-Planned Cessation: A Retrospective Study of the Strategies and Resources Used by Individuals in Quitting and Remaining Quit. Doctoral Dissertation. University of Illinois, Urbana, Illinois. Ann Arbor, University Microfilms International, Thesis No. 81-08458, 1980. CARTWRIGHT, A., MARTIN, F.M., THOMSON, J.G. Distribution and development of smoking habits. Lancet 2(7105):725-727, October 31, 1959. CASTRO, F.G., MADDAHIAN, E., NEWCOMB, M.D., BENTLER, P. A multivariate model of the determinants of cigarette smoking among adolescents. Journal of Health and Social Behavior, in press. CHARLTON, A. Smoking and weight control in teenagers. Public Health (London) 98:277-281, 1984. CHASSIN, L., PRESSON, C., SHERMAN, S.J. Cognitive and social influence factors in adolescent smoking cessation. Addictive Behaviors 9L483-390, 1984. CHASSIN, L., PRESSON, C.C., SHERMAN, S.J. Stepping backward in order to step forward: An acquisition-oriented approach to primary prevention. Journal of Consulting and Clinical Psychology 53(5):612-622, 1985. CHEREK, D.R. Effects of smoking different doses of nicotine on human aggressive behavior. Psychopharmacology 75(4):33%345. December 1981. CHRISTEN, A.G., GLOVER, E.D. Psychological satisfactions derived from smoking cigarettes in fifty-seven dental patients. Journal of Drug Education 13W95102, 1983. CLAIBORN, W.L., LEWIS, P., HUMBLE, S. Stimulus satiation and smoking: A revisit. Journal of Clinical Psychology 28(7):4X-419, 1972. CLAVEL, F., BENHAMOU, S., COMPANY-HUERTAS, A., FLAMANT, R. Helping people to stop smoking; randomized comparison of groups being treated with acupuncture and nicotine gum with control group. British Medical Journal 291(6508):1538-1539, November 30, 1985. COBB, S. Social support as a moderator of life stress. Psychosomatic Medicine 38(5):300-314, September-October 1976. COELHO, R.J. Self-efficacy and cessation of smoking. Psychological Reports 54(1):309-310, February 1984. COHEN, S., HOBERMAN, H.M. Positive events and social supports 88 buffers of life change stress. Journal of Applied Social Psychology 13(2):99-125, March-April 1983. COHEN, S., LICHTENSTEIN, E., MERMELSTEIN, R., KINGSOLVER, K.. BAER, J. S., KAMARCK, T. W. Social support interventions for smoking cessation. In: Gottlieb, B.H. (eds.) Creating Support Groups: Formats, Processes and Effect-s. New York: Sage, in press. COHEN, S., SHERROD, D.R., CLARK, M.S. Social skills and the stress-protective role of social support. Journal of Personality and Social Peychologr 50963-973, 1986. 537 COHEN, S., WILLS, T.A. Stress, social support, and the buffering hypothesis. Psychological Bulletin 9&2):31&357, 1985. COLLE'ITI, G., KOPEL, S.A. Maintaining behavior change: An investigation of three maintenance strategies and the relationship of self-attribution to the long-term reduction of cigarette smoking. Journal of Consulting and Clinical Psychology 47t3k614-617, 1979. COLLETM, G., SUPNICK, J.A., PAYNE, T.J. The Smoking Self-Efficacy Question- naire @SE&): Preliminary scale development and validation. Behavioral Assesa- ment 7249-260, 1985. COLLETTI, G., SUPNICK, J.A., RIZZQ, A.A. An Analysis of Relapse Dstenninnnta for D-co&d Smoken. Paper presented at the Annual Convention of the American Psychological Association, Los Angeles, California, August 1981. COLLEITI, G., SUPNICK, J.A., RIZZO, A.A. Long-term follow-up (3-4 years) of treatment for smoking reduction. Addictive Behaviors 7(4):429-03, 1982. CONDIOlTE, M.M., LICHTENSTEIN, E. Self-efficacy and relapse in smoking cessation programs. Journal of Consulting and Clinical Peychology 49(5):-, October 1981. CONNE'IT, J.E., STAMLER, J. Responses of black and white males to the special intervention program of the Multiple Risk Factor Intervention Trial. American Heart Journal 108839848, September 1984. COOMBS, R.H., FAWZY, I.F., GERBER, B.E. Patterns of cigarette, alcohol and other drug use among children and adolescents: A longitudinal study. The Znternationul Journal of the Addictions 21(8):897-913, 1986. COONEY, N.L., KOPEL, S.A. Controlled Relapse: A Social Learning Approach to Reventing Smoking Recidivism. Paper presented at the Annual Meeting of the American Psychological Association, Montreal, Canada, September 1986. COOPER, R., DAVID, R. The biological concept of race and ita application to public health and epidemiology. Journnl of Health Politics, Policy and Law 11(1):97-116, 1986. COOPER, R., SIMMONS, B.E. Cigarette smoking and ill health among Black Americans. New York State Journal of Medicine %X7):344-349, July 1985. COPPOTELLI, H.C., ORLEANS, C.T. Partner support and other determinants of smoking cessation maintenance among women. Journal of Consulting and Clinical Psychology 5X4):455-460, August 1985. CORTY, E., McFALL, R.M. Response prevention in the treatment of cigarette smoking. Addictive Behaviors 9405-408, 1984. COYNE, J.C., DELONGIS, A. Going beyond social support: The role of social relationships in adaptation. Journal of Consulting and Clinical &choiogy 54(4):454-460, August 1986. CUMMINGS, KM., GIOVINO, G., JAEN, C.R., EMRICH, L.J. Reports of smoking withdrawal symptoms over a 21 day period of abstinence. Addictive Behaviors 10:373-381, March 1985. CUMMINGS, K.M., GIOVINO, G., MENDICINO, A.J. Cigarette advertising and racial differences in cigarette brand preferences. Public Health Reports 102(6):698701, November-December 1987. CUMMINGS, K.M., JAEN, CR.. GIOVINO, G. Circumstances surrounding relapse in a group of recent exsmokers. Preventive Medicine 14(2):195202, 1985. CUMMINGS, J.R., GORDON, J., MARLATI', G.A. Relapse: Prevention and predic- tion. In: Miller, W.R. ted.) The Addictive Behaviors. Treatment of Alcoholism, l)rug Abuse, Smoking, and Obesity. Oxford: Pergamon, 1986, pp. 291321. CURRY, S. Cigarette Smoking Among Women: Prevention and Intervention. Paper presented at the 29th Annual Convention of the Association for the Advancement of Behavior Therapy, Chicago, November 1986. 538 CURRY, S., MARLA'IT, G.A.. GORDON, J.R. Abstinence violation effect: Validation of an attributional construct with smoking cessation. Journal of Consulting and Clinical Psychology 5X2):145-149, 1987. DANAHER, B.G. Research on rapid smoking: Interim summary and recommenda- tions. Addictive Behaviors 2:X1-166, 1977. DANAHER, B.G., JEFFERY, R.W., ZIMMERMAN, R., NELSON, E. Aversive smoking using printed instructions and audiotape adjuncts. Addictive Behavion 5(4):353-358, 1980. DANIELL, H.W. Osteoporosis of the slender smoker. Vertebral compression fractures and loss of metacarpal cortex in relation to postmenopausal cigarette smoking and lack of obesity. Archives of Internal Medicine X%X3):298-364, March 1976. DAVIS, J.R. Relapse Prevention and Smoking Cessation. Doctoral Dissertation. Wayne State University, Detroit, Michigan. Ann Arbor, University Microfilms Intema- tional, Thesis No. 83-15586, 1983. DAVIS, J.R., GLAROS, A.G. Relapse prevention and smoking cessation. Addictive Behaviors 11:105-114, 1986. DAVIS, R.M. Current trends in cigarette advertising and marketing. New England Journal of Medicine 316(12):725-732, March 19, 1987. DAVISON, G.C., VALINS, S. Maintenance of self-attributed and drug-attributed behavior change. Journal of Personality and Social Z%ychology 11:25-33, 1969. DEAN, A., LIN, N. The stress-buffering role of social support. The Journal of Nervous and Mental Disease X5:403-417, 1977. DELONGIS, A., COYNE, J.C., DAKOF, G., FOLKMAN, S., LAZARUS, R.S. Relation- ship of daily hassles, uplifts, and major life events to health status. Health Psychology 1(2):119-136, 1982. DEMBROSKI, T.M. Stress and substance interaction effects on risk factors and reactivity. Behavioml Medicine Update 6(3):16-20, 1984. DEMELLWEEK, C., GOUDIE, A.J. Behavioural tolerance to amphetamine and other psychostimulants: The case for considering behavioural mechanisms. Peychophar- macologv 80287-307, 1983. DENISTON, R.W. Cancer knowledge, attitudes and practices among black Americans. In: Mettlin, C., Murphy, G.P. (eds.) Cancer Among Black Populations. New York: Alan R. Liss, Inc., 1981, pp. 225-237. DICLEMENTE, C.C. Self-efficacy and smoking cessation maintenance: A preliminary report. Cognitive Therapy and Research M2):175-187, June 1981. DICLEMENTE, C.C. Self-efficacy and the addictive behaviors. Journal of Social and Clinical Wychology 4362-315, 1986. DICLEMENTE, CC., PROCHASKA, J.O. Processes and stages of change: Coping and competence in smoking behavior change. In: Shiffman, S., Wills, T.A. (eds.) Coping and Substance Use. Orlando: Academic Press, 1985, pp. 319-343. DICLEMENTE, C.C., PROCHASKA, J.O., GIBERTINI, M. Self-efficacy and the stages of self-change of smoking. Cognitive Thempy and RaPearch 9181-200, 1985. DOBBS, S.D., STRICKLER, D.P., MAXWELL, W.A. The effects of stress and relaxation in the presence of stress on urinary pH and smoking behaviors. Addictive Behaviors 6(4):345-353, 1981. DOMINO, E.F. Behavioral, electrophysiological, endocrine and skeletal muscle actions of nicotine and tobacco smoking. In: Remond, A., Izard, C. (eds.1 Electraphysiological Effects of Nicotine. Amsterdam: ElsevierlNorth-Holland Biomedical Press, 1979, pp. 133-146. DUNN, W.L. Jr. (ed.) Smoking Behavior: Motives and Incentives. Washington, D.C.: V.H. Winston and Sons, 1973. EDMUND& C.W. On the action of lobeline. American Journal of Physiology 11:79, 1994. EISINGER, R.A. Psychological predictors of smoking recidivism. Journal of Health and Social Behavior 12:355-362, December 1971. EISINGER, R.A. Psychosocial predictors of smoking behavior change. Social Science and Medicine 6(1):137-144, February 1972. ELLIOlT, C.H., DENNEY, D.R. A multiple-component treatment approach to smoking reduction. Journal of Consulting and CZinical Wychology 46(6):133(j1339, 1978. EMONT, S.L., CUMMINGS, K.M. Weight gain following smoking cessation: A possible role for nicotine replacement in weight management. Addictive Behauiom 12:151-155, 1987. ENG, E., HATCH, J., CALLAN, A. Institutionalizing social support through the church and into the community. Health Education Quurterly 1%1):81-92, Spring 1985. ENGELMAN, L., HARTIGAN, J.A. K-means clustering. In: Dixon, W.J. bd.) BMDP Statistical Software. Berkeley: University of California, 1981. ENSMINGER, M.E., BROWN, C.H., KELLAM, S.G. Sex differences in antecedenti of substance use among adolescents. Journal of Social Issues 38(2W5-42. 1982. EPSTEIN, L.H., CLUSS, P.A. A behavioral medicine perspective on adherence to long- term medical regimens. Journal of Consulting and Clinical wyehology 50(6):950-971, 1982. ERICKSON, L.M., TIFFANY, S.T., MARTIN, E.M., BAKER, T.B. Aversive smoking therapies: A conditioning analysis of therapeutic effectiveness. Behaviour Re- search and !l'hempy 21(6):595-611, 1983. ERSHLER, J., LEVENTHAL, H., FLEMING, R., GLYNN, K. The quitting experience for smokers in sixth through twelfth grades. Addictive Behaviors, in press. ESSMAN, W.B. Nicotine-related neurochemical changes: Some implications for motivational mechanisms and differences. In: Dunn, W.L. Jr. ted.1 Smoking Behavior: Motives and Incentives. Washington, D.C.: V.H. Winston and Sons, 1973, pp. 514. ElXINGEFt, B.D., GREGORY, V.R., LANDO, H.A. Influence of group cohesion on the behavioral treatment of smoking. Journal of Consulting and Clinical Atychology 52(6):108&1086, 1984. EVANS, D., LANE, D.S. Smoking ceesation follow-up: A look at postworkshop behavior. Addictive Behavior 6(4):32&329, 1981. EVANS, R.I. Smoking in children: Developing a social psychological strategy to deterrence. Preventive Medicine 5122-127, 1976. EVANS, R.I., ROZELLE, R.M., MI'ITELMARK, MB., HANSEN, W.B., BANE, A.L., HAVIS, J. Deterring the onset of smoking in children: Knowledge of immediate physiological effects and coping with peer pressure, media pressure, and parent modeling. Journal of Applied Social Wychology 8(2):126X% April-June 1978. FAGERBTROM, K. Measuring degree of physical dependence on tobacco smoking with reference to individualization of treatment. Addictive Behaviore 3(3/4):23&241, 1978. FAGERBTROM, K.-O. Effecta of a nicotine-enriched cigarette on nicotine titration, daily cigarette consumption, and levels of carbon monoxide, cotinine, and nicotine. Psychopharmacology 77(2):X%-167, June 1982a. FAGERSTROM, K. A comparison of psychological and pharmacological treatment in smoking cessation. Journal of Behavioml Medicine 5(3):343-351, September 1986. FAGERSTROM, K.-O. Effects of nicotine chewing gum and follow-up appointmenta in physician-based smoking cessation. Preventive Medicine 1X5):517-627, September 1984. FAGERSTROM, K.-O. Reducing the weight gain after stopping smoking. Addictive Behaviors 12:91-93, 1987. FAGERSTROM, K.-O. Efficacy of nicotine chewing gum: A review. In: Pomerleau. 0.. Pomerleau, C. (eds.) Nicotine Replacement: A Critical Evaluation. New York: Alan R. Liss, in press. 540 FAGERSTRC)M, K.-O., MELIN, B. Nicotine chewing gum in smoking cessation: Efficiency, nicotine dependence, therapy duration, and clinical recommendations. In: Grabowski, J., Hall, S. (eds.) Pharmacological Adjuncts in Smoking Cessation, NIDA Research Monograph 53. U.S. Department of Health and Human Services, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse. DHHS Publication No. (ADM) 851333,1985, pp. 102-109. FAGERSTROM, K.-O., STROM, H.G. The effects of different instructions on smoking cessation for individuals with different degrees of dependence. Behaviouml Psychothempy 9(4):31&315, 1981. FEE, W.M., STEWART, M.J. A controlled trial of nicotine chewing gum in a smoking withdrawal clinic. Practitioner 226(1363):148-151, January 1982. FERNO. O., LICHTNECKERT, S., LUNDGREN, C. A substitute for tobacco smoking. Psychopharmacologia 31:201-204. 1973. FISHER, D.A., MAGNUS, P. "Out of the mouths of babes..." The opinions of 10 and 11 year old children regarding the advertising of cigarettes. Community Health Studies 5(1):22-26, 1981. FLAY, B.R. Psychosocial approaches to smoking prevention: A review of findings. Health Wychology 4(5):449-488, 1985a. FLAY, B.R. What we know about the social influences approach to smoking prevention: Review and recommendations. In: Bell, C.S., Battjes, R. (eds.) Preuen- tion Research: Deterring LIrug Abuse Among Children and Adolescents, NIDA Research Monograph 63. U.S. Department of Health and Human Services, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, Nation- al Institute on Drug Abuse. 198513, pp. 67-112. FLEMING, R., LEVENTHAL, H., GLYNN, K., ERSHLER, J. The role of cigarettes in the initiation and progression of early substance use. Addictive Behaviors, in press. FOXX, R.M., AXELROTH, E. Nicotine fading, self monitoring and cigarette fading to produce cigarette abstinence or controlled smoking. Behauiour Research and Therapy 21(1):17-27, 1983. FOXX, R.M., BROWN, R.A. Nicotine fading and self-monitoring for cigarette abstinence or controlled smoking. Journal of Applied Behavior Analysis 12(1):111-125, 1979. FRANK, R.G., UMLAUF, R.L., WONDERLICH, S.A., ASHKANAZI, G.S. Hypnosis and behavioral treatment in a worksite smoking cessation program. Addictive Behaviors 11:59-62, 1986. FREDERICKSEN, L.W. Controlled smoking. In: Krasnegor, N.A. (ed.) Behauiornl Analysis and Treatment of Substance Abuse, NIDA Research Monograph 25. U.S. Department of Health and Human Services, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse. 1979, pp. 128-139. FRIEDMAN, G.D., SIDNEY, S., POLEN, M.R. Smoking habits among multiphasic examinees, 1979 to 1984. Western Journal of Medicine 145(5):651&56, November 1986. FRIEDMAN, L.S., LICHTENSTEIN, E., BIGLAN, A. Smoking onset among teens: An empirical analysis of initial situations. Addictive Behaviors lO:l-13, 1985. FULLER, J.A. Smoking withdrawal and acupuncture. The Medical Journal of Australia 128-29, 1982. GAMBRILL, E.D., RICHEY, C.A. Criteria used to define and evaluate socially competent behavior among women. Psychology of Women Quarterly 10(1):183-196, March 1986. GARVEY, A.J., HEINOLD, J.W., ROSNER. Self-help approaches to smoking cessa- tion: A report from the normative aging study. Addictive Behaviors, in press. 541 GARVEY, H.A., HITCHCOCK, J.L. Relapse after smoking cessation: A proepectiw analysis. Presented at the meeting of the Annual Conference American Psycholog- ical Association, New York, New York, August 1987. GILBERT, D.G. Paradoxical tranquilizing and emotion-reducing effects of nicotine. Psychological Bulletin 86(4):643-661, July 1979. GILBERT, D.G., HAGEN, R.L. The effects of nicotine and extraversion on self-report, skin conductance, electromyographic, and heart responsea to emotional stimuli Addictive Behaviors 5(3):247-257, 1989. GIOVINO, G.A., OSSIP-KLEIN, D.J., SHULMAN, E., BLACK, P., LURIER, A., SEMENTILLI, E., et al. Determinants of Relapse and Redictom of Outcome fir Callers to a Smoking Relapse Prevention Hotline. Presented at the meeting of the Association for Advancement of Behavior Therapy, Chicago, Illinois, November 1986. GLASGOW, R.E., KLESGES, R.C., MIZES, J.S., PECHACEK, T.F. Quitting smoking: Strategies used and variables associated with success in a stop-smoking contest. Journal of Consulting and Clinical l?&wlogy 53(6):905-912, December 1985. GLASGOW, R.E., KLESGES, R.C., VASEY, M.W. ControlIed smoking for chronic smokers: An extension and replication. Addictive Behaviors 8(2):143-150, 1983. GLASGOW, R.E.. LANDO, H., RAND. Pharmacologic treatment of tobacco depen- dence: Proceedings of the world congress, November 1985. Health Ftzycholqy Supplement 5t53-68, 1986. GLASGOW, R.E., LICHTENSTEIN, E. Long-term effecta of behavioral smoking cessation interventions. Behavior Thempy 18297324, 1987. GLASGOW, R.E., LICHTENSTEIN, E., BEAVER, C.. O'NEILL, K. Subjective reactions to rapid and normal paced aversive smoking. Addictive Behauiorn 6Gk53-59, 1981. GLASSMAN, A.H., JACKSON, W.K., WALSH, T., ROOSE, S.P., ROSENFELD, B. Cigarette craving, smoking withdrawal, and clonidine. Science 226:864-866,1984. GLASSMAN, A.H., STETNER, F., WALSH, B.T., RAIZMAN, P.S., FLEX@, J.L., COOPER, T.B., COVEY, L.S. Heavy smokers, smoking cessation, and clonidine: Results of a double-blind, randomized trial. Journal of the American Medical Aeeociation 259(19):286%2866, May 29, 1988. GLYNN, K., LEVENTHAL, H., HIRSCHM AN, R. A cognitive developmental ap preach to smoking prevention. In: Bell, C.S., Battjea, R. &da.) Bwentim Reseamk Deterring Drug Abuse Among Children and Adolescents, NIDA Rasearch IUon+ graph 63. U.S. Department of Health and Human Services, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse. 1985, pp. l-152. GLYNN, S.M. Self-Effxacy Enhancement and Smoking C&ration. Presented at the meeting of the Association for the Advancement of Behavior Therapy, Houston, Texas, 1985. GLYNN, S.M., GRUDER, C.L., JEGERSKI, J.A. Effects of biochemical validation of self-reported cigarette smoking on treatment success and on misreporting absti- nence. Health Psychology 5(2):X%-136, 1986. GLYNN, T. J., PEARSON, H.W., SAYERS, M. (eda. Women and Drugs. Rockville. MD: National Institute on Drug Abuse, 1983. GODDING, P.R., GLASGOW, R.E. Selfefficacy and outcome expectations as predic- tors of controlled smoking status. Cogxitiue Therapy and Resazmh 9:583-590,1985. GODLEY, M.D., LUTZKER, J.R., LAMAZOR, E.A., MARTIN, J.A. Advances in behavioral approaches to adolescent health care. In: Hersen, M., Eisler, R.M., Miller, P.M. (eds.) Progress in Behavior Modifuxrtion, Volume 18. Orlando: Academic Press, 1984, pp. 227-265. GOLDBERG, S.R., SPEALMAN, R.D., RISNER, M.E., HENNINGFIELD, J.E. Control of behavior by intravenous nicotine injections in laboratory animals. PharmacoZo- gy Biochemistry and Behuuior 19(6):1011-1026, December 1983. 542 GOLDING, J., MANGAN, G.L. Arousing and de-arousing effects of cigarette smoking under conditions of stress and mild sensory isolation. Psychophysiology 19(4):449-456, July 1982. GOLDSTEIN, S.J. Maintenance of Nonsmoking Following Self-initiated Cessation. Doctoral Dissertation. Ann Arbor, University Microfilms International, Thesis No. 82-12783, 1981. GOTTLIEB, A.M. The Effects of Nicotine Gum and Expectancy on Smoking Withdraw- al Symptoms and Relapse: A Balanced Placebo Stud-v. Doctoral Dissertation. University of Washington, 1985. GO'ITLIEB, A., FREIDMAN, L.F., COONEY, N., GORDON, J., MARLATT, G. A. Quitting Smoking in Self-Help: Relapse and Survival in Unaided Quitters. Paper presented at the meeting of the Association for the Advancement of Behavior Therapy, Toronto, Canada, November 1981. GO'ITLIEB, A.M., KILLEN, J.D., MARLA'IT, G.A., TAYLOR, C.B. Psychological and pharmacological influences in cigarette smoking withdrawal: Effects of nicotine gum and expectancy on smoking withdrawal symptoms and relapse. Journal of Consulting and Clinical Psychology 55t4):606-608, August 1987. GRABOWSKI, J.G., HALL, S.M. (eds.1 Pharmacological Adjuncts in Smoking Cessation, NIDA Research Monograph 53. U.S. Department of Health and Human Services, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse. DHHS Publication No. (ADM) 85-1333, 1985. GRADY, K.E., BRANNON, R., PLECK, J.H. The Male Sex Role: A Selected and Annotated Bibliography. U.S. Department of Health, Education, and Welfare. DHEW Publication No. (ADM) 79-790. 1979. GRAHAM, R., GIBSON, R.W. Cessation of patterned behavior: Withdrawal from smoking. Social Science and Medicine 5(4):319-337, August 1971. GREAVES, L., BARNES, G.E., VULCANO, B.A. Quit for gocd: Regina smoking cessation program. In: Forbes, W.F., Frecker, R.C., Nostbakken, D. (eds.) Proceed- ings of the Fifth World Conference on Smoking and Health, Volume 2. Winnipeg, Canada: Canadian Council on Smoking and Health, 1983, pp. 193-199. GREEN L.W. Diffusion and adoption of innovations related to cardiovascular risk behavior in the public. In: Enelow, A.J., Henderson, J.B. (eds.)Applying Behavioral Science to Cardiovascular Risk. New York: American Heart Association, 1975. GREENSTEIN, R.A., EVANS, B.D., McLELLAN, A.T., O'BRIEN, C.P. Predictors of favorable outcome following naltrexone treatment. Drug and Alcohol Dependence 12173-180, 1983. GREGORY, V.R. The Efficacy of a Cognitive-behavioral Treatment Aimed at Relapse Prevention in Smokers. Doctoral Dissertation. Iowa State University, Ames, Iowa. Ann Arbor, University Microfilms International, Thesis No. 84-23635, 1984. GRITZ, E. Women and smoking: A realistic appraisal. In: Schwartz, J.L. (ed.) Progress in Smoking Cessation. Proceedings of the International Conference on Smoking Cessation. New York: American Cancer Society, 1979, pp. 119-141. GRITZ, E.R. The female smoker: Research and intervention targets. In: Cohen, J., Cullen, J.W., Martin, L.R. (eds.) Psychosocial Aspects of Cancer. New York: Raven, 1982, pp. 39-49. GRITZ, E.R. Cigarette smoking by adolescent females: Implications for health and behavior. Women and Health 9(2/3):103-115, Summer-Fall 1984. GRITZ, E.R. Gender and the teenage smoker. In: Ray, B., Braude, M. (eds.) Women and Drugs: A New Em for Research. NIDA Monograph 65. U.S. Department of Health and Human Services, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse, 1986, pp. 70-79. 543 GRITZ, E.R., JARVIK, M.E. Pharmacologicai aids for the cessation of smoking. In: Steinfeld, J., Griffiths, W., Ball, K., Taylor, R.M. teds.) Health Consequences, Education, Cessation Activities, and Governmental Action, Volume II. Proceedings of the Third World Conference on Smoking and Health. DHEW Publication No. (NIH) 77-1413. 1977, pp. 575-591. GRUNBERG, N.E. The effects of nicotine and cigarette smoking on food consumption and taste preferences. Addictive Behaviors 7(4):317-331, 1982. GRUNBERG, N.E. Behavioral and biological factors in the relationship between tobacco use and body weight. In: Katkin, E.S., Manuck, S.B. (eds.) Advances in Behavioral Medicine, Volume 2. Greenwich, Connecticut: JAI Press, Inc., 1986, pp. 97-129. GRUNBERG, N.E., BOWEN, D.J., WINDERS, S.E. Effects of nicotine on body weight and food consumption in female rats. Psychopharmacology 9@1):101-105, August 1986. GRUNBERG, N.E., WINDERS, S.E., POPP, K.A. Sex differences in nicotine's effects on consummatory behavior and body weight in rats. Psychopharmacology 91:221-225, 1987. GUERNICA, A., KASPERUK, I. Reaching the Hispanic Market Effectively: The ?fleedia, The Market, The Methods. New York: McGraw-Hill, 1982. GUILFORD, J.S. Sex differences between successful and unsuccessful abstainers from smoking. In: Zagona, S.V. (ed.) Studies and Issues in Smoking Behavior. Tucson, Arizona: University of Arizona Press. 1967, pp. 95-102. GUNN, R.C. Smoking clinic failures and recent life stress. Addictive Behaviors 8(1):83-87, 1983a. GUNN, R.C. Does living with smokers make quitting cigarettes more difficult? Addictive Behaviors 8(4):429-432, 1983b. GUNN, R.C. Reactions to withdrawal symptoms and success in smoking cessation clinics. Addictive Behaviors 11:49-53, 1986. GUNN, R.C., SHAPIRO, A. Life stress, weight gain, and resuming smoking after success in a cessation clinic. Psychological Reports 57(3, Part 2):1035-1039, December 1985. HALL, R.G., SACHS, D.P.L., HALL, S.M. Medical risk and therapeutic effectiveness of rapid smoking. Behavior Therapy l&249-259, 1979. HALL, R.G., SACHS, D.P.L., HALL, S.M., BENOWITZ, N.L. Two-year efficacy and safety of rapid smoking therapy in patients with cardiac and pulmonary disease. Journal of Consulting and Clinical Psychology 52(4):57-l, August 1984. HALL, SM., BACHMAN, J., HENDERSON, J.B., BARSTOW, R., JONES, R.T. Smoking cessation in patients with cardiopulmonary disease: An initial study. Addicticre Behaviors 3(1):33-42, 1983. HALL, SM., GINSBERG, D., JONES, R.T. Smoking cessation and weight gain. Journal of Consulting and Clinical Psychology 54(3):342-346. June 1986. HALL, SM., HERNING, R.I., JONES, R.T., BENOWITZ, N.L., JACOB, P. III. Blood cotinine levels as indicators of smoking treatment outcome. CZinicaZ Pharmucology and Therapeutics 35(61:819-814. June 1984. HALL, S.M., RUGG, D., TUNSTALL, C., JONES, R.T. Preventing relapse to cigarette smoking by behavioral skill training. Journal of Consulting and Clinical Psycholo- gy 52(3):372-382, 1984. HALL, SM., TUNSTALL, C., GINSBERG, D., BENOWITZ, N.L., JONES, R.T. Nicotine gum and behavioral treatment: A placebo controlled trial. Journal of Consulting and Clinical Psychology 55(4M?O3-605, 1987. HALL, S.M., TUNSTALL, C., RUGG, D., JONES, R.T., BENOWITZ, N. Nicotine gum and behavioral treatment in smoking cessation. Journal of Consulting and Clinical Psychology 53(2):256-258, April 1985. 544 HAMILTON, S.B., BORNSTEIN, P.H. Broad-spectrum behavioral approach to smoking cessation: Effects of social support and paraprofessional training on the maintenance of treatment effects. Journal of Consulting and Clinical Psychology 47(3):598-600, 1979. HANSEN, W.B., COLLINS, L.M., JOHNSON, C.A., GRAHAM, J.W. Self-initiated smoking cessation among high school students. Addictive Behaviors 10:26!%271, 1985. HARACKIEWICZ, J.M., SANSONE, C., BLAIR, L.W., EPSTEIN, J.A., MANDER- LINK, G. Attributional processes in behavior change and maintenance: Smoking cessation and continued abstinence. Journal of Consulting nnd Clinical Psychology 55:372-378, 1987. HARRIS, J.E. Cigarette smoking among successive birth cohorts of men and women in the United States during 199080. Journal of the National Cancer Institute 71(3):473479, September 1983. HATSUKAMI, D., HUGHES, J.R., PICKENS, R. Characterization of tobacco with- drawal: Physiological and subjective effects. In: Grabowslci, J., Hall, S.M. (eds) Pharmacological Adjuncts in Smoking Cessntion, NIDA Research Monograph 53. U.S. Department of Health and Human Services, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse. DHHS Publication No. (ADM) 851333, 1985, pp. 58-67. HAUGEN, G.B., DIXON, H.H., DICKEL, H.A. A Therap.y for Anxiety Tension Reactions. New York: Macmillan, 1953. HENNESSY, M.B., FOY, T. Nonedible material elicits chewing and reduces the plasma corticosterone response in mice. Behavioral Neuroscience 101~237-245, 1967. HENNINGFIELD, J.E. Behavioral pharmacology of cigarette smoking. In: Thompson, T., Dews, P.B., Barrett, J.E. teds.) Advances in Eehuuioral Pharmacology, Volume 4. Orlando: Academic Press, 1984, pp. 131-210. HENNINGFIELD, J.E., BROWN, B.S. Do replacement therapies treat craving7 NIDA Notes 2 13-9, 1987. HENNINGFIELD, J.E., GOLDBERG, S.R. Control of behavior by intravenous nicotine injections in human subjects. Pharmacology Biochemistry and Behuvior 19(6):1621-1026, December 1983. HENNINGFIELD, J.E., GOLDBERG, S.R. Stimulus properties of nicotine in animaIs and human volunteers: A review. In: Seiden, L.S., BaIster, R.L. &Is.) Behauioml Phurmacology. The Current Status. New York: Alan R. Lisa 1986, pp. 4334tS. HENNINGFIELD, J.E., JASINSKI, D.R. Pharmacological basis for nicotine replace ment. In: Pomerleau, O.F., Pomerleau, C.S., Fagerstrijm, K.O., Henningfield, J.E., Hughes, J.R. bds.) Nicotine Replacement: A Critical Evaluation. New York: Alan R. Liss, in press. HENNINGFIELD. J.E., l.ONDON, E.D., JAFFE, J.H. Nicotine Reward: Studies of Abuse Liability and Physical Dependence Potential. In: Engel, J., Oreland, L. @Is.) Bruin Reward Systems and Abuse. New York: Raven Press, 1987, pp. 143164. HENNINGFIELD, J.E., MIYASATO, K., JOHNSON, R.E., JASINSKI, D.J. Rapid physiologic effects of nicotine in humans and selective blockade of behavioral effects by mecamylamine. In: L.S. Harris (ed.) Pm6Zem-s of Drug Dependence, I982, NIDA Research Monograph 43. U.S. Department of Health and Human Services, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse. 1982, pp. 259-265. HENNINGFIELD, J.E., SAMPSON, A., NEMETH-COSLETT, R. Effmts of Nicotine Replacement in Tobacco Withdrawal. Presented at the American Psychological Association Convention, Washington, DC., August 1986. HENNINGFIELD, J.E., STITZER, M.L., GRIFFITHS, R.R. Expired air carbon monoxide accumulation and elimination as a function of number of cigarettes smoked. Addictiue Behaviors 5(3):2f%5-272, 1980. 545 HERMAN, C.P., POLIVY, J. Anxiety, restraint, and eating behavior. Journnl of A bnormnl Psychology W6W6-672, 1975. HJRSCHMAN, R.S., LEVENTHAL, H., GLYNN, K. The development of smoking behavior: Conceptualization and supportive cross-sectional survey data. Joumal of Applied Social Psychology 14:184-206, 1984. HIRVONEN, L. Premises and results of smoking withdrawal. In: Forbes, W.F., Frecker, R.C., Nostbakken, D. (eds.) Proceedings of the Fifth World Conference on Smoking and Health, Volume 2. Winnipeg, Canada: Canadian Council on Smoking and Health, 1983, pp. 215-220. HJALMARSON, A.I.M. Effect of nicotine chewing gum in smoking eeasation. A randomized, placebo-controlled, doubleblind study. Journal of the American Medical Association 252GOW35-2636, November 23-36, 1984. HJAIMABSON, A.I.M. Effects of nicotine chewing gum on smoking cessation in routine clinical use. British Journal of Addiction 80~321324, 1985. HOLMES, T.H., RAHE, R.H. The social readjustment rating scale. Journal of Psychosomatic Research 11:213-218, 1967. HOLROYD, J. Hypnosis treatment for smoking: An evaluative review. International Journal of Clinical and Experimental Hypnosis 28341357, 1980. HORAN, J.J., HACKETT, G., NICHOLAS, W.C., LINBERG, S.E., STONE, C.I., LUKASKI, H.C. Rapid smoking: A cautionary note. Journal of Consulting and Clinical Psychology 45(3):341-343, June 1977. HORWITZ, M.B., HINDI-ALEXANDER, M., WAGNER, T.J. Psychosocial mediators of abstinence, relapse, and continued smoking: A one-year follow-up of a minimal intervention. Addictive Behaviors 1029-39, 1985. HUBA, G.J., NEWCOMB, M.D., BENTLER, P.M. Adverse drug experiences and drug use behaviors: A one-year longitudinal study of adolescents. Journul of Pediatric Wychology 11(2):203-219, 1986. HUGHES, J.R. Genetica of smoking: A brief review. Behavior Therapy 17~335-345, 1986. HUGHES, J.R. Dependence potential and abuse liability of nicotine replacement therapies. In: Pomerleau, O.F., Pomerleau, C.S., Fagerstrom, K.-O., HenningfIeld, J.E., Hughes, J.R. (e&x) Nicotine Replacement: A Critical Eualuation New York: Alan R. Lii, 1988, pp. 261-2'77. HUGHES, J.R., GUST, S.W., KEENAN, R.M., SKOOG, K.P., PICKENS, R.W., RAMLET, D., HEALEY, M. Efficacy of nicotine gum in geneml practice. Paper presented at the annual meeting of the American Psychological Association, Washington, August 1966. HUGHES, J.R., GUST, SW.. KEENAN, R.M., SKOOG, K.P., PICKENS, R., RAMLET, D., HEALY, M., HIGGINS, S.T. Efficacy of nicotine gum in general practice: One year follow-up. In: Harris, L.S. (ed.1 Problems of Dnrg &pendenc~ NIDA Research Monograph. U.S. Department of Health and Human Services, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse, 1988. HUGHES, J.R., HATSUKAMI, D. Short term effects of nicotine gum. In: Grabowski, J., Hall, S.M. (eds.) Phcrrmeco logical Adjuncts in Smoking Ceesotion, NIDA Reeearch Monograph 53. U.S. Department of Health and Human Services, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, Nation- al Institute on Drug Abuse. DHHS Publication No. (ADM) 851333,1985, pp. 69-61. HUGHES, J.R., HATSUKAMI, D. Sii and symptoms of tobacco withdrawal. Archives of Geneml &ychiatry 43(3):269-294, March 1986. HUGHES, J.R., HATSUKAMI, D.K., PICKENS, R.W., KRAHN, D., MALINS, S., LUKNIC, A. Effect of nicotine on the tobacco withdrawal syndrome. Wychophar- macology 83(1):82-87, April 1984. HUNT, W.A., BARNE'IT. L.W., BRANCH, L.G. Relapse rates in addiction programs. Journal of Clinical Aychology 27(4):455-M, October 1971. 546 HUNT, W.A., MATARAZZO, J.D. Habit mechanisms in smoking. In: Hunt, W.A. (ed.) Leaning Mechanisms in Smoking. Chicago: Aldine, 1970, pp. 65-106. HUNT, W.A., MATARAZZO, J.D. Three years later: Recent developments in the experimental modification of smoking behavior. Journal of Abnormal Psychology 81(2):107-114, April 1973. HYMAN, G.J., STANLEY, R.D., BURROWS. G.D., HORNE, D.J. Treatment effective ness of hypnosis and behavior therapy in smoking cessation: A methodological refinement. Addictive Behaviors 11:355-365, 1986. HYMOWITZ, N., LASSER, N.L., SAFIRSTEIN, B.H. Effects of graduated external filters on smoking cessation. Preventive Medicine 1185-95, 1982. IKARD, F.F., GREEN, D.E., HORN, D. A scale to differentiate between types of smoking as related to the management of affect. International Journal of the Addictions 4(4):64-g, December 1969. IKARD, F.F., TOMKINS, S. The experience of affect as a determinant of smoking behavior: A series of validity studies. Journal of Abnormal Psycholqy 81(2):17%181. April 1973. JACOBS, M.A., SPILKEN, A.Z., NORMAN, M.M., WOHLBERG, G.W., KNAPP, P.H. Interaction of personality and treatment conditions associated with success in a smoking control program. Psychosomatic Medicine 33(8X&-556, November-De cember 1971. JACOBSON, B. The Ludykillers: Why Smoking is a Feminist Issue. London: Pluto Press, 1981. JACOBSON, N.L., JACOBSON, A.A., RAY, J.P. Noncombustible cigarette: Altema- tive method of nicotine delivery. (Abstract.) Chest 76355-356, September 1979. JAFFE, J.H. Drug addiction and drug abuse. In: Gilman, A.G., Goodman, L.S., RaII, T.W., Murad, F. (eds.) Goodman and Gilman$ The Pha rmacologic Basis of Therapeutics, 7th Edition. New York: MacMillan, 1985, pp. 532-581. JAMROZIC, K., FOWLER, G., VESSEY, M., WALD, N. Placebo controlled trial of nicotine chewing gum in general practice. British Medical Journal 289(6448):794-797, September 29, 1984. JARVIK, M.E. Overview: Alternate forms of pharmacologic treatment. In: Ockene, J.K. ted.) The Pharmacologic Treatment of Tobacco Dependence: Prwceedinga of the World Congress. Cambridge, Massachusetts: Institute for the Study of Smoking Behavior and Policy, 1986, pp. X4-157. JARVIK, M.E., SCHNEIDER, N.G. Degree of addiction and effectiveness of nicotine gum therapy for smoking. American Journal of Psychiatry 141(6):790-791, June 1984. JARVIS, M. Gender and smoking: Do women really find it harder to give up? British Journal of Addiction 79263-387, 1984. JAFWIS, M.J. Nasal nicotine solution: Its potential in smoking cessation and as a research tool. In: Ockene, J.K. ted.1 The Pharmnco logic !lYeatment of Tobacco lkpendcnca: Pwceedings of the World Congress. Cambridge, Massachueette: Institute for the Study of Smoking Behavior and Policy, 1986, pp. 167-173. JARVIS, M.J., RAW, M., RUSSELL, M.A.H., FEYERABEND, C. Randomized controlled trial of nicotine chewing-gum. British Medical Journal 2856341):537-540, August 21, 1982. JARVIS, M.J., RUSSELL, M.A.H. Smoking withdrawal in patients with smoking related diseases. (Letter.) British Medical Journul 286(6369):976-977, March 19, 1983. JASINSKI, D.R., HENNINGFIELD, J.E. Conceptual basis of replacement therapies for chemical dependence. In: Pomerleau, O.F., Pomerleau, C.S., Fagerstrijm, K.-O., Henningfield, J.E., Hughes, J.R. (eds.) Nicotine Replacement: A Critical Evalu- ation. New York: Alan R. Liss, 1988, pp. 13-34. 547 JASINSKI, D.R., JOHNSON, R.E., KOCHER, T.R. Clonidine in morphine withdrawal: Differential effects on signs and symptoms. Archives of Geneml Psychiatry 42:1663-1066, November 1985. JAVEL, A.F. One-session hypnotherapy for smoking: A controlled study. Psycho&i- caI Reports 46(Part 0895-899, June 1980. JESSOR, R., JESSOR, S.L. Problem behavior and psychosocial development: A longitudinal study of youth. New York: Academic Press, 1977. JOFFE, R., LOWE, M.R., FISHER, E.B. Jr. A validity test of the Reasons for Smoking Scale. Addictive Behaviors w041-45, 1981. JOHNSTON, L.M. Tobacco smoking and nicotine. Lancet 2742, 1942. JONES, C.L., BA'ITJES, R.J. The context and caveats of prevention research and drug- abuse. In Jones, C.L., Battjes, R.J. Ms.) Etiology of Dnrg Abuse: Zmplicatione for Prevention, NIDA Research Monograph 56. U.S. Department of Health and Human Services, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse. 1985, pp. 1-12. KABAT, G.C., WYNDER, E.L. Determinants of quitting smoking. American Journal of Public Heulth 77:1361-1305, 1987. KANDEL, D., FAUST, R. Sequence and stages in patterns of adolescent drug use. Archives of General Psychiatry 32(7):92%932, July 1975. KANDEL, D., SIMCHA-FAGAN, O., DAVIES, M. Risk factors for delinquency and illicit drug use from adolescence to young adulthood. The Journal of Drug Zssues 1667-90, 1986. KAROL, R.L., RICHARDS, C.S. Cognitive maintenance strategies for smoking reduction. JSAS Catalog of Selected Dxumente in Paycholosy 11:15, 1981. KATZ, N.W. Hypnosis and the addictions: A critical review. Addictive Behaviors kqlk41-47, 1980. KILLEN, J.D., MACCOBY N., TAYLOR, C.B. Nicotine gum and self-regulation training in smoking relapse prevention. Behavior Therapy 15(3)234-248, 1984. KLESGES, R.C., KLESGES, L.M. Cigarette smoking as a dieting strategy in a university population. International Journal of Eating Disorders, in press. KLESGES, R.C., MEYERS, A.W., HANSON, CL., ECK. L. Smoking cessation and weight gain in males and females. Poster to be presented at: The Association for the Advancement of Behavior Therapy, Boston, Massachusetts, 1987. KORNITZER, M., KI'FI'EL, F., DRAMAIX, M., BOURDOUX, P. A double-blind study of 2 mg vs 4 mg nicotine chewing gum in an industrial setting. Jounual of Psychoeomatic Research 31(2):171-176, 1987. KOZLOWSKI, L.T., WILKINSON, D.A. Use and misuse of the concept of craving by alcohol, tobacco, and drug researchers. British Journnl of Addiction 8231-36, 1987. KROSNICK, J.A., JUDD, CM. Transitions in social influence at adolescence: Who induces cigarette smoking? Developmental Psychology lq3k359-368, 1982. LAMBE, R., OSIER, C., FRANKS, P. A randomized controlled trial of hypnotherapy for smoking cessation. Journal of Family Pmctiee 22:61-66, 1986. LANDO, H.A. A comparison of excessive and rapid smoking in the modification of chronic smoking behavior. Journal of Consulting and Clinical psvChology 4x3):350-355, June 1975. LANDO, H.A. Successful treatment of smokers with a broad-spectrum behavioral approach. Journal of Consulting and Clinical &chology 45(3):361-366, 1977. LANDO, H.A. Stimulus control, rapid smoking, and contractual management in the maintenence of nonsmoking. (Ahtract. Behavior Thempy 91962963, 1978. LANDO, H.A. Effects of preparation, experimenter contact and a maintained reduction alternative on a broad*pectrum program for eliminating smoking. Addictive Behaviors 6123-133, 1981. LANDO, H.A. A factorial analysis of preparation, aversion, and maintenance in the elimination of smoking. Addictive Behauiors 7(2):141154, 1982. 548 LANDO, H.A. Long-term modification of chronic smoking behavior: A paradigmatic approach. Bulletin of the Society of Psychologists in Addictive Behaviors 5(l)&17, 1986. LANDO, H.A. Lay facilitators as effective smoking cessation counselors. Addictive Behaviors 1269-72, 1987. LANDO, H.A., McGOVERN, P.G. Three-year data on a behavioral treatment for smoking: A follow-up note. Addictive Behaviors 7:177-181, 1982. LANDO, H.A., McGGVERN, P.G. Nicotine fading as a non-aversive alternative in a broad-spectrum treatment for eliminating smoking. Addictive Behaviors 10:153-161, 1985. LAZARUS, R.S. The stress and coping paradigm. In: Eisdorfer, C., Cohen, D., Kleinman, A., Maxims, P. (e&s.) Theoretical Bases for Psychopathology New York: Spectrum, 1981. LEVENTHAL, H., AVIS, N. Pleasure, addiction, and habit: Factors in verbal report or factors in smoking behavior? Journal of Abnormal Psychology 85(5):478-488,1976. LEVENTHAL, H., CLEARY, P.D. The smoking problem: A review of the research and theory in behavioral risk modification. Psychological Bulletin 88(2):370-405, 1980. LEVIN, E.D., MORGAN, M.M., GALVEZ, C., ELLISON, G.D. Chronic nicotine and withdrawal effects on body weight and food and water consumption in female rats. Phyeiology and Behavior 39(4):441-444, 1987. LEVINSON, B.L., SHAPIRO, D., SCHWARTZ, G.E., TURSKY, B. Smoking elimina- tion by gradual reduction. Behavior Thempy 6(5):696-698, 1975. LI, V.C., COATES, T.J., SPIELBERG, L.A., EWART, C.K., DORFMAN, S., HUSTER, W.J. Smoking cessation with young women in public family planning clinics: The impact of physician messages and waiting room media. Reuentive Medicine 13(5):477-489, September 1984. LICHSTEIN, K.L., SALLIS, J.F. Covert sensitization for smoking: In search of efficacy. Addictive Behaviors 6(1):83-91, 1981. LICHTENSTEIN, E. The smoking problem: A behavioral perspective. Journal of Consulting and Clinical Psychology 50(6):804-819, 1982. LICHTENSTEIN, E. Clinic based cessation strategies. In: Ockene, J.K. fed.1 The Pharmacologic %atment of Tobacco Dependence: Proceedings of the World Congress. Cambridge, Massachusetts: Institute for the Study of Smoking Behavior and Policy, 1986, pp. 205-217. LICHTENSTEIN, E., GLASGOW, R.E. Rapid smoking: Side effects and safeguards. Journal of Consulting and Clinical Psychology 45(5j:81M21. October 1977. LICHTENSTEIN, E., GLASGOW, R.E., ABRAMS, D.B. Social support in smoking cessation: In search of effective interventions. Behavior Thempy 17:607~19,1986. LICHTENSTEIN, E., HARRIS, D.E., BIRCHLER, G.R., WAHL, J.M., SCHMAHL, D.P. Comparison of rapid smoking, warm, smoky air, and attention placebo in the modification of smoking behavior. Journal of Consulting and Clinical Peychology 46(1):9%98, February 1973. LINEHAN, M.M. Interpersonal effectiveness in assertive situations. In: Blechman, E.A. (ed.) Behavior Modification with Women. New York: Guilford, 1984, pp. 143-169. LINEHAN, M.M., EGAN, K.J. Assertion training for women. In: Bellack, A.S., Hersen, M. (eds.) Research and Practice in Social Skills Daining. New York: Plenum Press, 1979, pp. 237-271. LIVSON, N. Smoking motives: Bases for prevention/quitting strategies. In: On-Going Research in Smoking and Health: 1984-1985 Directory. U.S. Department of Health and Human Services, Public Health Service, Office of the Assistant Secretary for Health. DHHS Publication No. (PHS) 8650208, 1985, pp. 209-210. MacHOVEC, F.J., MAN, S.C. Acupuncture and hypnosis compared: Fifty-eight cases. American Journal of Clinical Hypnosis 21(1):45-47, 1978. 549 MAHONEY, M.J. Cognition and Behavior Modification. Cambridge, Massachusetts: Ballinger Publishing Company, 1974. MALCOLM, R., CURREY, H.S., MITCHELL, M.A., et al. Silver acetate gum as a deterrent to smoking. Chest 96(1):107-111, July 1986. MALCOLM, R.E., SILLE'IT, R.W., TURNER, J.A.M., BALL, K.P. The use of nicotine chewing gum as an aid to stopping smoking. Psychopharmacology 70:295-296, October 1980. MALOTI', J.M., GLASGOW, R.E., O'NEILL, H.K., KLESGES, R.C. Co-worker social support in a worksite smoking control program. Journal of Applied Behauior Analysis 17(4):486-496, Winter 1984. MANLEY, R.S., BOLAND, F.J. Side-effects and weight gain following a smoking cessation program. Addictive Behaviors 3(4):375-3J30, 1983. MARCUS, A.C., CRANE, L.A. Smoking behavior among US Latinos: An emerging challenge for public health. American Journal of Public Health 75(2):X&172, February 1986. MARCUS, A.C., CRANE, L.A. Current Estimates of Adult Cigamtte Smoking by Race/Ethni&ty. Paper presented at the Interagency Committee on Smoking and Health, Washington, D.C., March 31,1987. (Available from the Office on Smoking and Health, Rockville, Maryland.) MARKIDES, K.S., COREIL, J., RAY, L.A. Smoking among Mexican-Americans: A three-generation study. American Journal of Public Health 77(6):708711, June, 1987. MARLA'IT, G.A., GORDON, J.R. Determinants of relapse: Implications for the maintenance of behavior change. In: Davidson, P.O., Davidson, S.M. teds.1 Behavioml Medicimz Changing Health Lifestyles. New York: Brunner/Masel, 1986, pp. 410-452. MARLAll', G.A., GORDON, J.R. (eds.) Relapse Prevention. Maintenance Stmtegies in the Treatment of Addictive Behnviore. New York: Guilford Press, 1986. MARTIN, J.E., PRUE, D.M., COLLINS, F.L., Jr., THAMES, C.J. The effects of graduated filters on smoking exposure: Risk reduction or compensation? 6167-176, 1981. MAUSNER, B., BRANDSPIEGEL, D. The relation of pattern of support for smoking and achievement motive in young women. In: On-going Research in Smoking and Health: 1984-1985 D&ctory. U.S. Department of Health and Human Servicea, Public Health Service, Office on Smoking and Health. DHHS Publication No. (PHS) 8660298, 1986. McDILL, MS. Structure of social systems determining attitude, knowledge, and behavior toward disease: Micro social structures. In: Enelow, A., Henderson, J. (eds.) Applying Behavioml Science to Cardiovascular Risk. New York: American Heart Association, 1975, pp. 18-32. McFALL, R.M. Smokingcessation research. Journal of Consulting and Clinical Psychology 46(4):703-712, August 1978. McGOLDRICK, K.E. Playing with fire: Women and tobacco. Journul of the American Medical Womens Association 41(1):228, January-February 1986. MCINTYRE, K.O., LICHTENSTEIN, E., MERMELSTEIN, R.J. Selfefficacy and relapse in smoking cessation: A replication and extension. Journal of Consulting and Clinical Psychology 51t41632-633, August 1983. McINTYREKINGSOLVER, K., LICHTENSTEIN, E., MERMELSTEIN, R.J. Spouse training in a multicomponent smokingcessation program. Behavior Thempy 17:67-74, 1986. McMORROW, M.J., FOKX, R.M. Nicotine's role in smoking: An analysis of nicotine regulation. Psychological Bulletin 9X2):302327, February 1983. McNABB, M.E., EBERT, R.V., McKUSKER, K. Plasma nicotine levels produced by chewing nicotine gum. Journal of the American Medical Association 243(7):%X1-363, August 20, 1982. McNEILL, A.D.. WEST, R.J.. JARVIS, M., JACKSON, P., BRYANT, Q. Cigarette withdrawal symptoms by adolescent smokers. Psychopharmacology 90(4):533-536, 1986. MERBAUM, M., AVIMIER. R., GOLDBERG, J. The relationship between aversion, group training and vomiting in the reduction of smoking behavior. Addictive Behaviors 4(3):279-235, 1979. MERMELSTEIN, R., COHEN, S., LICHTENSTEIN, E., BAER, J.S., KAMARCK, T. Social support and smoking cessation and maintenance. Journal of Consulting and Clinical Psychology 54(4):447453. 1966. MERMELSTEIN, R., LICHTENSTEIN, E.. MCINTYRE, K. Partner support and relapse in smokingcessation programs. Journal of Consulting and Clinical Psychology 51(3):46&466, June 1983. MITIC, W.R., McGUIRE, D.P., NEUMANN, B. Perceived stress and adolescents' cigarette use. Psychological Reports 57(3, Part 21:1043-1048, December 1985. MORETON, W.J., EAST, R. What quitters need to know. In: Forbes, W.F., Frecker, R.C., Nostbakken, D. (eds.) Proceedings of the Fifth World Conference on Smoking and Health, Volume 1. Winnipeg, Canada: Canadian Council on Smoking and Health, 1983, pp. 397-401. MO'IT, T., Jr. The clinical importance of hypnotizability. American Journal of Clinical Hypnosis 21(4):263-269, April 1979. MURRAY, D.M., O'CONNELL, C.M., SCHMID, L.A., PERRY, CL. The validity of smoking self-reports by adolescents: A reexamination of the bogus pipeline procedure. Addict&e Behaviors 12:7-15, 1987. MURRAY, M., KIRYLUK, S., SWAN, A.V. Relation between parents' and children's smoking behaviour and attitudes, Journal of Epidemiology and Community Health 39(2):169-174, 1985. MURRAY, M., SWAN, A.V., JOHNSON, M.R.D., BEWLEY, B.R. Some factors associated with increased risk of smoking by children. Journal of Child Psychology and Psychiatv 24(2):223-232, April 1983. MURRAY, R.G., HOBBS, S.A. Effects of self-reinforcement and self-punishment in smoking reduction: Implications for broad-spectrum behavioral approaches. Addic- tive Behaviors 6Ub63-67, 1981. NEMETH-COSLE'IT, R., BENOWITZ, N.L., ROBINSON, N., HENNINGFIELD, J. Nicotine Gum: Effects of Chew Rate on Physiology and Self-Reported Responses and Plasma Nicotine Level. Presented at the American Psychological Association Convention, Los Angeles, California, 1985. NEMETH-COSLE'IT, R., HENNINGFIELD, J.E. Effects of nicotine chewing gum on cigarette smoking and subjective and physiologic effects. Clinical Pharmacology and Therapeutics 39(6):625-630, June 1986. NEMETH-COSLEIT, R., HENNINGFIELD, J.E., O'KEEFE, M.K., GRIFFITHS, R.R. Effects of mecamylamine on human cigarette smoking and subjective effects. fiychopharmacology @X4):42(1-425, 1986. NEMETHCOSLETT, R., HENNINGFIELD, J.E., O'KEEFE, M.K., GRIFFITHS, R.R. Nicotine gum: Dose-related effects on cigarette smoking and subjective ratings. Psychopharmacology 92(1):424430, May 1987. NICKI, R.M., REMINGTON, R.E., MACDONALD, G.A. Self-efficacy, nicotine-fad- ing/self-monitoring and cigarettesmoking behaviour. Behavioral Research and Thempy 22~477465, 1984. NOLTE, A.E., SMITH, B.J., O'ROURKE, T. The relative importance of parental attitudes and behavior upon youth smoking behavior. Journal of School Health 53(4):264-271, April 1983. NORTON, G.R., BARSKE, B. The role of aversion in the rapid-smoking treatment procedure. Addictive Behaviors 2(1):21-25, 1977. 551 OCKENE, J.K.. BENFARI. R.C.. NUTIALL, R.L., HURWITZ, I., OCKENE, IS. Relationship of psychosocml factors to srnokmg behavior change in an intervention program Prewntzce Medicine 11!11:13-28, Jaj,uarp 1982. OCKENE, J.K., NUTALL. R., RENFARI, R.C., HURWITZ, I., OCKENE, I.S. A psychosocial model of smoking cessation and maintenance of cessation. Preventive Medicine lOS23-633, 1981. O'CONNELL, K.A.. MARTIN. E.J. Highly temptmg situations associated with abstinence, temporary lapse, and relapse among participants in smoking cessation programs. Journal of Cirnsultin~ an Ur Clinical Psychology 55(3):367-371, 1987. O'CONNOR, K.P., STRAVYNSKI, A. Evaluation of a smoking typology by use of a specific behavioural substitution method of self-control. Behauiour Research and Therapy 20(3!:279-288, 1982. OLSEN, J., RACHOOTIN, P., SCHIODT, A.V., DAMSBO. N. Tobacco use, alcohol consumption and infertility. International Journal of Epidemiology 12(23:179-184, June 1983. ORLANDI, M.A. Gender differences in smoking cessation. Women and Health 11(3/4):237-251, Fall-Winter 1986. ORLEANS, C.T. Understanding and prtimoting smoking cessation: Overview and guidelines for physician int.ervention. Annual Reuiew of Medicine: Selected Topics in the Clinical Sciences 36:51-61, 1985. ORLEANS, C.T., SCHOENBACH, V.J., SALMON, M.A., STRECHER V.J., KALS BEEK, W., NUMAN, K.B., KONRAD. T.R., THOMPSON, B. Black Americans' Smoking and Quitting Patterns: Clinical and Public Health Implications. Paper presented at the annual meeting of the Society of Behavioral Medicine, March 1987. (Available from Health Services Research Center, University of North Carolina, Chapel Hill). OSSIP-KLEIN, D.J., GIOVINO, G.A., BLACK, P., SHULMAN, E., BONANNI, A.M., SEIDMAN, R., et al. Determinants of Smoking Relapse and Predictors of Outcome. Presented at the meeting of the Society of Behavioral Medicine, San Francisco, California, March 1986. OTERO-SABOGAL, R., SABOGAL, F., MARIN, G., MARIN, B.V., PEREZ-STABLE, E. Consequences of Smoking and Quitting Among Hispanics and White Non- Hispanics. Hispanic Smoking Cessation Research Project, Technical Report #7, 1986. PAGANINI-HILL, A., ROSS, R.K., GERKINS, V.R., HENDERSON, B.E., ARTHUR, M., MACK, T.M. Menopausal estrogen therapy and hip fractures. Annals of Internal Medicine 95(1):2%31, July 1981. PAGE, A., WALTERS, D.J.. SCHLEGEL, R.P., BEST, J.A. Smoking cessation in family practice: The effects of advice and nicotine chewing gum prescription. Addictive Behacliors 11:443346, 1986. PAXTON, R. The effects of a deposit contract as a component in a behavioural programme for stopping smoking. Behacioural Research and Therapy 18i045-50, 1980. PAXTON, R. Deposit contracts with smokers: Varying frequency and amount of repayments. Behavioural Research 2nd Therapy 1912):117-123, 1981. PAXTON, R. Prolongmg the effects of deposit contracts with smokers. Behauioural Research and Therapy 21141:425-433, 1983. PECHACEK, T.F. Modification of smoking behavior. In. Krasnegor, N.A. (ed.) The Behavioral Aspects of Smoking, NIDA Research Monograph 26. U.S. Department of Health, Education and Welfare, Public Health Service, Alcohol, Drug Abuse, and h1ental Health Administration, National Institute on Drug Abuse. 1979, pp. 127-188. 552 PECHACEK. T.F.. DAXAHER, B.G. How and why people quit smoking: A cognitive- behavioral analysis. In: Kendall. P.C . iIollon, S.D. teds.1 Cognitive-BehavioraZ Interventions: Theory, Reaearth and Procedures. New York: Academic Press, 1979, pp. 389-422. PEREZ-STABLE, E. Issues in Latino Fiealth Care--Medical Staff Conference, University of California, San Francisco. Ivestern Journnl of Medicine 146:213-218. February, 1987. PERRY, C., GELFAND, R., MARCOVITCH, P. The relevance of hypnotic susceptibili- ty in the clinical context. .Journal of Abnormal Psychoicg? 88(5):592-603, 1979. PERRY, C., MULLEN, C. The effects of hypnotic susceptibiilty of reducing smoking behavior treated by an hypnotic technique. Journal of Clznical Psycholog 31(3):49%505. July 1975. PETTIGREW. A.B., FELL, G.S. Microdiffuslon method for estimation of cyanide in whole blood and its application to the study ot conversion of cyanide to thiocyanate. Clinical Chpmrstry 19'51:46&4il, May 1973. PICKWORTH. U'.B., HERNIPiG, RI.. HENXLNGFIELD. J.E. Electroencephalograph- ic effects of nicotine chewing gum in humans. Pharnradog~ f3L~chemistr-y ad Behacror 25(41:879-S&2. October 1986. POMERLEAU, C.S., POMERLEAL'. O.F. The effects of a psychological stressor on cigarette smoking and subsequent behavioral and physloiogical responses. Psyho- physioLog,\' 24(31:278-28.5, May 1987. POMERLEAU. C.S., POMERLEAC, O.F.. MAJCHRZAK, M.J. Mecamylamine pre- treatment increases subsequent nicotine self-administration as indicated by changes in plasma nicotine level. Psvchoph~lr.nlacolog~ 91(3):391-393, March 1987. POMERLEAU, 0.. ADKINS. D., PERTSCHUK, M. Predictors of outcome and recidivism in smoking cessation treatment. Addtct2r.e Behac,iurs 3(2):65-70, 1978. POMERLEAU. O.F.. POMERLEAU. C.S Neuroregulators and the reinforcement of smoking: Towards a biobehavioral explanation. ~Veuroscienre and Riobehavioral Reviews 8(4):503-513, Winter 1984. POMERLEAU, O.F., POMERLEAU, C.S., FAGERSTROIM. K -0.. HENNINGFIELD, J.E., HUGHES. J.R. teds.! LVicotine Replacement. A Critical Er,aluation. New York: Alan R. Liss. Inc., 1988. POMERLEAU. O.F., TURK, D C.. FERTIG. J.B. The effects of cigarette smoking on pain and anxiety. AddictiL,e Behaviors 9t3):265-271, 1984. POOLE, A.D., SANSON-FISHER. R.`rV., GERM.\S, GA The rapid-smoking tech- nique: Therapeutic effectiveness. Behac~ioural Research and Thempy 19(5):389-397, 1981. POOLE, A.D., SANSON-FISIIER, R.W., GERMAN, G.A., HARKER, J. The rapid smoking technique: Some physiological effects. Behuc,ioral Research and Therapy 18(6):581-586. 1980. POWELL, D.R.. MCCANN, B.S. The effects of a multiple treatment program and maintenance procedures on smoking crssation. Preuenfit~e Medicrne 10:94-104, 1981. PROCHASKA, J.O., DICLEMENTE. C.C. Stages and processes of self-change of smoking: Toward an integrative model of change. .Journa: of Consulting and Clinical Psyhologv 51(3):390-395. June 1983. PROCHASKA. J.O., DICLEMENTE. CC. Common processes of self-change in smoking, weight control, and psychological distress. In: Shiffman, S., Wills, T.A. (eds.) Coping and Substance Use. Orlando: Academic Press. 1985, pp. 367-386. PROCHASKA, J.O.. DICLEMENTE, C.C. Toward a comprehensive model of change. In: Miller, W.R.. Heather. N. ced.s.1 Treatrng Addictlue Behaviors. NPW York: Plenum Press, 1986. PROCHASKA. J.0, DICL.EMENTE, CC., VELICER, W.F.. GINFlL, S.. NORCROSS, J.C. Predicting change in smokin,: status lor srlf-changers. Addictic-e Behac?ors 10:395-4066. 198.5. 553 PRUE, D.M., DAVIS, C.J., MARTIN, J.E., MOSS, R.A. An investigation of a minimal contact brand fading program for smoking treatment. Addictive Behaviors 8(3):307-310, 1983. PUSKA, P.. BJORKQVIST. S., KOSKELA, K. Nicotinecontaining chewing gum in smoking cessation: A double blind trial with half year follow-up. Addictiue Behaviors 4(2):141-146, 1979. RABKIN, S.W., BOYKO, E., SHANE, F., KAUFERT, J. A randomized trial comparing smoking cessation programs utilizing behaviour modification, health education or hypnosis. Addictive Behaviors %21:X7-173, 1984. RAW, M., JARVIS, M.J., FEYERABEND, C., RUSSELL, M.A.H. Comparison of nicotine chewing-gum and psychological treatments for dependent smokers. British Medical Journal 281:481482. 1980. RAW, M., RUSSELL, M.A.H. Rapid smoking, cue exposure and support in the modification of smoking. Behauiour Research and Therapy 18(5):363-372, 1980. REMINGTON, P.L., FORMAN, M.R., GENTRY, E., MARKS, J., HOGELIN, G., TROWBRIDGE, F. Current smoking trends in the United States: The 1981-1983 behavioral risk factor surveys. Journal of the American Medical Association 2X3(20):2975-2978, May 24-31, 1985. RESNICK, J.H. Effects of stimulus satiation on the overlearned maladaptive response of cigarette smoking. Journal of Consulting and Clinical Psychology 32(5):501-505, 1968. RINGOLD, A., GOLDSMITH, J.R., HELWIG, H.L., FINN, R., SCHUE'ITE, F. Estimating recent carbon monoxide exposures. A rapid method. Archives of Environmental Health 5(4):308-318, October 1962. ROGERS, E.M., SHOEMAKER, F.F. Communication of Znnouations: A Cross-Cultuml Approach, Second Edition. New York The Free Press, 1971. ROSE, J.E. Transdermal nicotine as a strategy for nicotine replacement. In: Ockene, J.K. (ea.1 The Pharmacologic Treatment of Tobacco Dependence: Proceedings of the World Congress. Cambridge, Massachusetts: Institute for the Study of Smoking Behavior and Policy, 1986, pp. 158-166. ROSE, J.E., XNANDA, S., JARVIK, M.E. Cigarette smoking during anxiety provoking and monotonous tasks. Addictive Behaviors 8(4):3X%359, 1983. ROSE, J.E., HERSKOVIC, J.E., TRILLING, Y., JARVIK, M.E. Transdermal nicotine reduces cigarette craving and nicotine preference. Clinical Pharmacology and Therapeutics 38(4):450-456, October 1985. ROSE, J.E., JARVIK, M.E., ROSE, K.D. Transdermal administration of nicotine. Drug and Alcohol Dependence 13(3):209-213, May 1984. ROSE, J.E., SAMPSON, A., HENNINGFIELD, J.E. Blockage of smoking satisfaction with mecamylamine. Paper presented to the American Psychological Association, Los Angeles, California, August 26, 1985. ROSECRANS, J.A., MELTZER, L.T. Central sites and mechanisms of action of nicotine. Neuroscience and Biobehauioml Reviews 5(4):497-501, Winter 1981. RUSSELL, M.A.H. Tobacco smoking and nicotine dependence. In: Gibbins, R.J., Israel, Y., Kalant, H., Popham, R.E., Schmidt, W., Smart, R.G. (eds.) Research Advances in Alcohol and Drug Problems. New York: John Wiley and Sons, 1976, pp. l-47. RUSSELL, M.A.H. Conceptual framework for nicotine substitution. In: Ockene, J.K. (ed.) The Pharmacologic Treatment of Tobacco Dependence: Proceedings of the World Congress. Cambridge, Massachusetts: Institute for the Study of Smoking Behavior and Policy, 1986, pp. 9&107. RUSSELL, M.A.H., FEYERABEND, C. Cigarette smoking: A dependence on high- nicotine boli. Drug Metabolism Reuiew HIk29-57, 1978. RUSSELL, M.A.H., FEYERABEND, C., COLE, P.V. Plasma nicotine levels after cigarette smoking and chewing nicotine gum. British Medical Journal 1(6017):1043-1046, May 1, 1976. 554 RUSSELL, M.A.H.. JARVIS, M.J., FEYERABEND, C., FERNO, 0. Nasal nicotine solution: A potential aid to giving up smoking? BritLsh Medical Journal 286(6366):683-684, February 26, 1983. RUSSELL, M.A.H., JARVIS, M.J., SUTHERLAND, G., FEYERABEND, C. Nicotine replacement in smoking cessation: Absorption of nicotine vapor from smoke-free cigarettes. Journal of the American Medical Association 257(23):3262-3265, June 19, 1987. RUSSELL, M.A.H., MERRIMAN. R., STAPLETON. J., TAYLOR, W. Effect of nicotine chewing gum as an adjunct to general practitioners' advice against smoking. British Medical Journal 287(6407):1782-1785, December 10, 1983. RUSSELL, M.A.H., RAW, M., JARVIS, M.J. Clinical use of nicotine chewing gum. British Medical Journal 280(6231):1599-1602, June 28, 1980. RUSSELL, M.,4.H., WILSON, C., FEYERABEND. C., COLE, P.V. Effect of nicotine chewing gum on smoking behaviour and as an aid to cigarette withdrawal. British Medical Journal 2(6032):391-395, August 14, 1976. RUSSELL, M.A.H., WILSON, C., TAYLOR, C., BAKER, C.D. Effects of general practitioners' advice against smoking. British Medical Journal 2(6184):231-235, July 28, 1979. RUSSELL, P.O., EPSTEIN, L.H.. DICKSON, B.E. Behavioral and physiological effects of low-nicotine cigarettes during rapid smoking. Journal of Consulting and Clinical Psychology 51(2):312, 1983. RUST, J.O., LLOYD, M.W. Sex-role attitudes and preferences of junior high school age adolescents. Adolescence 17(65):37-43. Spring 1982. SACHS, D.P.L. Cost-benefit analysis of tobacco dependency treatment. In: Ockene, J.K. (ed.) The Pharmacologic Treatment of Tobacco Dependence, Proceedings of the World Congress. Cambridge, Massachusetts: Institute for the Study of Smoking Behavior and Policy, 1986, pp. 270-280. SACHS, D.P.L., HALL, R.G., PECHACEK, T.F., FITZGERALD, J. Classification of risk-benefit issues in rapid smoking. Journal of Consulting and Clinical Psychology 47(6):1053-1060, December 1979. SAMET, J.M., SCHRAG, SD., HOWARD, C.A., KEY, C.R., PATHAK, D.R. Respira- tory disease in a New Mexico population sample of Hispanic and non-Hispanic Whites. American Reuieu: of Respiratory Disease 125(2):152-157, February 1982. SAUMET, J.L., DITTMAR, A. Heat loss and anticipatory finger vasoconstriction induced by the smoking of a single cigarette. Physiology and Behauior 35(2):229-232, August 1985. SCHACI'ER, S. Recidivism and self-cure of smoking and obesity. American Psycholo- gist 37(4):436-444, April 1982. SCHACHTER, S., SILVERSTEIN, B.. PERLICK, D. Psychological and pharmacologi- cal explanations of smoking under stress. Journal of Experimental Psychology: General 106:31-40, 1977. SCHINKE, S.P.. GILCHRIST, L.D. Preventing cigarette smoking with youth. Journal of Primary Prevention 5(1):48-56, Fall 1984. SCHNEIDER, N.G., JARVIK, M.E. Nicotine vs placebo gum: Comparisons of withdrawal symptoms and success rates. In: Grabowski, J., Hall, S. (eds.) Pharmacological Treatments in Smoking Cessatton, NIDA Research Monograph 53. U.S. Department of Health and Human Services, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse. DHEW Publication No. (ADM) 85-1333, 1985, pp. 83-101. SCHNEIDER, N.G., JARVIK, M.E., FORSYTHE, A.B. Nicotine vs. placebo gum in the alleviation of withdrawal during smoking cessation. Addictive Behaviors 9(2):149-156, 1984. SCHNEIDER, N.G., JARVIK, M.E., FORSYTHE, A.B., READ L.L.. ELLIOTT, M.L., SCHWEIGER, A. Nicotine gum in smoking cessation: A placebo-controlled, double- blind trial. Addicticle Behaviors &31:2X-261, 1983. 555 SCHUBERT, D.K. Comparison of hypnotherapy with systematic relaxation in the treatment of cigarette habituation. &~urnal of Clinical Psychology 39(2):19&202, March 1963. SCHWARTZ. J.L. Rerllew and Evaluation of Smoking Cessation Methods: United States and Canada, 1978-1985. US. Department of Health and Human Services, Public Health Service, National Institutes of Health, NIH Publication No. 87-2940, April 1987. SCOTT, R.R., PRUE, D.M., DENIER, CA., KING, A.C. Worksite smoking intervention with nursing professionals: Long-term outcome and relapse assessment. Journal of Consulting and Clinical Z'sychologv 54:809-813, 1986. SEPKOVIC, D.W., COLOSIMO, S.G., AXELRAD, CM., ADAMS, J.D., HALEY, N.J. The delivery and uptake of nicotine from an aerosol rod. American Journal of Public Health 76:1343-1344, 1986. SHAPIRO, R.M. The Freedom Line: A Relapse-Preuention Intervention for the Control of Smoking. Doctoral Dissertation. University of Rochester. Ann Arbor, University Microfilms International, Thesis No. 84-27950, 1984. SHAPIRO, R., OSSIP-KLEIN, D.J., STIGGINS, J. Freedom Line Phase ZZ: The Evaluation of a Relapse-Prevention Hotline for Ex-Smokers. Presented at the meeting of the 17th Annual Convention of the Association for the Advancement of Behavior Therapy, Washington, D.C.. December 1983. SHAPIRO, D., TURSKY, B., SCHWARTZ, G.E., SHNIDMAN, S.R. Smoking on cue: A behavioral approach to smoking reduction. Journal of Health and Social Behavior 12(2):10%113, June 1971. SHIFFMAN, S. The tobacco withdrawal syndrome. In: Krasnegor, N.A. (ed.) Cigarette Smoking as a Dependence Process, NIDA Research Monograph 23. U.S. Depart- ment of Health Education and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse. 1979, pp. 158-184. SHIFFMAN, S. Relapse following smoking cessation: A situational analysis. Journal of Consulting and Clinical PsyehoZogy 50111:71-86, February 1982. SHIFFMAN. S. Cognitive antecedents and sequelae of smoking relapse crises. Journal of Applied Social Psychology 14(3):296-309, 1984a. SHIFFMAN, S. Coping with temptations to smoke. Journal of Consulting and Clinical Psychology 52(21:261-267, April 1984b. SHIFFMAN, S. Coping with temptations to smoke. In: Shiffman, S., Wills, T.A. (eds.1 Coping and Substance Use. Orlando: Academic Press, 1985, pp. 223-242. SHIFFMAN, S. Overview: Integrating pharmacological and behavioral approaches to smoking cessation. In: Ockene, J.K. (ed.) The Pharmacologic Treatment of Tobacco Dependence: Proceedings of the World Congress. Cambridge, Massachusetts: Institute for the Study of Smoking Behavior and Policy, 1986a, pp. 196-204. SHIFFMAN, S. Psychosocial factors in smoking and quitting: Health beliefs, self- efficacy, and stress. In: Ockene, J.K. (ed.1 The Pharmacologic Treatment of Tobacco Dependence: Proceedings of the World Congress. Cambridge, Massachusetts: Institute for the Study of Smoking Behavior and Policy, 1986b, pp. 48-62. SHIFFMAN, S. A cluster-analytic classification of smoking relapse episodes. Addic- tive RehaLww 11!3):295-307, 1986c. SHIFFMAN, S., JARVIK. M.E. Smoking withdrawal symptoms in two weeks of abstinence. Psvchopharmacologia 50:3%39, 1976. SHIFFMAN, S., JARVIK, M.E. Situational determinants of coping in smoking relapse crises. Journal of Applied Social Psychology 17(1):3-15, 1987. SHIFFMAN, S., MALTESE, J., JARVIK. M.E. Coping skill and coping style in the maintenance of nonsmoking. In: Shiffman, S. 1,ed.j Coping Strategies in the Maintenance of ?Vonsmoking. A symposium conducted at the meeting of the American Psychological Association, Washington, D.C, August, 1982. 556 SHIFFMAN. S., PRANGE, M. Self-reported and self-monitored smoking patterns. (Abstract.) PharrnacoZogy Biochemistry and Behauior 20(6):966, June 1984. SHIFFMAN, S., READ, L., JARVIK, M.E. Smoking relapse episodes: A preliminary typology. Zntemational Journal of the Addictions 29:315-322, 1985. SHIFFMAN, S., READ, L., MALTESE, J., RAPKIN, D., JARVIK, M.E. Preventing relapse in ex-smokers: A self-management approach. In: Marlatt, G.A., Gordon, J.R. (eds.) Relapse prevention. Maintenance Strategies in the Treatment of Addictive Behaoiors. New York: Guilford Press, 1985, pp. 472-520. SHIFFMAN, S.A., SHUMAKER, S., ABRAMS, D.. COHEN, S., GARVEY, E., GRUNBERG, N.E., SWAN, G. Models of smoking relapse. Health Psychology MSupplement):13-27, 1986. SHUMAKER, S.A., GRUNBERG, N.E. Proceedings of the National Conference of Smoking Relapse. Health Psychology S(Supplement), 1986. SILVERSTEIN, B., FELD, S., KOZLOWSKI, L.T. The availability of low-nicotine cigarettes as a cause of cigarette smoking among teenage females. Journal of Health and Social Behavior 21(4):383-388, December 1980. SILVERSTEIN, B., KELLY, E., SWAN, J., KOZLOWSKI, L.T. Physiological predispo- sition toward becoming a cigarette smoker: Experimental evidence for a sex difference. Addictive Behaviors 7(1):83-86, 1982. SIMMS, M., SMITH, C. Teenage mothers and smoking. Health Education Joumal 42(3):87439, 1983. SINGLE, E., KANDEL, D., FAUST, R. Patterns of multiple drug use in high school. Joumal of Health and Social Behavior 15(4):344-357, December 1974. SJC)BERG, L., JOHNSON, T. Trying to give up smoking: A study of volitional breakdowns. Addictive Behaviors 3(3/4):149-164, 1978. SKINNER, W.F., MASSEY, J.L., KROHN, M.D., LAUER, R.M. Social influences and constraints on the initiation and cessation of adolescent tobacco we. Journal of Behauioml Medicine 8(4):353-376, December 1985. SLOSS, E. M., FRERICHS, R.R. Smoking and menstrual disorders. International Joumul of Epidemiology 12(1):107-109, March 1983. SNOW, L.F. Traditional health beliefs and practices among lower class Black Americans. The Western Journal of Medicine 1346):820-828, 1983. SNYDER, F., DAVIS, F., HENNINGFIELD, J.E. Pmceedings of the Eastern Psycholog- ical Association, 1985. SORENSEN, G., PECHACEK, T.F. Attitudes toward smoking cessation among men and women. Joumal of Behavioml Medicine 10(2):129-137, April 1987. SPIEGEL, H. A single-treatment method to stop smoking using ancillary self- hypnosis. International Journal of Clinical and Experimental Hyprwsis 18(4):235-250, October 1970. STEPNEY, R. Human smoking behavior and the development of dependence on tobacco smoking. In: Balfour, D.J.K. (ed.) Nicotine and the Tobacco Smoking Habit. Oxford: Pergamon Press, 1984, pp. 153-176. STERN, M.P., HASKELL, W.L., WOOD, P.D.S., OSANN, K.E., KING, A.B., FARQU- HAR, J.W. Affluence and cardiovascular risk factors in Mexican-Americans and other whites in three Northern California communities. Journal of Chronic D&uses 28(11/12):62s36, December 1975. STEWART, P.J., DUNKLEY, G.C. Smoking and health care patterns among pregnant women. Canadian Medical Association Journal 133(10):969-994, November 15, 1985. STILL, J., MANNION, M. Smoking and pregnancy. Physician Assistant 7(7):114-115, 120, 124, July 1983. STITZER, M.L., BIGELOW, G.E. Contingent reinforcement for reduced carbon monoxide levels in cigarette smokers. Addictive Behaviors 7:40.3-412, 1982. 557 STITZER, M.L., GROSS, J. Smoking relapse: The role of pharmacological and behavioral factors. In: Pomerleau, O.F., Pomerleau, C.S., Fagerstram, K.O., Henningfield, J.E., Hughes, J.R. (eds.1 Nicotine Replacement. A Critical Evalu- ation. New York: Alan R. Liss, Inc., 1988, pp. 163-184. STOLERMAN, I.P. Discriminative stimulus properties in nicotine: Correlations with nicotine binding. Proceedings of the International Symposium on Tobacco Smoking and Health: A Neurobiologic Approach, 1986. STOLERMAN, I.P., GOLDFARB, T., FINK, R., JARVIK, M.E. Influencing cigarette smoking with nicotine antagonists. Psychopharmacologia 28(3):237-259, 1973. SUSHINSKY, L.W. Expectation of future treatment, stimulus satiation, and smoking. Journal of Consulting and Clinical Psychology 39(2):343, October 1972. SWAN, G.E., DENK, C.E. Dynamic models for the maintenance of smoking cessation: Event history analysis of late relapse. Journal of Behavioral Medicine, in press. SWAN, G.E., DENK, C.E., PARKER, S.D., CARMELLI, D., FURZE, D.T., ROSEN- MAN, R.H. Risk factors for late relapse in male and female ex-smokers. Addictive Behaviors, in press. TENNANT, F.S., TARVER, A.L., RAWSON, R.A. Clinical evaluation of mecamyla- mine for withdrawal from nicotine dependence. In: Harris, L.S. (ed.) Problems of ZIrug Dependence 1983, NIDA Research Monograph 49. U.S. Department of Health and Human Services, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse. 1984, pp. 239-246. THOITS, P.A. Social support as coping assistance. Journal of Consulting and Clinical Psychology 54(4):41-23, August 1986. TIFFANY, S.T., MARTIN, E.M., BAKER, T.B. Treatments for cigarette smoking: An evaluation of the contributions of aversion and counseling procedures. Behauiour Research and Therapy 24(4):437-I52, 1986. TINBERGEN, N. "Derived" activities; their causation, biological significance, origin, and emancipation during evolution. Quarterly Review of Biology 27(1):1-32, March 1952. TONNESEN, P. International update on Nicorette. In: Ockene, J.K. (ed.) The Pharmacologic Treatment of Tobacco Dependence: Z'roceedings of the World Congress, November 4-5, 1985. Cambridge, Massachusetts: Institute for the Study of Smoking Behavior and Policy, 1986. TONNESEN, P., FRYD, V., HANSEN, M., HELSTED, J., GUNNERSEN, A.B., FORCHAMMER, H., STOCKNER, M. Two and four mg nicotine chewing gum and group counseling in smoking cessation: An open, randomized, controlled trial with 22 month follow-up. Addictive Behaviors, in press. TONGAS, P.N., PATTERSON, J., GOODKIND, S. Cessation of Smoking Through Behavior Modification: Treatment and Maintenance. Presented at the meeting of the Association for the Advancement of Behavior Therapy. New York, December 1976. TURNER, J.A. McM., SILE'M', R.W., TAYLOR, D.M., McNICHOL, M.W. The effects of supplementary nicotine in regular cigarette smokers. Post Graduate Medical Journal 53:683-685, 1977. U.S. DEPARTMENT OF COMMERCE. We, The Black Americans. Bureau of the Census, 1986. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse- quences of Smoking: Cancer. A Report of the Surgeon General. U.S. Department of Health and Human Services, Public Health Services, Office on Smoking and Health. DHHS Publication No. IPHS) 8260179, 1982. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. National Center for Health Services, National Health Interview Survey, 1984a. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse- quences of Smoking: Chronic Obstructive Lung Disease. A Report of the Surgeon General. U.S. Department of Health and Human Services, Public Health Service, Office on Smoking and Health. DHHS Publication No. (PHS) 8450205, 1984b. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse- quences of Smoking: Cancer and Chronic Lung Disease in the Workplace. A Report of the Surgeon General. U.S. Department of Health and Human Services, Public Health Service, Office on Smoking and Health. DHHS Publication No. (PHS) 85 56207, 1985. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. Cancer Among Blacks and Other Minorities: Statistical Profiles. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Cancer Institute. NIH Publication No. 86-2785, March 1986. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. Cancer Prevention Awareness Survey Wave ZZ: Management Summary. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Cancer Institute. NIH Publication No. 87-2908, 1987. U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE. Smoking and Health. A Report of the Surgeon General. U.S. Department of Health. Education, and Welfare, Public Health Service, Office of the Assistant Secretary for Health, Office on Smoking and Health. DHEW Publication No. (PHSI 79-50066, 1979. U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE. The Health Consequences of Smoking for Women: A Report of the Surgeon General. U.S. Department of Health and Human Services, Public Health Service, Office of the Assistant Secretary for Health, Office on Smoking and Health. 1980, VELICER, W.F., DICLEMENTE, C.C., PROCHASKA, J.O., BRANDENBURG, N. Decisional balance measure for assessing and predicting smoking status. Journal of Personality and Social Psychology 48(5):1279-1289, May 1985. VOGT, T.M., SELVIN, S., WIDDOWSON, G., HULLEY, S.B. Expired air carbon monoxide and serum thiocyanate as objective measures of cigarette exposure. American Journal of Public Health 67(6):545-549, June 1977. WAGNER, T.J., HINDI-ALEXANDER, M., HORWITZ, M.B. A one-year follow-up study of the Damon Group Hypnosis Smoking Cessation Program. Journal of the Oklahoma State Medical Association 76(12):414-417, December 1983. WARNECKE, R.B., GRAHAM, S., ROSENTHAL, S., MANFREDI, C. Social and psychological correlates of smoking behavior among Black women. JournaZ of Health and Social Behavior 1%4):397410, December 1978. WARNER, K.E. Selling Smoke: Cigarette Advertising and Public Health. Washington, D.C.: American Public Health Association, 1986. WEISSMAN, W., GLASGOW, R., BIGLAN, A., LICHTENSTEIN, E. Development and Evaluation of a Cessation Program for Adolescent Smokers. Boston: Harvard University, Institute for the Study of Smoking Behavior and Policy, 1986. WESNES, K., WARBURTON, D.M. Smoking, nicotine and human performance In: Balfour, D.J.K. (ed.) Nicotine and the Tobacco Smoking Habit. Oxford: Pergamon Press, 1964, pp. 13%152. WEST, L.J. Hypnosis in treatment of the tobacco smoking habit. In: Jarvik, M.E., Cullen, J.W., Gritz, E.K., Vogt, T., West, L.J. (eds.) Research in SmokingRehaoior, NIDA Research Monograph 17. U.S. Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse. US. DHEW Publication No. 78581, 1977, pp. 364-372. WEST, R.J. Psychology and pharmacology in cigarette withdrawal. Journal of Psychosomatic Research 28(5):379-386, 1984. WEST, R.J., JARVIS. M.J.. RIJSSELL. M.A.H.. CARRUTHERS, M.E., FEYERA- BEND, C. Effect of nicotine replacement on the cigarette withdrawal syndrome. British ~Journal of Addiction 79(2):215-219, June 1984. WEST, R.J.. JARVIS, M.J., RUSSELL, M.A.H., FEYERABEND, C. Plasma nicotine concentrations from repeated doses of nasal nicotine solution. British Journal of Addiction 79:443-%45, 1984. WEST, R.J., RUSSELL, M.A.H Effects of withdrawal from long-term nicotine gum use. Psychological Medicrne 15(4):891-893, November 1985. WEST, R.J., RUSSELL, M.A.Ii. Dependence on nicotine chewing gUm. Journal of the American Medical Associatwn 256(23):3214-3215, December 19, 1986. WEST, R.J.. SCHINEIDER, N. Craving for cigarettes. British Journal of Addiction 82:407-415. 1987. WESTMAN, M., EDEN, D.. SHIROM, A. dab stress, cigarette smoking and cessation: The conditioning effects of peel support. Social Science and Medicine 20(6X37-644, 1985. WIKLER. A. Conditioning factors in opiate addiction and relapse. In: Wilmer, D.M., Kassebaum, G.G. (eds I .Varrntirs. New York: McGraw-Hill, 1965. WILCOX, N.S., PROCHASKA. J .O., VELICER, W.F., DICLEMENTE, C.C. Subject characteristics as predictors of se!f-change in smoking. Addictive Behaviors 10:407-412, 1985. WILHELMSEN, L., HJAIMARSON, A. A smoking cessation experience in Sweden. Canadian Family Physician 26:737-743, 1980. WILLE'IT, W., STAMPFER, M.J., BAIN, C., LIPNICK, R., SPEIZER, F.E., ROSNER, B., CRAMER. D., HENNEKEIZS, C.H. Cigarette smoking, relative weight, and menopause. IZnzerican Journal of Epidemiology 117(6):651-658, June 1983. WILLS, T.A., SHIFFMAN. S. Coping and substance use: A conceptual framework. In: Shiffman, S., Wills, T.A. teds.1 Coping and Substance C'se. Orlando: Academic Press, 1985, pp. 3-24. WILSON. D hf.C., BEST, J.A., LINDSAY-MCINTYRE, E., GILBERT, J.R., TAYLOR, D.W., SINGER, J. Can training family physicians improve compliance with nicotine gum use? In: Ockene, J.K. (ed) The Pharmacologic Treatment of Z'obucco Dependence: Proceeding of the World Congress. Cambridge, hlassachusetts: Insti- tute for ttz Study cf Smoking Behavior and Policy, 1986, pp. 218-225. WINDSOR, R.H., CUTTER, G., MORRIS, J., REESE, Y.. MANZELK, B., BARTLE'M', E.E.. SAMUELSON, C., SPANOS, D. The effectiveness of smoking cessation methods for smokers in public health maternity clinics: A randomized trial. American Journal of Public ffealth 75(12):1389-i392, 1985. WITTENBERG, C.K. Summary of market research for "Healthy Mothers, Healthy Babies" campaign. Public Health Reports 98(4):35&359, July-August 1983. WOHLFORD, P., GIXMMONA, S.`l' Personality and social variables related to the initiation of smoking cigarettes. *Journal of School Health 39(8):544-552, October 1969. YAMAGUCHI, K.. KANDEL. D.B. Patterns of drug use from adolescence to young adulthood: II. Sequences of progression. American Journal of Public Health 74(7):66&&2, July 1984. YATES, A.J.. THAIN. J. Self-efficacy as a predictor of relapse following voluntary cessation of smoking. Addic,tl?e Bphuliors 10291-298, 1985. ZEIDENBERG, P., JAFFE. J H., KANZLER, M., LEVITT, M.D., LANGONE, J.J., VAN VUNAKIS, H. Nicotine: Cotinine levels in blood during cessation of smoking. ComprehensiLle Pyvchiatn 18(11:93, January-February 1977. 560 APPENDIX A TRENDS IN TOBACCO USE IN THE UNITED STATES 561 CONTENTS Introduction ..,,..................................................... 565 Prevalence of Smoking in the United States ............ .565 Trends in Cigarettes Consumed .............................. .565 Trends in the Tar and Nicotine Content of Cigarettes Consumed ......................................................... 566 Surveys of Self-Reported Cigarette Smoking in Adults. 567 General Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .567 National Health Interview Surveys.. . . . . . . . . . . . . . . . . . . .568 Demographic Trends in Smoking Prevalence in Adults.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 569 Other Social Correlates of Smoking. . . . . . . . . . . . . . . . . . . . 571 Other Surveys Reporting Adult Prevalence of Smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 572 Trends in Adolescent Smoking . . . . . . . . . . ..*................... 573 Trends in the Proportion of Smokers Who Are Heavy Smokers.. . . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . , . . . . . . . , . . . . . . . . . . . . 577 Trends in Quitting Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .577 Trends in Cigar, Pipe, and Roll-Your-Own Cigarette Smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 580 Trends in Smokeless Tobacco Use.. . . . . . . . . . . . . . . . . . . . . . . . . . . 580 Summary and Conclusions ...................................... 582 References ........................................................... 585 563 Introduction The focus of this Appendix is on trends in the prevalence and demographic correlates of tobacco use. Findings from selected data sources (US DHHS 1986b; USDA 1986; US FTC 1981, 1986; US DHHS 1988) will be reported as well as findings from analyses of trend data found in these sources. Prevalence of Smoking in the United States Several surveys using different methodologies have reported the prevalence of current cigarette smoking in the United States. The reported prevalence of smoking between 1944 and 1986 is shown in Table 1. However, different methodologies can lead to variations in the estimation of prevalence. The same general survey methodology has been used throughout the National Health Interview Surveys (NHIS 1965 to 1985). These surveys have indicated a steady decline in smoking prevalence beginning in the late 1960s to 30.4 percent of adults 20 years of age and older in 1985. These data parallel the per capita consumption of cigarettes in the United States, which has declined each year since 1973 (Table 2). Based on population estimates and the NHIS, the total number of adult smokers (aged 20 years and older) in the United States declined from approximately 52,400,OOO in 1976 to approximately 51,100,OOO in 1985. The total number of former smokers increased from approximately 29,500,OOO to 40,900,OOO within this time period. Trends in Cigarettes Consumed In the United States, cigarettes are taxed at the wholesale level, in advance of retail sales. Tax data may not reflect retail sales in any particular year insofar as different inventory levels are held over time. However, the number of cigarettes taxed is a standard index used to estimate the number of cigarettes consumed over time. Total cigarette consumption as estimated by this index in the United States increased steadily from 1920 until 1981 when an estimated total of 640 billion cigarettes were smoked (Table 2). Since 1981, there has been a steady decline in consumption and the number of cigarettes smoked in 1987 is estimated at 574 billion. These data are frequently divided by the population of adults 18 years of age and older to give a per capita estimate of consumption. It should be noted that this per capita estimate could be biased if there is a trend over time for more people to start smoking regularly under 18 years of age. Since 1973, there has been a decline of 23 percent in the number of cigarettes smoked on a per capita basis. Although there has been a TABLE l.-Percentage of current cigarette smokers among adults, by year and survey, United States, 1944-1986 Year Surrey Current cigarette smokers (percentage) Men Women Total 1944 1949 1955 1964 1965 1966 196; 196-S 1970 1974 1975 1976 1978 1960 1983 1985 1986 GP 18 48.0 36.0 41.0 GP 18 54.0 33.0 44.0 CPS 18 54.2 24.5 37.6 WSH 21 52.9 31.5 40.3 NHIS 17 51.1 33.3 41.7 CPS 17 500 32.3 40.6 NCSH 21 51.9 33.7 42.2 CPS 17 49.1 32.1 40.1 CPS 17 47.0 312 38.6 NHIS 17 43.5 31.1 36.9 NCHS 21 42.3 30.5 36.2 NHIS 17 42.7 31.9 37.0 NCSH 21 39.3 28.9 33.8 NHIS 20 41.9 32.0 36.7 XHIS 11 37.5 29.6 33.2 NHIS 20 38.3 29.4 33.6 NHIS 20 35.7 29.4 32.4 CPS 16 31.8 25.4 23.4 NHIS 20 33.2 27.9 30.4 OSH 17 29.5 23.8 26.5 NOTE GP. Gallup Poll, CPS. Current Population Survey (SupplementI; NCSH. National Clearinghouse for Smokmg and Health (Adult Use of Tobacco Surveys: NHIS, Natmnal Health interview Survey: OSH. Office on Smokmg and Health (Adult Use of Tobacco Survey). NHIS data are not age adjusted SOURCE LX DHHS 11987~1 decline in every one of these 15 years, the rate of decline has varied from 0.2 to 7.2 percent with a mean of 1.9 percent per year (Table 2). Trends in the Tar and Nicotine Content of Cigarettes Consumed Data on the market share of cigarettes of different smoking machine determined tar and nicotine yield have been published by the Federal Trade Commission (FTC) from information supplied to the agency by cigarette companies. The FTC is no longer generating these data. Trends in the sales-weighted average yield of tar and nicotine for cigarettes sold are shown in Figure 1. The sales-weighted average represents the tar and nicotine content found in specific brands averaged by the quantity of sales for that specific brand. Throughout the 1970s there was a steady decline in the sales- weighted average. This decline may have occurred because of consumer beliefs that lower-yield brands are less hazardous. The impression that low-yield brands may be less hazardous may have resulted in part from cigarette advertising implying that low-yield brands are less hazardous or safe (Davis 1987). 566 TABLE 2.-Total cigarette consumption and consumption per capita 18 years of age and older, 1973 to 1987, United States Year Total consumption iblllionsl Per raprta Per capita consumption change consumption from previous year / 2 1P years old! `percentagel 1973 1974 1975 1976 1977 1978 1979 1980 1981 1982 1983 1964 1985 1986 1987 lest I 58Y 7 599.0 607.2 613 5 61i 0 616.0 621 5 6315 640.0 634 0 6000 600.4 594 0 583 8 574.0 4.14P 4.141 4.123 4.OY2 4,051 396i 3,661 3,644 3.836 3.iY9 3,488 3.446 3.370 3x74 3.196 -0.2 a.4 4.8 -10 -2.1 -2 7 a.4 -0.2 -2.6 -7 2 -1.2 -2.3 -2.9 -2.4 SOURCE USDA 1986, From 1982 to 1985, the declining sales-weighted tar and nicotine yield leveled off. This change may be related to one or a combination of the following factors: (1) a persistent brand loyalty of some smokers to moderate- or high-yield brands because of brand image; (2) a diminishing perception that low-yield brands are less hazard- ous; (3) some smokers are now smoking cigarettes of such low tar and nicotine yields that further reductions in those yields may be unacceptable; i.e., the "lower boundary" of comfortable cigarette use has been reached (Kozlowski 1987; Chapter IV). The 1981 Surgeon General's Report (US DHHS 1981) cautioned that the health benefits of switching to low-yield brands are minimal compared with giving up cigarettes entirely. Surveys of Self-Reported Cigarette Smoking in Adults General Considerations The validity of self-reported smoking status from community surveys affects the usefulness of these data in reporting historical trends. Respondents' sensitivity to social stigma associated with 567 18 - 16 - lE 14- z - 2 12- E .P T '0: 2 8- h? 6- 4- 2- -0.6 - 0.4 - 0.2 ol I . I . , . I I I 1 I I . I Lo.0 67 69 71 73 75 77 79 81 63 85 1959~1985 FIGURE l.-Sales-weighted averages of tar and nicotine per cigarette, MB-1985 (1985 data preliminary) SOURCE: U.S. Federal Trade Commission (February 1988l. smoking is cited as a major reason why persons might underreport their smoking status (Warner 1978; Kozlowski 1986). Whereas biochemical assessment is significantly more reliable than self- reports in assessing level of nicotine intake (see Chapters II and IV), self-reported data appear valid for estimating prevalence of smoking in the population. For example, studies of patients in several settings (Petitti, Friedman, Kahn 1981; Pojer et al. 19841, as well as two large community studies (Fortmann et al. 1984; Pierce, Dwyer et al. 1987), have shown that measurements of smoking by self-report and biochemical markers give approximately the same estimates of prevalence. It is possible that the accuracy of self-reported data will vary depending on whether the data collection method is face-to-face or by telephone interview. However, biochemical validation data do not exist to allow quantification of such a difference. In addition, serious concerns have been expressed about the validity of data (Thornberry 1987) reported by one person on behalf of another (proxy response). National Health Interview Surveys The National Health Interview Survey (NHIS), which is conducted regularly by the National Center for Health Statistics, uses a 568 sampling frame developed by the U.S. Bureau of the Census and is based on a multistaged random probability sampling design. Infor- mation on behavioral health risk factors is collected in face-to-face interviews. Basic smoking information has been collected for several years, including 1965, 1976, 1978, 1979, 1980, 1983, and 1985 (data for 1965 are based on both self-report and proxy reporting; all of the more recent surveys were based on self-reports). The 1987 survey results were not available for this Report. Beginning in 1985, an adequate sample of blacks was ensured by the survey design (using the technique of oversampling). The NHIS generally has a response rate of 96 percent (Thornberry 1987). However, the smoking informa- tion is collected only by self-report in a supplement. This extra step in data collection procedures leads to a decrease in the response rate to approximately 90 percent. Demographic Trends in Smoking Prevalence in Adults Between 1965 and 1985, smoking prevalence decreased in all age, sex, and race categories with the exception of women aged 65 years and older (Table 3). This exception can be explained as a birth cohort effect (Warner and Murt 1982). Both black and white males have decreased their smoking by an average of a percentage point per year over this 20-year period. However, in 1985,41 percent of black males smoked, compared with 32 percent of white males. For all races, the largest decrease in smoking occurred in younger males; the 20- to 24-year-old age group decreased an average of 1.4 percentage points per year. The marked gradient in the degree of change per year across age groups suggests that a birth cohort effect may have occurred, with many more young males never having become regular smokers. Proportionately fewer women smoke than men within every age group and race category except for persons 20 to 40 years old in 1985 (31.0 percent for men, 32.1 percent for women). However, the yearly rate of decline in smoking prevalence across these categories is, on average, three times less than the male rate of decline. Moreover, the decline in female smoking appears mainly in the under-44-year age group. This may indicate that uptake of smoking among women in the more recent birth cohorts is beginning to decline. Of particular importance is the almost complete lack of change in smoking prevalence among black women from 1965 to 1985. Smoking rates among Hispanics have been reported using NHIS data (Marcus and Crane 1985,1987), but the small sample size of this subpopulation reduces the reliability of the estimates. According to the 1985 NHIS, the prevalence of smoking among Hispanic males and females aged 18 and older was 31.3 percent and 20.8 percent, respectively (Marcus and Crane 1987). Information on Hispanic smoking is also available from the Hispanic Health and Nutrition 569 TABLE 3.-Twenty-year trends in smoking prevalence (percentage) among adults 20 years of age and older, by sex, race, and age, United States Difference sex. race. age 1965 1976 1980 1985 196s1985 Men Total ' z 52.1 41.6 37.9 32.7 -19.4 Race ' whm 51.3 41.0 37.1 31.8 -19.5 Black 59 6 501 44.9 40.6 -19.0 Age 2 20-24 59.2 45.9 39.7 31.0 -28.2 25-34 607 48.5 43.1 38.2 -22.5 3% 58.2 47.6 42.6 37.6 -20.6 45-64 51.9 41.3 40.8 33.4 -18.5 265 28.5 23.0 17.9 19.6 4.9 Total 1.1 34.2 32.5 29.8 28.3 -5.9 Race ' White Black 34.5 32.4 30.0 28.3 -6.2 32.7 34.7 30.6 31.6 -1.1 Age2 20-24 25-34 w4 4s64 >a 41.9 342 32.7 32.1 -9.8 43.7 37.5 316 32.0 -11.7 43.7 38.2 349 31.5 -12.2 32.0 34.8 30.8 29.9 -2.1 9.6 12.8 16.8 13.5 13.9 : Age-adjusted prevalence rates. `Includes white. black. and other SOURCE U.S. PHS i19R7) Examination Survey (HHANES), which was conducted by the National Center for Health Statistics between 1982 and 1984. This study surveyed 9,OW Mexican-Americans in the Southwest, 4,000 Puerto Ricans in the Northeast, and 1,500 Cuban-Americans in Miami. For males aged 20 to 74 the age-adjusted smoking rates were 43 percent for Mexican-Americans, 42 percent for Cuban-Americans, and 40 percent for Puerto Rican-Americans. Among females, the smoking prevalence was 24 percent for Mexican-Americans and Cuban-Americans and 30 percent for Puerto Rican-Americans (Haynes 1987). Estimates of smoking prevalence among other minority groups may be unreliable because of small sample sizes included in the NHIS. Trend data are not available because Hispanic status was not ascertained on earlier surveys. 570 TABLE 4.-Smoking prevalence (percentage) among adults 18 years of age and older, by sociodemographic subgroups, United States, 1985 subgroup Men Women Total Education Less than high school 40.1 31.4 35.4 High school graduate 36.6 31.0 33.4 some college 29.9 24.9 27.3 College graduate 22.6 17.1 20.1 Postgraduate 17.3 15.1 16.5 Occupation Employed White-collar Blue-collar setice Unemployed Not in workforce!Unknown 33.8 30.0 32.1 264 28.0 27.5 40.1 33.9 39.7 40.3 354 37.2 443 28.0 36.1 28.6 25.3 26.4 Marital status Never married 30.0 26.3 28.3 Divorced/Separated 48.2 42.4 44.7 MarriedKohabitating 31.9 27.7 29.7 Widowed 29.3 20.1 21.6 Income < 510,ooo 36.3 29.7 32.3 $10,ooa-19,999 37.0 29.8 33.1 t20,-,999 33.1 28.1 30.7 2 835,ooo 27.0 25.1 26.1 SOURCE: Natwnal Center for Health Statistics, National Health Internew Survey 1985. Other Social Correlates of Smoking The prevalence of smoking varies across so&demographic catego- ries. A detailed analysis of the sociodemographic correlates of smoking status in the 1985 NHIS survey is presented below. Current smoking prevalence by sex, occupation, marital status, employment, education, and income groups for 1985 is shown in Table 4. Current smoking prevalence was inversely related to educational status. Persons who were employed were less likely to be current smokers than unemployed persons. Persons employed in white-collar jobs were less likely to be smokers than persons employed in blue-collar or service jobs. Persons with higher income and persons who were single, married, or widowed had a lower prevalence of smoking than persons with lower income or who were divorced or separated. Because blacks were oversampled in the 1985 NHIS and subse- quent sample designs, it is possible to make detailed comparisons 571 TABLE B.-Percentage of current smokers in 1985, by age, race, and sex sex. age White Black Men R-24 291 26.6 25-34 37.1 45.2 :35-44 36.3 449 4!G54 33.4 47.4 55-64 30.1 44.6 65-74 21.2 31.0 275 13.9 21.4 Women lb24 33.0 24.2 25-34 32.6 35.7 35-44 31.4 40.2 45-54 32.9 37.0 5=4 27.4 26.9 674 17.8 18.6 275 7.1 8.0 SOURCE National Center for Health StaLlstirs. National Health Interview Sur'vey 1985. between blacks and whites in smoking prevalence. Table 5 shows that across all age categories, except among those aged 18 to 24 years, blacks have higher smoking prevalence than whites. The lower smoking prevalence among blacks in this age group may reflect an older age of initiation among blacks. In a multivariate analysis of NHIS data, controlling for sex, age, employment, poverty status, education, and marital status, blacks were no more likely to be ever smokers than whites (Novotny et al., in press). In this study, blacks were less likely than whites to quit smoking. Blacks also were less likely than whites to be heavier smokers (2 15 cigarettes per day). Other Surveys Reporting Adult Prevalence of Smoking The 1986 Adult Use of Tobacco Survey showed slightly lower rates of smoking than that expected from the trends observed in the National Health Interview Surveys (NHIS). These data, based on a telephone interview of 13,031 adults aged 17 and older, were weighted to reflect the U.S. population according to age, sex, education level, and region. An estimated 29.5 percent of males (95 percent confidence interval, 28.4 to 30.6) and 23.8 percent of females (95 percent confidence interval, 22.7 to 24.9) smoked cigarettes regularly. Differences from the NHIS may reflect differences in age of respondents (NCHS-age 18 and above, Adult Use Survey-age 17 and above), methodology (Waksberg 19781, or response rates (NCHS approximately 90 percent, Adult Use Survey approximately 74 572 percent). The exclusion of households lacking telephones appears to account for an underestimate of approximately 1 percentage point in telephone surveys; persons living in households without telephones have a higher smoking prevalence than those in households with telephones (US DHHS 1987c). In 1985, a supplement to the Current Population Survey contained smoking information collected by household interviews. These data are particularly relevant because of the large sample population. However, 45 percent of responses were by proxy. Of the 114,342 persons surveyed, the overall smoking prevalence for persons 16 years of age and older was 31.8 percent for males and 25.4 percent for females (Table 1). A detailed analysis of this data set is available from the Office on Smoking and Health (Marcus and Crane 1987). Since 1981, the Centers for Disease Control has coordinated the collection of State-specific data on several behavioral risk factors in the Behavioral Risk Factor Surveillance System (BRFSS). In 1986,25 States and the District of Columbia participated in this telephone interview system (Table 6). Median State smoking prevalence among adults 18 years of age and older varied between 18 percent and 35 percent (US DHHS 1987c), with marked geographical distribution patterns. States east of the Mississippi appeared to have the highest smoking prevalences (US DHHS 1987dl. These States also had the highest adult per capita consumption of cigarettes (Tobacco Institute 19861, as measured by sales of cigarettes taxed in each State. Trends in Adolescent Smoking The National Institute on Drug Abuse (NIDA) conducted house- hold surveys on drug use in 1979,1982, and 1985. Data were obtained from a stratified random sample of 8,000 U.S. households; approxi- mately 2,000 interviews were conducted with respondents in the 12- to 17-year-old age group. Questions included whether any cigarettes were smoked within 30 days as well as within the previous year. These surveys indicated that approximately 26 percent of the teenage population surveyed smoked at least one cigarette at some time during 1985 (Table 7). In 1985, 15.6 percent of this population had smoked within the previous month. However, these overall mean values probably underestimate the level of experimentation and uptake of smoking during these ages due to response bias or underreporting. Comparisons with 1979 are not appropriate, because in that year, there was a markedly different definition of smoking compared with later years ("at least 100 cigarettes in lifetime" compared with "any smoking in last 30 days"). The "Monitoring of the Future" project, sponsored by NIDA, is conducted by the Institute for Social Research at the University of Michigan. It consists of a yearly survey of a representative sample of 573 TABLE 6.-Current smoking prevalence (percentage) in 25 States and the District of Columbia, 1986 Current smokers state Sample size Men Percentage Women Total 95 percent confidence interval Alabama 559 30.3 20.0 ACZ0na 1,175 24.4 24.7 Cahfornia 1,579 25.4 23.9 District of Columbia 1,145 32.1 22.5 Florida 1,162 309 27.8 Georgia 1,140 29.3 24.8 Hawaii 1.551 27.8 20.3 Idaho 1.165 30.9 16.2 Illinois 1,142 32.7 23.6 Indiana 1,162 31.6 23.5 Kentucky 1,216 37.2 32.6 ,2Iassachusetcs 1,105 27.1 27.5 Minnesota 3.023 25.3 25.0 Missouri 673 29.4 23.0 Montana 1,176 23.5 22.6 Sew Mexico 1,139 29.9 22 4 New York 1,135 26.7 26.1 North Carolma 1,622 30.7 22.5 North Dakota 1.182 27.4 25.1 Ohio 1.158 29 4 26.9 Rhode Island 1,535 31.0 31.1 South Carolina 1,793 28.6 24 4 Tennessee 1.779 30.7 25.5 Urah 1,188 208 15.1 West I'Lgmia 1.380 32.2 26.9 Wisconsin 1,268 31.5 21.1 24.6 -24.1 24.5 k2.8 24.6 12.4 26.7 k3.1 29.3 f2.8 26.7 rt2.9 24.1 22.9 23.4 k-2.6 27.9 k2.8 27.3 23.0 34.8 +3.2 27.3 k3.0 25.1 k1.7 26.0 23.3 23.0 22.7 26.1 k2.8 27.4 23.0 26.4 k2.4 26 2 22.9 28.1 k2.8 30.9 t2.5 26.3 +2.4 28.0 k2.4 17.8 k2.5 29.5 22.8 26.2 r2.6 SOURCE: US DHHS 1198iai high school seniors. This approach does not include students who do not complete high school (estimated to be about 15 percent of the population by the U.S. Bureau of Census in 1978). Dropouts tend to have a higher smoking prevalence than in-school students (Kandel 1980; Pirie, Murray, Luepker 1988); however, Johnston and O'Malley (1985) estimate that the underestimate of the true popula- tion prevalence is no more than 5 percentage points. The latter researchers argue that the magnitude of this bias is unlikely to change between the yearly surveys; thus, the estimate of the rate of change should reflect the true rate of population change. Smoking prevalence among female high school seniors was higher than among males in 1986 (Table 81, and there are marked 574 TABLE `I.-Prevalence (percentage) of cigarette use among youth 12 to 17 years of age, 1979, 1982, 1985 surveys, United States Survey year 1979 ' 1982 Any use in Used I" !ast last year 30 days 13.3 1' 1 24.8 14 7 TABLE &-Thirty-day prevalence of daily use of cigarettes by subgroups, high school class of 1986 Percentage who used qaettes daily in last :jO dnxs Subgroups s 1approx ) One or ","I? All seniors 15.200 sex Me" 7.100 Women l.ioo college plans None or under 4 wars 5.100 Complete 4 fears 9.100 Region Northeast 3.600 North-central 4.300 South 4.7cK! west 2.600 SOURCE: Johnston. O'Malley. Bachmar. !195:1 18.i 11.4 16.Y 10.: 19.8 116 28.2 19 2 12.8 64 24.9 15.6 19 9 12.3 15 8 10.0 I3 4 6.5 geographic differences in smoking prevalence among students. In addition, those students who plan to complete 4 years of college have a smoking rate less than half that of students without such plans. The prevalence of daily use within the previous 30 days among high school seniors fell substantially from 1975 to 1986 for males and females (Figure 2). Since 1976, there has been an overall 35 percent reduction in smoking prevalence in this population. Most of this decline occurred between 1977 and 1981. For all students, the prevalence has fallen an average of 0.68 percentage points per year during this period (to 18.7 percent in 19861, similar to the rate of 575 "[ - Any daily use \ r1/2 pack daily o Men 0 Women FIGURE 2.-Trends in 3May prevalence of daily cigarette use (smoking one or more cigarettes/day) among high school seniors, by sex SOURCE Johnston. O'Malley. Bachman (1987). decline noticed in adults (see Tables 1, 3). However, the rate of decline has tapered off in recent years. The smoking rates among females have consistently exceeded the rates among males. The Monitoring of the Future Project has also followed representa- tive samples from each graduating class since 1976. This was done by selecting two matched panels from each graduating class and following each panel in alternate years. The data obtained from these surveys are presented in Figure 3. Recently, differences in prevalence of any cigarette smoking within the last 30 days has disappeared between those still in high school and those who have graduated, suggesting that far fewer young adults are taking up smoking after high school, and that most uptake has occurred by the time of high school graduation. However, when either the 30day prevalence of daily use or the 30-day prevalence of the use of half a pack or more per day is considered, there is a clear marked increase in smoking prevalence in the early years after high school, suggest- ing that occasional and experimenting high school smokers become regular smokers once they leave school. Trends in the Proportion of Smokers Who are Heavy Smokers The average reported number of cigarettes smoked per day in 1985 by age, race, and sex is presented in Table 9. There are marked differences between the black and white population in the number of cigarettes reported. Both black males and females report smoking one-third fewer cigarettes per day than do their white counterparts. Even though blacks smoke fewer cigarettes per day than whites, their smoking patterns and choices of brands may provide the nicotine content necessary to maintain daily blood nicotine levels similar to whites (Chapter VII; Cummings, Giovino, Mendicino 1987). Across all race and age categories, females report smoking fewer cigarettes than males. In the over 35 age groups this difference is approximately 20 percent. Successful quitting behavior may not be uniform across all smokers. Heavy smokers (defined as those who report smoking 25 or more cigarettes per day) are more likely to have a strong nicotine dependence (Chapter IV) and, therefore, are less likely to be successful at quitting than lighter smokers. Thus, one would expect the cross-sectional surveys over time to indicate an increasing proportion of heavy smokers as the smoking prevalence declined. These data from self-reported consumption measures are presented in Table 10. The percentage of heavy smokers reported by the 1965 survey may be biased due to the use of proxy interviews which were not used in subsequent surveys. Between 1976 and 1985, there was no substantial change in the proportion of smokers reporting smoking 25 or more cigarettes per day. In 1985, approximately one-third of all male smokers and one- fifth of all female smokers were classified as heavy smokers. Three times as many white as black adults were classified as heavy smokers. For both males and females, the proportion peaked in the group aged 35 to 44, possibly indicative of a higher mortality rate among older smokers. Trends in Quitting Activity Public health efforts to reduce the prevalence of smoking concen- trate on reducing the proportion of the population that begins to smoke cigarettes as well as increasing the proportion of smokers who quit. One indicator of quitting activity is the prevalence of former smokers. However, this variable is of limited use due to marked 577 40 - 30 - Pi 2 & 20- c: B lo- Years bevond h CI ,hrc hwl o ?????? !n.odal age ia) A 1.2Yea:s (maaalage 19-20) 0 3.4 Years modal a9e 21-Z) o 5-6 Years (mood age 23-24) 0 7-E Years (modal age 25-26) 0 9.10 Years (modal ac,e 27-W 40- 30 - $ i!? E 20- 0 h 10 - . . . 76 77 78 79 80 it 8; 83 84 85 86 Year Daily use 0' I 1 1 1 I I I 1 . 1 1 76 77 78 79 80 81 82 83 64 85 66 Year 40- 30 - 0) 9 z al- 0 d 10 - 2 Half-pack/day o' , r r , r r r . . r r 76 77 78 79 80 81 02 83 84 05 86 YE% FIGURE 3.-Trends in 30-day cigarette smoking prevalence, daily use, and use of a half-pack or more per day among young adults, by age group SOURCE Johnston. O'hlalley. Bachman 11987). 578 TABLE R-Average number of cigarettes smoked per day by current smokers, by race, age, and sex, united states, 1985 h/Age Men Women Difference All races 21.8 18.1 3.7 BladU 14.7 13.5 1.2 Whites 23.4 19.1 4.5 18-24 17.2 15.3 1.9 2534 20.3 18.0 2.3 3a44 24.3 20.1 4.2 4554 24.7 19.9 4.8 !55-64 23.9 18.0 5.9 265 20.2 16.0 4.2 SXJRCX: National Center for Health Statistica, National Health Interview Survey 1985 TABLE IO.-Twenty-year trends in the proportion of smokers reporting smoking 26 or more cigarettes per day, by sex, race, and age, united states ser. race, age 1965 1976 1980 1985 24.1 30.7 34.2 32.8 Bate White Black he !20-24 2x34 35-44 45-64 265 Women Total Bace White Black Age 20-24 25-34 3544 4544 265 28.0 33.3 37.3 36.5 8.6 10.8 13.8 10.7 15.4 18.5 19.8 17.1 24.3 `28.7 30.1 28.5 31.5 39.2 40.7 42.3 28.0 37.4 42.6 39.3 13.8 18.2 25.2 25.4 13.0 13.9 20.9 25.2 22.8 4.6 5.6 8.6 6.7 9.1 14.5 15.9 12.2 15.5 20.5 24.2 21.3 17.1 21.8 32.7 27.8 13.6 21.5 24.9 22.7 6.4 11.8 13.1 13.4 19.0 23.2 20.6 SCNJRCR: National Center for Health Statistics, National Health Interview Surveys 1965, 1976, 198i), 1986. 579 differences in uptake of cigarettes between males and females in different birth cohorts (Warner and Murt 1982). A more meaningful index of quitting behavior has been defined as the quit ratio (Pierce, Aldrich et al. 1987tthe proportion of former smokers in a given population divided by the proportion of that population who have ever been smokers. Trends in this quit ratio are presented in Figure 4. The quit ratio has consistently been higher among men compared with women. Quit ratios among both males and females increase with age. In 1985, nearly one-third of those persons aged 25 to 34 who reported that they had ever smoked had quit smoking by 1985. Among those aged 65 or older, the quit ratio was over 60 percent for women and 70 percent for men. Moreover, over the last 20 years, successful quitting activity has been increasing in all age groups. The quit ratio differences between men and women increased with age from 1965 to 1985 (several possible explanations for this phenomenon exist; see Chapter VII). Trends in Cigar, Pipe, and Roll-Your-Own Cigarette Smoking Figure 5 shows 20-year trends in pipe and cigar smoking among adult males. For both tobacco products, there has been an 80 percent decline in prevalence. In fact, cigar smoking in 1964 (30 percent) was as prevalent as cigarette smoking in 1985 (30.4 percent). Hand-rolled cigarettes are the least expensive cigarettes to con- sume. According to the 1986 Adult Use of Tobacco Survey, only 0.4 percent of smokers aged 17 and older use roll-your-own cigarettes (US DHHS 1988). Trends in Smokeless Tobacco Use The prevalence of both snuff and chewing tobacco use by younger men has increased substantially between 1970 and 1986, as shown in Figure 6. Among women, use of smokeless tobacco products de- creased between 1970 and 1986, but prevalence of use in this group has always been low. In 1986, less than 0.4 percent of females used snuff or chewing tobacco, whereas 8.2 percent of men used these products (Novotny and Lynn, in press). Additionally, among men, almost half of current users reported initiation of smokeless tobacco use before age 17 (Table 11). In 1985, the NIDA National Household Survey of persons 12 years of age and older found that 12 percent of men and 1 percent of women used chewing tobacco, snuff, or other kinds of smokeless tobacco in the year of the survey. Smokeless tobacco use rates were highest among young males (12-25 years old) who were residents of nonmetropolitan areas (Rouse, in press). 580 Age 20 24, Age 25 34 8o 11 70 j 0 Men 9 Men + Women 9 Women 60 I &so- -m g 40 i,v Ol.,.,.,.,.,.,.,.,.,.,. 64 66 68 70 72 74 76 78 80 82 84 86 1964 - 1986 64 66 68 70 72 74 76 76 80 82 84 86 1964 1966 80 I Age 45 64 o!,,.,.,.,.,.,.,.,.,.,. 64 66 66 70 72 74 76 78 80 82 84 86 1964 1986 20 - . 0 Men lo- + Women 0 .,.,.,.,.,.,.,.,.,.,C 64 66 68 70 72 74 76 76 80 82 84 86 1964 1986 FIGURE 4.-Quit ratios (ratios of former smokers to ever smokers), by age and sex, 1965-1985 SOURCE: US DHHS (1986bl The BRFSS collected data from 25 States and the District of Columbia in 1986. In this survey, smokeless tobacco use among men ranged from 0.7 percent in New York to 21.4 percent in West Virginia (median State prevalence, 6.5 percent) (US DHHS 1987b). In addition, there was a regional pattern of use, with highest 581 80 70 60 64 0 Cigarette O Cigar O Pipe L 86 1964 - 1986 FIGURE 5.-Trends in prevalence of cigarettes, cigars, and pipes, adult men, 1964-1986 SOURCE US. PHS 11970. 1975. 19861, US DHHS (1987~~). prevalence found in Southern and North Central States, just as in the NIDA survey mentioned above. Summary and Conclusions 1. An estimated 32.7 percent of men and 28.3 percent of women smoked cigarettes regularly in 1985. The overall prevalence of smoking in the United States decreased from 36.7 percent in 1976 (52.4 million adults) to 30.4 percent in 1985 (51.1 million adults). 2. In 1985, the mean reported number of cigarettes smoked per day was 21.8 for male smokers and 18.1 for female smokers. 3. Smoking is more common in lower socioeconomic categories (blue-collar workers or unemployed persons, less educated persons, and lower income groups) than in higher socioeconom- ic categories. For example, the prevalence of smoking in 1985 among persons without a high school diploma was 35.4 percent, compared with 16.5 percent among persons with postgraduate college education. 582 7 6 5 5 4 E 8 $3 1970 2- 1.2 r-l Chewing tobacco 6.5 u El Snuff 2.0 1.9 r 1 - Age +I 1986 4 -I 2.7 4.2 FIGURE B.-Prevalence of chewing tobacco and snuff use among men, 1970 and 1986 SOURCE C S DHHS `1986a, Sorotn> and Lynn tan pm6 583 TABLE Il.-Reported age at initiation, by current smokeless tobacco users (percentage), both sexes, 1986, United States Age at imtiatlon An?; smokeless tobacco Chewmg tobacco Snuff < 17years 44.3 42.5 43.5 17-24 years 37.9 27.3 35.1 2 25 years 17.8 30.2 21.4 SOURCE Novotny and Lynn i,n press,. 4. An estimated 18.7 percent of high school seniors reported daily use of cigarettes in 1986. The prevalence of daily use of one or more cigarettes among high school seniors declined between 1975 and 1986 by approximately 35 percent; the smoking prevalence among females has consistently been slightly higher than among males. Most of the decline occurred between 1977 and 1981. 5. The use of cigars and pipes has declined 80 percent since 1964. 6. Smokeless tobacco use has increased substantially among young men and has declined among older men since 1975. An estimated 8.2 percent of 17- to 19-year-old men were users of smokeless tobacco products in 1986. 584 References CUMMINGS, K.M., GIOVINO, G., MENDICINO, A.J. Cigarette advertising and black-white differences in brand preference. Public Health Reports 102(6):69%701, November-December 1987. DAVIS, R.M. Current trends in cigarette advertising and marketing. New England Journal of Medicine 316(12):725-732, March 19, 1987. FORTMANN, S.P., ROGERS, T., VRANIZAN, K., HASKELL, W.L., SOLOMON, D.S., FARQUHAR, J.W. Indirect measures of cigarette use: Expired-air carbon monox- ide versus plasma thiocyanate. Preventive Medicine 13(1):127-135, January 1984. HAYNES, S. The impact of cigarette smoking on minority populations. Presentation to the Federal Interagency Committee on Smoking and Health. Washington, D.C., March 31, 1987. JOHNSTON, L.D., O'MALLEY, P.M. Issues of validity and population coverage in student surveys of drug use. In: Rerse, B.A., Koxel, N.J., Richards, L.G. (eds.) Self Report Methods of Estimating Drug Use: Meeting Current Challenges to Validity, NIDA Research Monograph 57. U.S. Department of Health and Human Services, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse. DHHS Publication No. (ADM) 85-1402, 1985. JOHNSTON, L.D., O'MALLEY, P.M., BACHMAN, J.G. National Trends in Drug Use and Related Factors Among American High School Students and Young Adults, 1975-66. U.S. Department of Health and Human Services, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse. DHHS Publication No. (ADM) 87-1535, 1987. KANDEL. D.B. Drug and drinking behavior among youth. Annual Review of Sociology 61235-285, 1980. KOZLOWSKI, L.T. Pack size, self-reported smoking rates and public health. American Journal of Public Health 76(11):1337-1338, November 1986. KOZLOWSKI, L.T. Less hazardous smoking and the pursuit of satisfaction. American Journal of Public Health 77(5):539-541, May 1987. MARCUS, A.C., CRANE, L.A. Smoking behavior among US Latinos: An emerging challenge for public health. American Journal of Public Health 75(2):169-172, February 1985. MARCUS, A.C., CRANE, L.A. Use of Tobacco in the United States: Recent Estimates from the Current Population Suruey. Unpublished manuscript, 1987. NOVOTNY, T.E., WARNER, K.E., KENDRICK, J.E., REMINGTON, P.L. Socioeco- nomic factors and racial smoking differences in the United States. American Journal of Public Health, in press. NOVOTNY, T.E., LYNN, W. Smokeless tobacco use in the United States, 1970-86. Proceedings of the Sixth World Conference on Smoking and Health, November 912, 1987, in press. PETI'ITI, D.B., FRIEDMAN, G.D., KAHN, W. Accuracy of information on smoking habits provided on self-administered research questionnaires. American Journal of Public Health 71(3):308-311, March 1981. PIERCE, J.P., ALDRICH, R.N., HANRATTY, S., DWYER, T., HILL, D. Uptake and quitting smoking trends in Australia 1974-1984. Preventive Medicine 16(2):252-260, March 1987. PIERCE, J.P., DWYER, T., DIGIUSTO, E., CARPENTER, T., HANNAM, C., AMIN, A., YONG, C., SARFATY, G., SHAW, J., BURKE, N. Cotinine validation of self- reported smoking in commercially run community surveys. Journal of Chronic Diseases 40(7):689-f395, 1987. PIRIE, P.L., MURRAY, D.M., LUEPKER, R.V. Smoking prevalence in a cohort of adolescents, including absentees, dropouts, and transfers. American Journal of Public Health 78(2):176-178, February 1988. POJER, R.. WHITFIELD, J.B., POULOS, V., ECKHARD, I.F., RICHMOND, R., HENSLEY, W.J. Carboxyhemoglobin, cotinine, and thiocyanate assay compared for distinguishing smokers from non-smokers. Clinical Chemistry 30(8):1377-1380, 1984 ROUSE, B. Epidemiology of smokeless tobacco use: A national study. Journal of the National Cancer Institute. in press. THORNBERRY, O.T. An experimental comparison of telephone and personal health interview surveys. Data Evaluation and Methods Research, Series 2, No. 106. DHHS Publication No. fPHS) 87-1380. 1987. TOBACCO INSTITUTE. The Tax Burden on Tobacco, Volume 21. Washington, D.C.: The Tobacco Institute, 1986. U.S. DEPARTMENT OF AGRICULTURE. Tobacco Situation and Outlook. U.S. Department of Agriculture, Economics, Statistics, and Cooperatives Service. September 1986. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse- quences of Smoking: The Changing Cigarette. A Report of the Surgeon General. U.S. Department of Health and Human Services, Public Health Service, Office on Smoking and Health. DHHS Publication No. (PHS) 81-50156, 1981. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. Why People Smoke Cigarettes. US. Department of Health and Human Services, Public Health Service, 1983. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse- quences of Using Smokeless Tobacco. A Report of the Advisory Committee to the Surgeon General. NIH Publication No. 86-2874. Department of Health and Human Services, Public Health Service, National Institutes of Health, April 1986a. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. National Center for Health Statistics: Health. United States, 1986. U.S. Department of Health and Human Services, Public Health Service. DHHS Publication No. (PHS) 87-1232, December 1986b. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. Behavioral risk factor surveillance-selected states, 1986. Morbidity and Mortality Weekly Report 36(161:252-254, May 1, 1987a. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. Smokeless tobacco use in the United States: Behavioral risk factor surveillance system, 1986. Morbidity and Mortality Weekly Report 36(22):337-340, June 12, 1987b. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. Cigarette smoking in the United States, 1986. Morbidity and Mortality Weekly Report 36(35):581-585, September 11, 1987c. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. Regional variation in smoking, prevalence and cessation: Behavioral risk factor surveillance, 1986. Morbidity and Mortality Weekly Report 36(45):751-754, November 20, 1987d. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. Adult Use of Tobacco, 1986. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, Office on Smoking and Health. In press. U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE. Adult Use of Tobacco, 1970. U.S. Department of Health, Education, and Welfare, Public Health Service, Center for Disease Control, National Clearinghouse for Smoking and Health, June 1973. U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE. Adult Use of Tobacco, 1975. U.S. Department of Health, Education, and Welfare, Public Health Service, Center for Disease Control, National Clearinghouse for Smoking and Health, 1976. U.S. FEDERAL TRADE COMMISSION. Staff report on the cigarette advertising investigation. U.S. Federal Trade Commission, May 1981. 586 U.S. FEDERAL TRADE COMMISSION. Report to Congress pursuant to the Federal Cigarette Labeling and Advertising Act, 1985. U.S. Federal Trade Commission, February 1988. U.S. TOBACCO COMPANY. Annual Report 1986. Greenwich, Connecticut: United States Tobacco Company, 1986. WAKSBERG, J. Sampling methods for random digit dialing. Journal of the American Statistical Association 73(361):40-46, March 1978. WARNER, K. E. Possible increases in the underreporting of cigarette consumption. Journal of the American Statistical Association 73(362):314-318, June 1978. WARNER, K.E., MURT, H.A. Impact of the antismoking campaign on smoking prevalence: A cohort analysis. Journal of Public Health Policy 3(43:374-390, December 1982. 587 APPENDIX B TOXICITY OF NICOTINE 589 CONTENTS Introduction ........................................................ .593 Acute Intoxication. ................................................ 593 Chronic Nicotine Toxicity .................... Cardiovascular Disease .................. Hypertension ............................... Wound Healing ............................ Reproductive Hazards .................... Teratogenicity ....................... Pregnancy ............................ Pulmonary Toxicity ....................... Genotoxicity and Carcinogenicity ..... Gastrointestinal Disease ................. ...... ...... ...... ...... ...... ...... ...... ...... ...... ...... ..,,.. . . . . . . .*,... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...*. . . . . . . * . . 596 . . 596 . . . 600 . . . 601 . . . 601 . . . 601 . . . 602 . 603 . . 604 . . . 605 Summary and Conclusions ...................................... 607 References ........................................................... 609 591 introduction Knowledge of the toxicity of nicotine is important to help understand tobacco-induced human disease as well as to assess the potential risks associated with the therapeutic use of nicotine (e.g., nicotine polacrilex gum) as an aid to assist smoking cessation. This Appendix provides a brief overview of the toxic actions of nicotine per se, focusing on human studies wherever possible and selecting only those animal data which have direct implications in understanding mechanisms of human disease. The toxicity of cigarette smoke has been extensively reviewed in prior Surgeon General's reports (US DHHS 1982, 1983, 1984, 1985, 1986). In most cases the pathogenesis of tobacco-related diseases, including the role of nicotine, has not been fully elucidated. Therefore the potential contribution of nicotine to development of tobacco-related disease, even if unproved, will be considered. The chemistry and general pharmacology of nicotine have been reviewed in previous chapters (Chapters II and III) of this report and are not presented in detail in this Appendix. An appreciation of the basic pharmacologic actions of nicotine is, however, a necessary foundation for understanding the issues of toxicity which are discussed in this Appendix. Acute Intoxication As discussed in Chapter II, nicotine is a water and lipid soluble drug which, in the free base form, is readily absorbed via respiratory tissues, skin, and the gastrointestinal tract. Nicotine may pass through skin OF mucous membranes when in alkaline solutions, in which circumstance nicotine is primarily un-ionized. In experimental animals, the dose of nicotine which is lethal to 50 percent of animals (LD,,) varies widely, depending on the route of administration and the species used. Intravenous (i.v.) LD,, doses of nicotine in mice range between 0.3 to 1.8 mg/kg body weight (Borzelleca, Norman, McKennis 1962; Lindner 1963; Wirth and Gosswald 1965; Barlow and McLeod 1969). The intraperitoneal (ip.) LD,, values for nicotine bitartrate in mice and rats have been found to be 13 and 83 mg/kg body weight, respectively, while the values for five inbred hamster strains varied between 125 to 320 mglkg body weight (Bernfeld and Homburger 1972). The wide variation in sensitivity to the toxic effects of nicotine in rodents appears to be genetically determined (Garg 1969; Marks, Burch, Collins 1983; Miner, Marks, Collins 1984). In interpreting animal toxicity data it is important to recognize that the rate of administration is an important determinant of toxicity. Rapid i.v. injections result in the highest blood and brain concentrations and produce toxicity at the lowest doses. In contrast, 593 with oral or i.p. administration higher doses are required to produce toxicity. This is due to presystemic ("first pass") metabolism of nicotine and the gradual time course of absorption as compared with after i.v. dosing. With intermittent dosing, such as practiced by smokers, the total dose of nicotine absorbed per day could exceed the toxic or even lethal dose of a single injection. In humans, acute exposure to nicotine even in low doses (similar to the amounts consumed by tobacco users) elicits autonomic and somatic reflex effects as described in detail in Chapters II and III. Dizziness, nausea, and/or vomiting are commonly experienced by nonsmokers after low doses of nicotine, such as when people try their first cigarette. However cigarette smokers rapidly become tolerant to these effects (Chapter II). A number of poisonings and deaths from ingestion of nicotine, primarily involving nicotine-containing pesticides, have been report- ed in humans (Beeman and Hunter 1937; McNally 1923; Franke and Thomas 1936; Saxena and Scheman 1985). The lethal oral dose of nicotine in adults has been quoted to be 40 to 60 mg (Goldfrank, Melinek, Blum 1980; Larson, Haag, Silvette 19611, but it has not been well documented. Nicotine intoxication produces nausea, vomiting, abdominal pain, diarrhea, headaches, sweating, and pallor. More severe intoxication results in dizziness, weakness, and confu- sion, progressing to convulsions, hypotension, and coma. Death is usually due to paralysis of respiratory muscles and/or central respiratory failure. Dermal exposure to nicotine can also lead to intoxication. Such exposures have been reported after spilling or applying nicotine- containing insecticides on the skin or clothes (Lockhart 1933; Faulkner 1933; Benowitz et al. 1987) and as a consequence of occupational contact with tobacco leaves. Green tobacco sickness, an occupational illness in field workers harvesting tobacco leaves, has been attributed to dermal absorption of nicotine found in the dew on tobacco leaves (Weizenecker and Deal 1970; Gehlbach et al. 1974). The levels of cotinine in the urine of exposed workers exceed those of novice smokers who had smoked three cigarettes in succession (Gehlback et al. 1975). The symptoms of green tobacco illness are described in Table 1 (Gehlbach et al. 1975; Gehlbach, Williams, Freeman 1979). A similar syndrome has been reported in Asian Indian tobacco workers who harvest green tobacco leaves and handle cured tobacco (Ghosh et al. 1979). Tobacco harvesters who use tobacco products, either in the forms of cigarettes or smokeless tobacco, are usually not affected by green tobacco sickness owing to development of tolerance to nicotine (Gehlbach et al. 1974). Tolerance to the toxic effects may even develop during the course of nicotine poisoning, despite the persis- 594 TABLE l.-Symptoms of systemic nicotine poisoning (Green Tobacco Sickness) Symptom Nausea, vomiting Pallor Weakness Dizziness, hghtheadedness Headache Sweating Abdominal pain Chills Increased salivation SOURCE Adapted from Gehlbach et al 119741 Pt?KZelltage I53 Casesl 98 89 81 81 81 56 42 36 17 tence of nicotine in the blood at extremely high concentrations (200 to 300 ng/ml) (Benowitz et al. 1987). Acute intoxication may occur in children following ingestion of tobacco materials. Four children, each of whom ingested two cigarettes, developed salivation, vomiting, diarrhea, tachypnea, tachycardia, and hypertension within 30 min; followed by depressed respiration and cardiac arrhythmia within 40 min; and convulsions within 60 min (Malizia et al. 1983). All recovered and suffered no complication. Another six children who ingested one-half of a cigarette experienced salivation and vomiting only. In a Swedish report (Werner 19691, 355 children who ingested tobacco had only very mild symptoms. Severe poisoning has occurred in children who swallowed tobacco juice (expectorated by tobacco chewers). Although ingestions of tobacco are common, deaths due to ingestion of tobacco are extremely rare, due to early vomiting and first pass metabolism of the nicotine which is absorbed. Conceivably, intoxication from nicotine polacrilex gum could occur after accidental use by children or nonsmokers, or if an ex-smoker gum-user consumed several pieces at once or in rapid succession. One case report describes a smoker who developed apparent symp- toms of nicotine intoxication within 1 min of chewing a piece of 2-mg gum (Mensch and Holden 1984). However, based on the known absorption kinetics and the amount of nicotine in the gum, true nicotine intoxication is unlikely in this case. Swallowing nicotine polacrilex gum appears not to be of concern for development of toxicity. Although 30 to 85 percent of the nicotine content can be released from the gum into the gastrointestinal tract, the chances of nicotine intoxication are quite low because nicotine is 595 released slowly (transit time of the gums through the gastro-intesti- nal tract is 16 to 48 hr) (Brantmark and Fredholm 1974), and because the nicotine which is released undergoes extensive presystemic metabolism. Simultaneous ingestion of 10 unchewed pieces of 4-mg gum resulted in a peak blood concentration of nicotine of less than 10 ng/ml (Brantmark and Fredholm 1974), which is similar to the level attained by a smoker after smoking a single cigarette. Chronic Nicotine Toxicity As attested to in the Surgeon General's reports since 1964, smoking causes coronary and peripheral vascular disease (1983), cancer (1982), chronic obstructive lung disease (1984), peptic ulcer disease, and reproductive disturbances, including prematurity (1980). Tobacco smoke is a complex mixture of chemicals, including carbon monoxide, many of which have been implicated in human disease. Nicotine may contribute to tobacco-related disease, but direct causation has not been determined because nicotine is taken up simultaneously with a multitude of other potentially harmful substances that occur in tobacco smoke and smokeless tobacco. However, particularly now that nicotine per se may be prescribed in the form of gum or other delivery systems, the potential health consequences of chronic nicotine exposure deserve careful consider- ation. Cardiovascular Disease Smoking causes coronary and peripheral vascular disease (US DHHS 1983). Both nicotine and carbon monoxide may contribute to atherosclerotic vascular disease (Figure 1). Nicotine could contribute both to the atherosclerotic process and to acute coronary events by several mechanisms. Nicotine could promote atherosclerotic disease by its actions on lipid metabolism and coagulation, by hemodynamic effects, and/or by causing endothelial injury. Compared to nonsmok- ers, cigarette smokers have elevated low-density (LDL) and very-low- density lipoproteins (VLDL), as well as reduced high-density lipopro- tein (HDL) levels (Criqui et al. 1986; Brischetto et al. 1983), a profile associated with an increased risk of atherosclerosis. Chronic oral nicotine feeding has been shown to increase LDL in monkeys (Cluette-Brown et al. 1986). In one patient the use of nicotine polacrilex gum was reported to increase serum total and LDL cholesterol and triglycerides (Dousset, Gutierres, Dousset 1986). Nicotine may act by releasing free fatty acids, enhancing the conversion of VLDL to LDL, impairing the clearance of LDL and/or by accelerating the metabolism of HDL (Brischetto et al. 1983; Cluette-Brown et al. 1986; Gnasso et al. 1986; Hojnacki et al. 1986). 596 DIsturbed hpld hypercoagulability I Reduced myocardfal 02 SUPP'Y FIGURE l.-Smoking, nicotine, and coronary heart disease SOURCE Benowtz 11986dl Thrombosis is believed to play an important role in atherogenesis (Mehta and Mehta 1981). Platelets may release a growth hormone which promotes the growth of vascular endothelial cells, contribut- ing to the atherosclerotic plaque (Packham and Mustard 1986). The blood of smokers is known to coagulate more readily than the blood of nonsmokers (Billimoria et al. 1975). According to several studies, platelets of smokers are more reactive, and have a shorter survival than those of nonsmokers (Belch et al. 1984; Siess et al. 1982; Mustard and Murphy 1963). The importance of nicotine as a determinant of platelet hyperaggregability is supported by a study showing that the blood concentrations of nicotine, after smoking different cigarettes, correlated with the platelet aggregation re- sponse (Renaud et al. 1984). Nicotine could affect platelets by increasing the release of epinephrine, which is known to enhance platelet reactivity, by inhibiting prostacyclin, an antiaggregatory hormone secreted by endothelial cells, or perhaps directly (Cryer et al. 1976; Sonnenfeld and Wennmalm 1980). Alternatively, by in- creasing heart rate and cardiac output and thereby increasing blood turbulence or by direct action nicotine may promote endothelial injury. Structural damage and increased mitotic activity in the aortic endothelial cells of nicotine-treated animals have been reported (Booyse, Osikowicz, Quarfoot 1981; Zimmerman and McGeachie 1985, 1987). Nicotine has also been shown to modulate the structural and functional characteristics of cultured vascular cells (Csonka et al. 1985; Thyberg 1986). In rats, nicotine given i.v. or per OS p.o. produced dose-dependent increases in circulating anuclear carcasses of endothelial cells (Hladovec 1978). In support of the relevance of animal or in vitro studies to humans, Davis and colleagues (1985) reported an increase in the number of endothelial cells found in venous blood (reflecting endothelial injury) and a decrease in the platelet aggregate ratios (reflecting platelet aggregation) in non- smokers who smoked tobacco but not nontobacco (made from wheat, cocoa, and citrus plants) cigarettes. The above findings suggest that some substance unique to tobacco, such as nicotine, may contribute to the pathogenesis of atherosclero- sis and complications of atherosclerotic vascular disease. Although several potential mechanisms by which nicotine may promote atherogenesis have been considered, nicotine has not been demon- strated to produce or accelerate atherosclerosis in experimental animals. Wald and colleagues (1981) have presented an argument against the role of nicotine in promoting coronary heart disease in that pipe smokers, who consume comparable amounts of nicotine and have similar levels of nicotine but lower levels of carbon monoxide in the blood as cigarette smokers, do not share the same magnitude of increased risk for coronary heart disease. However, the possibility that nicotine inhaled in cigarette smoke, either due to rapid absorption or effects on pulmonary afferent nerves, affects the cardiovascular system differently than nicotine absorbed more slowly through mucous membranes must be considered (Benowitz and Jacob 1987). Based on its pharmacologic actions, it is likely that nicotine plays a role in causing or aggravating acute coronary events. Myocardial infarction can be due to one or more of three precipitating factors - excessive oxygen and substrate demand, thrombosis, and coronary spasm. Nicotine increases heart rate and blood pressure and, therefore, myocardial oxygen consumption. Carbon monoxide in- haled in cigarette smoke reduces the oxygen carrying and releasing capacity of the blood. When a healthy person smokes a cigarette, coronary blood flow increases to meet the increased demand (Nicod et al. 1984). In the presence of coronary artery stenosis, coronary blood flow cannot increase and ischemia may develop, resulting in angina pectoris, myocardial dysfunction, or myocardial infarction (Jain et al. 1977). Nicotine may also directly reduce the increase in coronary blood flow which occurs in response to increased metabolic demand, or even cause an inappropriate decrease in coronary blood 598 flow, so that flow no longer matches increased myocardial oxygen consumption (Kaijser and Berglund 1985; Klein et al. 1984; Nicod et al. 1984; Martin et al. 1984). The decrease in coronary blood flow with smoking appears to result from alpha-adrenergically mediated coronary vasoconstriction, due to sympathetic activation and/or increased circulating catecholamines, either of which is likely to be an effect of nicotine (Winniford et al. 1986). Chronic nicotine exposure has been reported to increase the size of experimentally induced myocardial infarcts in dogs (Sridharan et al. 1985). Nicotine consumed in the form of nicotine gum has been studied in patients with coronary artery disease. Nicotine gum (4-mg) increased myocardial contractility in healthy people, but in patients with coronary artery disease nicotine gum decreased contractility in the ischemic regions of the myocardium, consistent with aggravation of ischemia (Bayer, Bohn, Strauer 1985). In the most severe cases of coronary artery disease, overall contractility decreased after nic- otine polacrilex gum. This study supports the idea that nicotine contributes to smoking-induced myocardial ischemia in susceptible people. In addition to creating an imbalance between myocardial oxygen supply and demand, nicotine may promote thrombosis, as discussed previously. Nicotine may also induce coronary spasm by sympathetic activation or inhibition of prostacyclin. Coronary spasm has been observed during cigarette smoking (Maouad et al. 1984). Sudden cardiac death in smokers might result from ischemia, as discussed above, combined with the arrhythmogenic effects of increased amounts of circulating catecholamines released by nic- otine. However, smoking has not been demonstrated to increase the prevalence or magnitude of ventricular ectopy in patients with ischemic heart disease (Davis et al. 1985; Meyers et al. 1988). Cigarette smoking, most likely mediated by nicotine, facilitates AV nodal conduction, which could result in an increased ventricular response during atria1 fibrillation (Bekheit and Fletcher 1976; Peters et al. 1988). Thus, even if the frequency of arrhythmias is not increased by smoking, the actions of nicotine may render those arrhythmias which do occur more life-threatening. With respect to the arrhythmogenicity of nicotine, two case reports are of note. The first concerns a man who developed atria1 fibrillation with a rapid ventricular response rate (150) while chewing 30 pieces of 2-mg nicotine polacrilex gum per day (Stewart and Catterall 1985). The other case was that of a man with known paroxysmal atria1 fibrillation who developed a recurrence 5 min after chewing the day's first piece of nicotine gum (Rigotti and Eagle 1986). Cigarette smoking has been associated with an increased risk of cardiomyopathy, that is a generalized reduction in contractility of 599 heart muscle (Hartz et al. 19843. Cigarette smoke exposure induces cardiomyopathy in rabbits (Gvozdjakova et al. 1984). A role of nicotine is suggested by a study in which dogs received injections of nicotine fbr 2% months and developed impaired contraction of the heart muscle with evidence of some interstitial fibrosis on anatomi- cal examination (Ahmed et al. 1976). Exercise tolerance in patients with intermittent claudication improves after stopping cigarette smoking (Jonason and Bergstrom 1987; Quick and Cotton 1982). Nicotine could aggravate peripheral vascular disease by constricting small collateral arteries and/or by inducing local t.hrombosis. The effect of nicotine replacement therapy on symptoms of peripheral vascular disease, as on exercise tolerance, in comparison to cigarette smoking, requires further investigation. On balance, short-term nicotine administration, such as nicotine replacement therapy as an adjunct to smoking cessation therapy, presents little cardiovascular risk to healthy individuals. Patients with coronary or peripheral vascular disease are likely to suffer some increase in risk when taking nicotine, but considerably less risk than with cigarette smoking, which exposes them also to both carbon monoxide and higher levels of nicotine. Hypertension Although cigarette smoking and nicotine per se increase blood pressure, cigarette smoking alone is not a risk factor for chronic hypertension (Green, Jucha, Luz 1986). Conceivably, factors such as lower body weight or altered dietary intake, which may be associated with cigarette smoking, might lower blood pressure to compensate for any blood pressure elevation due to nicotine. However, progression of chronic hypertension to accelerated or malignant hypertension is much more likely in cigarette smokers (Isles et al. 1979; Petitti and Klatsky 1983). Nicotine could contribute to this progression by aggravating vasoconstriction, either via sympathetic activation or inhibition of prostaglandin synthesis. Animal studies indicate that nicotine may reduce renal blood flow which, in a patient with marginal renal blood flow due to hyperten- sive vascular disease, could cause renal ischemia and aggravate hypertension (Downey, Crystal, Bashour 1981). Thus, there is concern about nicotine replacement therapies in patients with severe hypertension. Tobacco, most likely due to effect of nicotine, may interact with particular hypertensive diseases. For example, a patient with pheochromocytoma (a catecholamine-secreting tumor) developed paroxysmal hypertension and angina pectoris following the use of oral snuff iMcPhau1 et al. 1984). Within 10 min, blood pressure increased from 110/70 mmHg to 300/103 mmHg and heart rate from 600 70 to 110. Rechallenge with snuff after surgical removal of the pheochromocytoma revealed only a mild blood pressure increase. Another patient with previously controlled essential hypertension presented with a blood pressure of 210/115 mmHg prior to surgery (Wells et al. 1986). A mass of snuff was found in the patient's cheek. The snuff was removed and blood pressure returned to 150!85 mmHg within 15 min. Wound Healing Adequate blood flow to the skin is important for wound healing. Cigarette smoking and nicotine polacrilex gum reduce skin blood flow (Fredholm and Sawe 1981; Allison and Roth 1969; Carlsson and Wennmalm 1983). In rats, exposure to cigarette smoke decreases survival of surgical flaps (Kaufman et al. 1984; Lawrence et al. 1984; Craig and Rees 1985). Cigarette smoking has been associated with a twelvefold increased risk of experiencing skin slough after facelift surgery (Rees, Liverett, Guy 1984). It is conceivable that nicotine substitution therapy might also delay wound healing, but no human data are as yet available. Reproductive Hazards Teratogenicity Nicotine rapidly crosses the placenta and enters the fetus (Suzuki et al. 1974). Nishimura and Nakai (19581, Landauer (19601, and Khan and coworkers (1981) have described teratogenic effects of high doses of nicotine, which interfered with skeletogenesis in mice and chick embryos. Chronic nicotine treatments of pregnant rats throughout gestation produced subtle neurological changes which manifested themselves as behavioral or electrophysiological alterations in the offspring (Peters and Ngan 1982; Hudson, Meisami, Timiras 1973; Martin and Becker 1971). Wang, Chen, and Schraufnagel (1984) found that pre- and postnatal exposure to nicotine induced structur- al changes in the lungs of fetal mice. Maternal exposure to nicotine also inhibited glucose metabolism in fetal lung tissue (Maritz 19861. Thus, several studies suggest that nicotine, at least in high doses, may have toxic effects on the fetus. Whether cigarette smoking is associated with increased rates of congenital malformations in humans is controversial. Several stud- ies show no association or a lower incidence of malformations in offspring of smoking mothers (Comstock and Lundin 1967; Goujard, Rumeau, Schwartz 1975; Meyer and Tonascia 1977; Evans, New- combe, Campbell 1979; Shiono, Klebanoff, Berendes 1986; Hem- minki, Mutanen, Salonieni 19831, but others report positive associa- tions (Himmelberger, Brown, Cohen 1978; Fedrick 1978; Kelsey et al. 19781. One study has reported an association between paternal 601 smoking and the incidence of congenital malformations (Mau and Netter 1974). Pregnancy Cigarette smoking during pregnancy increases the risk of low birth weight, prematurity, spontaneous abortion, and perinatal mortality in humans, which has been referred to as the fetal tobacco syndrome (Nieburg et al. 1985) (also reviewed in detail in the 1980 Surgeon General's Report). Nicotine influences implantation and embryo development in some laboratory animal studies (Hudson and Timiras 1972; Card and Mitchell 1979; Hammer and Mitchell 1979). At least one adverse outcome, reduced birth weight, is correlated with the level of cotinine, the major metabolite of nicotine, in the mother's serum (Haddow et al. 1987). Nicotine in high concentrations markedly decreases the in vitro development of rabbit preimplantation embryos and inhibits DNA synthesis (Balling and Beier 1985). Injection of nicotine, 7.5 mg twice each day from proestrus through pregnancy in rats, resulted in a delay in the entry of the ovum into the uterus, implantation, and subsequent development of the ovum (Yoshinaga et al. 1979). It was suggested that nicotine acted by delaying progesterone secretion, which is necessary to prepare the uterus for implantation, and by other disturbances of hormone release. Another study in rats reported that low doses of nicotine injected subcutaneously (0.1 mg/kg/day) from day 14 to the end of pregnancy had no effect on litter size or fetal development, but higher doses (1 mg/kg/day), comparable to those consumed by heavy smokers, reduced litter size and increased the number of still births (Hamosh, Simon, Hamosh 1979). Further research is needed to determine if there are direct adverse effects of nicotine on the embryo or fetus at levels of nicotine comparable to those observed in cigarette smokers. A likely mechanism for the reproductive problems in pregnant cigarette smokers is placental insufficiency, which is supported by evidence of placental hypoperfusion in cigarette smoking mothers (Naeye 1978; Philipp, Pateisky, Endler 1984). The factors most likely to affect the placenta are carbon monoxide and nicotine, both agents having the potential of impairing oxygen supply to the fetus. Inhalation of carbon monoxide results in elevation of both maternal and fetal carboxyhemoglobin (Asmussen and Kjeldsen 1975; Longo 1977). Nicotine infusion in pregnant sheep increases uterine vascular resistance and reduces uterine blood flow, effects which appear to be mediated by catecholamine release (Ayromlooi, Desiderio, Tobias 1981; Resnick, Brink, Wilkes 1979). Both cigarette smoking and nicotine gum increase fetal heart rate during the second trimester in humans, consistent with sympathetic activation (Lehtovirta et al. 1983). During the third trimester in humans, 602 cigarette smoking or nicotine gum chewing decreases fetal heart rate and reduces fetal breathing movements, both of which may be signs of fetal hypoxia (Lehtovirta et al. 1983; Gennser, Marsal, Brantmark 1975; Manning and Feyerabend 1976). Elevated levels of catechol- amines in amniotic fluid in human smokers during the third trimester indicate sympathetic activation in the fetus, consistent with fetal hypoxia and/or direct effects of nicotine (Divers et al. 1981X The above findings suggest that nicotine contributes to the adverse effects of cigarette smoking on reproduction probably by acting on the utero-placental circulation. Besides producing func- tional changes, carbon monoxide and nicotine might also be responsi- ble for the injury to the intimal ultrastructure of the umbilical artery seen in smoking mothers (Asmussen and Kjeldson 1975). Fetal hypoxemia has also been considered as a contributory cause of behavioral abnormalities, such as hyperactivity, short attention span, lower scores on spelling and reading tests, which occurred at a higher frequency in children whose mothers had smoked throughout pregnancy than in those born to nonsmoking mothers (Naeye and Peters 1984). Pulmonary Toxicity Cigarette smoking is the major cause of chronic obstructive lung disease (US DHHS 1984). Nicotine may directly or indirectly influence the development of emphysema in smokers. It rapidly accumulates in the pulmonary epithelial cells and some of its metabolites are retained in the lung for prolonged periods (Waddell and Marlowe 1976; Szuts et al. 1978). Chronic bronchial wall inflammation with accumulation of alveo- lar macrophages and polymorphonuclear neutrophils into the lung occur in response to habitual cigarette smoke exposure (Janoff 1983, 1985). Macrophages and neutrophils release elastase, an enzyme that destroys alveolar structure. Stone and colleagues (1983) found that alpha-1-antitrypsin, an inhibitor of elastase, may also be partially inactivated by cigarette smoke, probably related to effects of oxidant gases. Nicotine, which possesses chemotactic properties for neutro- phils (Totti et al. 1984; Jay, Kojima, Gillespie 1986) and can stimulate the production of elastase as shown for the pancreas in vivo (Morosco et al. 1981), may play a role in increasing elastase levels in the lungs. In addition, nicotine may adversely affect the repair of connective tissue since it has been reported to cause structural alterations and inhibition of collagen synthesis in fibro- blast cultures (Chamson et al. 1980; Chamson, Frey, Hivert 1982; Hurst and Gilbert 1979). Several other studies suggest that nicotine may contribute to the development of emphysema in smokers. Lai and Diamond (1987) showed that repeated inhalation of smoke from high, but not from 603 low, nicotine cigarettes significantly augmented experimentally induced emphysema in rats. Lelcuk and coworkers (1986) reported that nicotine instilled directly into the airways induced edema. In the rat, a variety of ingredients of both the particulate and vapor phase of cigarette smoke are capable of increasing vascular perme- ability and producing edema in the tracheobronchial mucosa (Lund- berg et al. 1983). This effect, which was traced to the stimulation of substance P-containing pulmonary vagal afferent neurons, was duplicated by nicotine (Lundberg, Saria, Martling 1982). In the guinea pig, inhaled cigarette smoke damaged the mucosal barrier and increased permeability to horseradish peroxidase by disrupting the intercellular tight junctions of the bronchial epithelium (Bouch- er et al. 1980). In smokers, Mason and coworkers (1983) documented an increase in pulmonary epithelial permeability in all lung regions using a radioaerosol procedure. In contrast, neither aerosolized nor injected nicotine, given over a period of 2 to 3 weeks, causes secretory cell hyperplasia (Rogers, Williams, Jeffery 1986) and there is little evidence that nicotine contributes to the development of chronic bronchitis. Further research is needed to define the magnitude of the contribution of nicotine to the pathogenesis of smoking-induced chronic lung disease. Nicotine can also worsen pulmonary function in smokers who already have lung disease. Acute exposure to nicotine induces constriction of both central and peripheral airways (Yamatake, Sasagawa, Yanaura 1978). The increase in airway resistance by nicotine involves vagal reflexes and stimulation of parasympathetic ganglia in the bronchial wall (Nakamura et al. 1986). The magnitude of bronchoconstriction observed in experimental animals and hu- mans following acute inhalation of cigarette smoke is correlated with the level of nicotine in the smoke (Shepherd, Collins, Silverman 1979; Rees, Chowienczyk, Clark 1982; Lee et al. 1983; Nakamura et al. 1985; Hartiala et al. 1985; Beck et al. 1986), suggesting that nicotine may be an important factor in the increased airway resistance of smokers. Genotoxicity and Carcinogenicity Smoking of cigarettes is causally related to cancer of the respira- tory tract, the upper digestive tract, pancreas, renal pelvis, and bladder; cigarette smokers also face an increased risk for cancer of the cervix (US DHHS 1982; IARC 1986). Many carcinogenic agents have been identified in cigarette smoke, however, not a single component nor chemical group(s) of components is solely responsible for the carcinogenic activity of cigarette smoke in the various organs. Laboratory bioassays suggest that polynuclear aromatic hydrocar- bons and N-nitrosamines play significant roles in the induction of cancer in smokers (US DHHS 1982; IARC 1986). Nicotine, the 604 principal alkaloid in tobacco smoke, has also been examined for its genotoxic and carcinogenic activity. In the Ames' Salmonella typhimurium mutagenesis and mammalian cell cytogenetic assays, nicotine did not possess any genotoxic activity, although it induced reparable DNA damage in the Escherichia coli pol A+ /A- system (Bishun et al. 1972; Florin et al. 1980; Riebe, Westphal, Fortnagel 1982; Riebe and Westphal 1983). In earlier studies, nicotine and its primary metabolites were reported to possess weak tumorigenic activity (Truhaut, De Clercq, Loisillier 1964; Boyland 19681, which subsequent investigations did not confirm (Schmahl and Osswald 1968; Martin et al. 1979; Toth 1982; LaVoie et al. 1985). Nicotine lacked cocarcinogenic activity in the urethane-induced mouse pulmonary adenoma model (Freelander and French 19561, but was found to be a cocarcinogen in the benzo(a)pyrene-tetradecanoyl phorbol acetate mouse skin tumorigen- esis model (Bock 1980). The mechanism of cocarcinogenic activity is not clearly understood. Two primary metabolites of nicotine, coti- nine and nicotine-N'-oxide, failed to promote N-(4-(5-nitro-2-fury&2 thiazyl) formamide (FANFTtinduced urinary bladder tumors in rats (LaVoie et al. 19851. On balance, it appears that nicotine does not possess direct carcinogenic activity. During processing and pyrolysis of tobacco, nicotine can be N'- nitrosated to form N'-nitrosonornicotine and other related com- pounds (Figure 2) (Hoffmann and Brunnemann 1983; Hoffmann and Hecht 1985). These tobacco-specific N'nitrosoamines are found in substantial concentrations in American snuff, as well as in main- stream tobacco smoke (Table 21, and in the saliva of snuff dippers (Hoffmann and Adams 1981; Palladino et al. 1986). Tobacco specific N-nitrosoamines are highly carcinogenic in animals and are suspect- ed to contribute to cancer related to cigarette smoking and smokeless tobacco use (Hoffmann, LaVoie, Hecht 1985; Hoffmann and Hecht 1985). There is also concern that nicotine may be N-nitrosated within the human body. Endogenous formation of N-nitrosoproline (a noncarcinogenic marker of endogenous N-nitrosation) has been documented in cigarette smokers (Hoffmann and Brunnemann 1983; Tsuda et al. 1986). Whether nicotine-derived nitrosoamines are formed endogenously in amounts sufficient to contribute humans exposed to nicotine per se (such as with ment therapy) remains to be determined. Gastrointestinal Disease In peptic ulcer disease, cigarette smoking is a risk factor for its development, and an even stronger risk factor for delayed healing, failure to respond to therapy, and relapse (Kikendall, Evaul, Johnson 1984). In animals, nicotine potentiates peptic ulcer forma- tion induced by histamine or pentagastrin (Konturek et al. 1971; Lee 605 NICOTINE NORNICOTINE ANABASINE ANATABINE Qe @Y & & Nl I-ROSATION NNAL NNK NNN NAB NAT FIGURE 2.-Formation of tobacco-specific nitrosamines SOTE: NNAL. 4~methyln~trosamino~l~3-pyr~dylIbu~n-l-ol; NNK. Umethylnitroeamino~l~kpyridyl~l-buts- none: NNN. N'-nltroso:`ornicotine. NAB. N'-nitrosoanabasine NAT, N'-nitrcexmatabine. SOURCE US DHHS f1986). TABLE 2.-Tobacco-specific nitrosamines in commercial U.S. tobacco products Tobacco product NNN NNK NAT + NAB Smokeless tobacco Chewmg tobacco ' Ippb) 3500-8200 KC-3ooo 500-7Ocm Snuff' `ppbl 80049,ooo 2oe4300 2oo4oo Mainstream smoke Cigarette. NF Ing/cig) 120-950 80-770 140-990 Cigarette. French Black, NF 500 220 350 Ctgarette. F lng/cigl x-310 30-150 m-370 Llrtle cgnr. F Ingicigar) 5500 4200 1700 Cigar \nyicigarl 32co 1900 1900 Sidestream smoke Cigarette. NF u&c@ 1700 410 270 Cqarette. F !ng/clgj 150 190 150 SOTE .VNN. N'-nltrosonornicotine. NNK. 4~methylnitrcsamino~liSpyridyl~I-butanone; NAT, N'-nitromena- rablne. NAB. N -natresoanabasme. NF. without filter tip, F, with Filter tip. ~`herw~~ tobacco and snuff also contam ~2CO ppb NNAL. 4~methylnitrosamino~l-(3pyridyl)butsn-lal. SOL'RCE Hoffman. IaVow. Hecht (19851 and Gruber 1952). Several mechanisms by which nicotine acts in this regard have been proposed. (1) Chronic treatment in rats increases basal acid secretion, an effect which appears to be mediated by parasympathetic mechanisms (Thompson and George 1972). Chronic cigarette smoking may induce hypersecretion of acid in response to secretory stimuli. (2) Infusion of nicotine in animals and cigarette smoking by people reduces pancreatic bicarbonate secretion, which normally neutralizes acid entering the duodenum (Solomon et al. 606 1974; Murthy et al. 1977). This could result in increased acid delivery to the duodenum, thereby increasing the risk of ulceration. (3) Smoking may impair the mucosal barrier to acid-mediated injury. Smoking, apparently acting through nicotine, decreases mucosal blood flow and inhibits mucosal prostaglandin synthesis, both of which may impair the effectiveness of the gastric mucosal barrier, which protects the stomach lining against acid (Chujoh and Nakaza- wa 1981; Kawano et al. 1982; Quimby et al. 1986). (4) Cigarette smoking reduces both lower esophageal and pyloric sphincter pressures (Chattopadhyay, Greaney, Irvin 1977; Valenzuela, Defilip- pi, Csendes 19761, resulting in gastroesophageal reflux and duodeno- gastric reflux, respectively. The former may result in reflux symp- toms (heartburn) (Stanciu and Bennett 19721, while the latter may cause reflux of bile acids and lysolecithin, which are known to break down the gastric mucous barrier. A direct role of nicotine is suggested by studies in opposums showing that intravenous nicotine reduces lower esophageal sphincter pressure (Rattan and Goyal 1975). The relative importance of local exposure to nicotine (as from swallowing nicotine from nicotine polacrilex gum) versus exposure to nicotine via the bloodstream in producing the above effects is unclear. In view of the extremely high concentrations of nicotine in saliva as compared to blood, local toxicity must be considered until proven otherwise to be an additional risk of nicotine polacrilex chewing gum for patients with ulcer disease or symptoms of esophageal reflux. Summary and Conclusions 1. At high exposure levels, nicotine is a potent and potentially lethal poison. Human poisonings occur primarily as a result of accidental ingestion or skin contact with nicotine-containing insecticides or, in children, after ingestion of tobacco or tobacco juices. 2. Mild nicotine intoxication occurs in first-time smokers, non- smoking workers who harvest tobacco leaves, and people who chew excessive amounts of nicotine gum. Tolerance to these effects develops rapidly. 3. Nicotine exposure in long-term tobacco users is substantial, affecting many organ systems (Chapters II and III). Pharmaco- logic actions of nicotine may contribute to the pathogenesis of smoking-related diseases, although direct causation has not yet been determined. Of particular concern are cardiovascular disease, complications of hypertension, reproductive disorders, cancer, and gastrointestinal disorders, including peptic ulcer disease and gastroesophageal reflux. 607 4. The risks of short-term nicotine replacement therapy as an aid to smoking cessation in healthy people are acceptable and substantially outweighed by the risks of cigarette smoking. 608 References AHMED, S.S.. MOSCHOS, C.B.. LYONS, MM, OLDEWERTEL, H.A., COUMBIS, R.J., REGAN, T.J. Cardiovascular effects of long-term cigarette smoking and nicotine administration. Americar .Journal of Curdiolog~ 37:39-40, January 1976. ALLISON, R.D., ROTH, G.M. Central and peripheral vascular effects during cigarette smoking. Archlues of Environmental Health 19.189-198, August 1969. ASMUSSEN. I.. KJELDSEN, K. !ntimal ultrastructure of human umbilicai arteries. Observations on arteries from newborn children of smoking and nonsmoking mothers. Circulation Research 36t51:579-589. May 1975. AYROMLOOI, J., DESIDERIO, D.. TOBIAS. M. Effect of nicotine sulfate on the hemodynamics and acid base balance of chronically instrumented pregnant sheep. Deuelopmental P,harmucology and Therapcutlcs 3:205-213. 1981. BALLING, R.. BEIER. H.M. Direct effects of nicotine on rabbit prcimplantation embryos. Z'oxicolo~~ 34141:309-313. $farch 1985. BARLOW, R.B., McLEOD, L.J. Some studies on cytisme and its methylated derivatives. British Journal of` Pharmacolq> 35,11:161-174, 1369. BAYER, F.. BOHN. I.L., STRXUER. B.E. Das kontraktionsverhalten des linken ventrikels unter nikotinexposition. [The comportment of the contraction behavior of the left ventrical under nicotine exposition.] Therapicuwhr 35:196&-1974, 1985. BECK, E.R., TAYLOR, R.F., LEE. L.Y., FRAZIER, D.T. Bronchoconstriction and apnea induced by cigarette smoke: Nicotine dose dependence. Lung 164:293-301, 1986. BEEMAN, J.A., HUNTER, WC. Fatal nicotine poisoning. A report of twenty-four cases. Archiws of Patholog.), 24:481485. 1937. BEKHEIT, S., FLETCHER, E. The effects of smoking on myocardial conduction in the human heart. American Heurt .lour~~n~ 9116):712-720. June 1976. BELCH. J.J.F., McARDLE. B.M. BLtRNS, P., LOWE, G.D.0, FORBES, C.D. The effects of acute smoking on platelet behaviour, fibrinolysis and haemorheology in habitual smokers. Thrombosis Haemostasis 51(1):6-8, February 28, i984. BENOWITZ, N.L.. JACOB, P. III Metahohsm. pharmacokinetics and pharmacody- namics of nicotine in man. In: Martin, W R.. Van Loon, G.R.. Iwamoto. E.T.. Davis, L. feds.) Tobacco Smoking and l\iicotine: A Neurobiological Approach. New York: Plenum Press, 1987, pp. 357-373. BENOWITZ, N.L., LAKE, T., KELLER, K.H., LEE, B L. Prolonged absorption with development of tolerance to toxic effects after cutaneous exposure to nicotine. Clinical Pharmacology and Therapeutics 42(1):119-220, 1987. BERNFELD, P., HOMBURGER. F. High nicotine tolerance of Syrian golden hamsters. (Abstract.) Toxicolog? and AppZDiwd Pharmacology 22(2):324-325. June 1972. BILLIMORIA. J.D., POZNER, H., METSELAAR, B., BEST, F.W., JAMES, D.C.O. Effect of cigarette smoking on lipids, lipoproteins, blood coagulation. fihrinolpsis and cellular components of human blood. =Itherosclerosis 21(1):61-76, January- February 1975. BISHUN, N.P., LLOYD. N.. RA\`EN, R.W., WILLIAMS, D.C. The in vitro and in vivo cytogenetic effects of nicotine. Acta Biolqqiru Academiae Sczentiarum Hungaricae 23(2):175-180, 1972. BOCK, F.G. Carginogenic properties of nicotine. In: Gori, G.. Bock, F.G. (eds.) Banbury, Report 3. A Safe Cigarette! New York: Cold Spring Harbor Laboratory, 1980, pp. 129-139. BOOYSE, F.M., OSIKOWICZ, G., QUARFOOT. A.J. Effects of chronic oral consumg tion of nicotine on the rabbit aortic endothelium. Amwran hunal of Pathology 102(2):229-238, February 1981. BORZELLECA, J.F.. BORMAN, E.R , McKENNIS. H. Studies on the respiratory and cardiovascular effects of t-,-cotinine. .Journal of Pharmacology and Experimental Therapeutics 137(31:313X318. September 1962. 609 BOUCHER, R.C., JOHNSON, J., INOUE, S., HULBERT, W., HOGG, J.C. The effect of cigarette smoke on the permeability of guinea-pig airways. Laboratory huestigo- tion 43(1):94-100, July 1980. BOYLAND E. The possible carcinogenic action of alkaloids of tobacco and betel nut. Pkzntu Medica ll(Supplement):13-22, 1968. BRANTMARK, B., FREDHOLM, B. Absorption of Nicotine from Swallowed Intact Buffered Nicoretre Chewing Gum, A. B. Leo Research Report No. 897. Helsinghorg, Sweden, 1974. BRISCHE'ITO, C.S.. CONNOR, W.E., CONNOR, S.L.. MATARAZZO, J.D. Plasma lipid and lipoprotein profiles of cigarette smokers from randomly selected families: Enhancement of hyperlipidemia and depression of high-density lipoprotein. American Journal of Cardiology 52(7):675-680, October 1, 1983. CARISSON, I., WENNMALM, A. Effect of cigarette smoking on reactive hyperaemia in the human finger. Clinical Physiology 3:453-469, 1983. CARD, J.P., MITCHELL, J.A. The effects of nicotine on implantation in the rat. BioZogy of Reproduction 20:532-539, April 1979. CHAMSON. A., FREY, J., HIVERT, M. Effects of tobacco smoke extracts on collagen biosynthesis by fibroblast cell cultures. Journal of Z'oricology and Environmental Health 9(5/6):921-932, May-June 1982. CHAMSON, A., GARRONE, R., AUGER, C., FREY, J. Effects of tobacco smoke extract on the ultrastructure of fibroblasts in culture. Journal of Submicroscopic Cytology 12(3):401-406, July 1980. CHATI'OPADHYAY, D.K., GREANEY, M.G., IRVIN, T.T. Effect of cigarette smoking on the lower oesophageal sphincter. Assessment of normal and symptomatic patients using the rapid pull-through technique of oesophageal manometry. Gut 18(10):833-835, October 1977. CHUJOH, C., NAKAZAWA, S. Inenmaku shogai ni kansura jikkenteki kenkyu toku ni sakusan kaiyo nochiyu ni oyobosu kitsuen no eikyo ni teuite. [Experimental study for the gastric mucosal damage.] Japanese Journal of Gastrventerology 78(12):2285-2294, 1981. CLUE'ITEBROWN, J., MULLIGAN, J., DOYLE, K., HAGAN, S., OSMOLSKI, T., HOJNACKI, J. Oral nicotine induces an atherogenic lipoprotein profile. &XX&- ings of the Society for Experimental Biology and Medicine 182(3):409-413, July 1986. COMSTOCK, G.W., LUNDIN, F.E. Jr. Parental smoking and perinatal mortality. American JournaZ of Obstetrics and Gynecology 98(5):708-718, July 1, 1967. CRAIG, S.. REES, T.D. The effects of smoking on experimental skin flaps in hamsters. Plastic and Reconstructive Surgery 75(6):842-846, June 1985. CRIQUI, M.H., COWAN, L.D., HEISS, G., HASKELL, W.L., LASKARZEWSKI, P.M., CHAMBLESS, L.E. Frequency and clustering of nonlipid coronary risk factors in dyslipoproteinemia. The Lipid Research Clinics Program Prevalence Study. Circulation 73(1, Part 2):1-4(&I-50, January 1986. CRYER, P.E., HAYMOND, M.W., SANTIAGO, J.V., SHAH, S.D. Norepinephrine and epinephrine release and adrenergic mediation of smoking-associated hemodynamic and metabolic events. I'Vew England Journal of Medicine 29X11):573-577, Septem- ber 1976. CSONKA, E., SOMOGYI, A.. AUGUSTIN, J.. HABERBOSCH, W., SCHE'PI'LER, G., JELLINEK, H. The effect of nicotine on cultured cells of vascular origin. Virchows Archiv A. Pathological Anatomy and Histology 407(4):441-447, 1985. DAVIS, J.W., SHELTON, L., EIGENBERG, D.A., HIGNITE, C.E., WATANABE, IS. Effects of tobacco and non-tobacco cigarette smoking on endothelium and platelets. Clinical Pharmacology and Therapeutics 37(5):529-533, May 1985. DIVERS, W.A. Jr., WILKES, M.M., BABAKNIA, A., YEN, S.S.C. Maternal smoking and elevation of catecholamines and metabolites in the amniotic fluid. American Journal of Obstetrics and Gynecology 141(6):625-628, November 1981. 610 DOUSSl!X, J.C., GUTIERRES, J.B., DOUSSET, N. Hypercholesterolaemia after administration of nicotine chewing gum. (Letter.) Lancet 2@520):1393-1394, December 13, 1986. DOWNEY, H.F., CRYSTAL, G.J., BASHOUR, F.A. Regional renal and splanchnic blood flows during nicotine infusion: Effects of beta adrenergic blockade. Journal of Pharmaco logy and Experimenkl Thempeutics 216(2):36X%7, February 1981. EVANS, D.R.. NEWCOMBE, R.G., CAMPBELL, H. Maternal smoking habits and congenitat malformations: A population study. British Medical Journal 2(6183):171-173, July 21, 1979. FAULKNER, J.M. Nicotine poisoning by absorption through the skin. Journal of the American Medical Association 100(21):1664-1665, May 27, 1933. FEDRICK, J. Factors associated with low birth weight of infants delivered at term. British Journal of Obstetrics and Gynuecology 85(1):1-7, January 1978. FLORIN, I., RUTBERG, L., CURVALL, M., ENZELL, C.R. Screening of tobacco smoke constitubnta for mutagenicity using the Ame's test. Toxicology l&219-232, 1980. FRANKE, F.E., THOMAS, J.E. The treatment of acute nicotine poisoning. Journal of the American Medical Association 106(1):507-512, January 4, 1936. FREDHOLM, B., SiiWE, U. Effects of Nicorette chewing and cigarette smoking on skin capillary blood flow. (Abstract.) Clinical Physiology 1(13:604-605, 1981. FREEDLANDER, B.L., FRENCH, F.A. Absence of co-carcinogenic action of oxidation products of nicotine in initiation of pulmonary adenomas in mice with urethan. (Abstract.) proceedings of the American Association for Cancer Research 2(2):109, April 1956. GARG, M. Variation in effects of nicotine in four strains of rats. Psychopha-ologin 14:43%438, 1969. GEHLBACH, S.H., WILLIAMS, W.A., FREEMAN, J.I. Protective clothing as a means of reducing nicotine absorption in tobacco harvesters. Archives of Environmental Health 34(2):111-114, March-April 1979. GEHLBACH, S.H., WILLIAMS, W.A., PERRY, L.D., FREEMAN, J.I., LANGONE, J.J., PETA, L.V., VAN VUNAKIS, H. Nicotine absorption by workers harvesting green tobacco. Lancer 1(7905):478-480, March 1, 1975. GEHLBACH, S.H., WILLIAMS, W.A., PERRY, L.D., WOODALL, J.S. Green-tobacco sickness. An illness of tobacco harvesters. Journal of the American Medical Association 229(14):1880-1883, September 30, 1974. GENNSER, G., MARSAL, K., BRANTMARK, B. Maternal smoking and fetal breathing movements. American Journal of Obstetrics and Gynecology X%(8):861-867, December 15, 1975. GHOSH, SK., PARIKH, J.R., GOKANI, V.N., KASHYAP, SK., CHA'ITERJEE, S.K. Studies on occupational health problems during agricultural operation of Indian tobacco workers. A preliminary survey report. Journal of Occupational Medicine 21(1):45-47, January 1979. GNASSO, A., HABERBOSCH, W., SCHE'M'LER, G., SCHMITZ, G., AUGUSTIN, J. Acute influence of smoking on plasma lipoproteins. Proceedings of the Society for Experimental Biology and Medicine 182:414-418, 1986. GOLDFRANK, L., MELINEK, M., BLUM, A. Nicotine. Hospital Physician 16(4):2%35, 1980. GOUJARD, J., RUMEAU, C., SCHWARTZ, D. Smoking during pregnancy, stillbirth and abruptio placentae. Biomedicine 23(1):2&22, February 10, 1975. GVOzDJAKovA, A., BADA, V., SANY, L., KUCHARSKA, J., KRUfi, F., BOZEK, P., TRYSTANSKq, L., GVOZDJbK, J. Smoke cardiomyopathy: Disturbance of oxidative processes in myocardial mitochondria. Cardiovascular Research 18:229-232, 1984. GREEN, M.S., JUCHA, E., LUZ, Y. Blood pressure in smokers and nonsmokers: Epidemiologic findings. American Heart Journal 3(5):932-940. May 1986. 611 HADDOW, J.E., KNIGHT, G.J., PALOMAKI, G.E., KLOZA, E.M., WALD, N.J. Cigarette consumption and serum cotinine in relation to birthweight. British Journal of Obstetrics and Gynaecology 94(7):678-681, July 1987. HAMMER, R.E., MITCHELL, J.A. Nicotine reduces embryo growth, delays implanta- tion, and retards parturition in rats. Proceedings of the Society for Experimental Biology and Medicine 162(2):333336, November 1979. HAMOSH. M., SIMON, M.R., HAMOSH. P. Effect of nicotine on the development of fetal and suckling rats. Biology of the Neonate 3X5/6):29&297, 1979. HARTIALA, J.J., MAPP. C., MITCHELL, R.A., GOLD, W.M. Nicotine-induced respiratory effects of cigarette smoke in dogs. Journal of Applied Physiology 59(l)%-71, July 1985. HARZ, A.J., ANDERSON, A.J., BROOKS, H.L., MANLEY, J.C., PARENT, G.T., BARBORIAK, J.J. The association of smoking with cardiomyopathy. The New England Journal of Medicine 311(19):1201-1206, November 8, 1984. HEMMINKI, K., MUTANEN, P., SALONIEMI, I. Smoking and the occurrence of congenital malformations and spontaneous abortions: Multivariate analysis. American Journal of Obstetrics and Gynecology 145(1):61-66, January 1, 1983. HIMMELBERGER, D.U., BROWN, B.W. Jr., COHEN, E.N. Cigarette smoking during pregnancy and the occurrence of spontaneous abortion and congenital abnormali- ty. American Journal of Epidemiology 108(6):470-479, December 1978. HLADOVEC, J. Endothelial injury by nicotine and its prevention. Experientia 34(12):1585X&6, December 15, 1978. HOFFMANN, D., ADAMS, J.D. Carcinogenic tobacco-specific N-nitrosamines in snuff and in the saliva of snuff dippers. Cancer Research 41:4305-4308, November 1981. HOFFMANN, D., BRUNNEMANN, K.D. Endogenous formation of N-nitrosoproline in cigarette smokers. Cancer Research 43(11):5570-5574, November 1983. HOFFMANN, D., HECHT, S.S. Nicotinederived N-nitrosamines and tobacco-related cancer: Current status and future directions. Cancer Research 4X3):935-944, March 1985. HOFFMANN, D., LaVOIE, E.J., HECHT, S.S. Nicotine: A precursor for carcinogens. Cancer Letters 26(1):67-75, February 1985. HOJNACKI, J., MULLIGAN, J., CLUETTE-BROWN, J., IGOE, F., OSMOLSKI, T. Oral nicotine impairs clearance of plasma low density lipoproteins. Proceedings of the Society for Experimental Biology and Medicine 182:414-418, 1986. HUDSON, D.B., MEISAMI, E., TIMIRAS. P.S. Brain development in offspring of rats treated with nicotine during pregnancy. Experientia 29(3):286288, March 15, 1973. HUDSON, D.B., TIMIRAS, P.S. Nicotine ingestion during gestation: Impairment of reproduction, fetal viability and development. Biology of Reproduction 7(2):247-253, 1972. HURST, D.J., GILBERT, G.L. Acute change in lung collagen synthesis produced by cigarette smoke components. (Abstract.) American Review of Respiratory Disease 119(4, Supplement):222, April 1979. INTERNATIONAL AGENCY FOR RESEARCH ON CANCER. Tobacco Smoking, IARC Monographs on the evaluation of the carcinogenic risk of chemicals to humans, Volume 38. World Health Organization, International Agency for Research on Cancer, 1986. ISLES, C., BROWN, J.J., CUMMING, A.M.M., LEVER, A.F., McAREAVEY, D., ROBERTSON, J.I.S., HAWTHORNE, V.M., STEWART, G.M., ROBERTSON, J.W.K., WAPSHAW, J. Excess smoking in malignant-phase hypertension. British Medical Journal 1(6163):579-581, March 3, 1979. JAIN, A.C., BOWYER, A.F., MARSHALL, R.J., ASATO, H. Left ventricular function after cigarette smoking by chronic smokers: Comparison of normal subjects and patients with coronary artery disease. American Journal of Cardiology 3%1):27-31, January 1977. 612 JANOFF, A. Biochemical links between cigarette smoking and pulmonary emphyse- ma. Journal of Applied Physiology: Respiratory, Environmental and Exercise Physiology 55(2):285-293, August 1983. JANOFF, A. Elasteses and emphysema: Current assessment of the protease-antipro tease hypothesis. American Review of Respimtory Disease 132(2):417433, August 1985. JAY, M., KOJIMA, S., GILLESPIE, M.N. Nicotine potentiates superoxide anion generation by human neutrophils. Toxicology and Applied Phannocology 86:484-487, December 1986. JONASON, T., BERGSTROM, R. Cessation of smoking in patients with intermittent claudication. Acta Medica Scandinavica 221(3):253-260, 1987. KAIJSER, L., BERGLUND, B. Effect of nicotine on coronary blood-flow in man. Clinical Physiology 5(6):541-552, December 1985. KAUFMAN, T., EICHENLAUB, E.H., LEVIN, M., HURWITZ, D.J., KLAIN, M. Tobacco smoking: Impairment of experimental flap survival. Annals of Plastic Surgery 13(6):468-472, 1984. KAWANO, S., SATO, N., FUKUDA, M., SHICHIRI, M., KAMADA, T., ABE, H. Inenmaku ketsuryu ni eikyo o oyobuso shoinshi no kento - (dai ippo) naishikyoka hansha supekutory kaiseki ni yory kitsuen no eiko no kento. [Effect of cigarette smoking on gastric hemodynamics. Analysis by reflectance spectrophotometry.] Japanese Journal of Gastroenterology 79:187-192, 1982. KELSEY, J.L., DWYER, T., HOLFORD, T.R., BRACKEN, M.B. Maternal smoking and congenital malformations. An epidemiological study. Journal of Epidemiology and Community Health 32(2):102-107, June 1978. KHAN, M.A., PROVENZA, D.V., OLSON, N.O., OVERMAN, D.O. Nicotine toxicity in chick vertebral chondrocytes in vitro. Chemico-Biological Interactions 35(3):363-367, 1981. KIKENDALL, J.W., EVAUL, J., JOHNSON, L.F. Effect of cigarette smoking on gastrointestinal physiology and non-neoplastic digestive disease. Journal of Clinical Gastmenteralogy 6(1):65-79, February 1984. KLEIN, L.W., AMBROSE, J., PICHARD, A., HOLT, J., CORLIN, R., TEICHHOLZ, L.E. Acute coronary hemodynamic response to cigarette smoking in patients with coronary artery disease. Journal of the American College of Cardiology 3(4):87%886, April 1984. KONTUREK, S.J., RADECKI, T., THOR, P., DEMBINSKI, A., JACOBSON, E.D. Effects of nicotine on gastric secretion and ulcer formation in cats Proceedings of the Society for Experimental Biology and Medicine 138(2):674-677, November 1971. LAI, Y.-L., DIAMOND, L. Effects of high or low nicotine cigarette smoke expcsure on elastase induced emphysema. (Abstract). American Review of Respimtory Disease 135fSupplement):150, 1987. LANDAUER, W. Nicotine-induced malformations of chicken embryos and their bearing on the phenocopy problems. Journal of Experimental Zaology 143(1):107-122, February 1960. LARSON, P.S., HAAG, H.S., SILVE'ITE, H. Tobacco: Experimental and Clinical Studies. A Comprehensive Account of the World Literature. Baltimore: Williams and Wilkins, 1961. LaVOIE, E.J., SHIGEMATSU, A., RIVENSON, A., MU, B., HOFFMANN, D. Evaluation of the effects of cotinine and nicotine-N'oxides on the development of tumors in rats initiated with N-[4-(5nitro2 furylh2-thiaxolyl] formamide. Journal of the National Cancer Institute 75(6):1075-1081, December 1985. LAWRENCE, W.T., MURPHY, R.C., ROBSON, M.C., HEGGERS, J.P. The detrimen- tal effect of cigarette smoking on flap survival: An experimental study in the rat. British Journal of Plastic Surgery 37(21:216-219, April 1984. 613 LEE, KS., GRUBER, C.M. Jr. The effect of nicotine on the production of peptic ulcers in histamine treated dogs. Archives of Znternationales de Pharmacodynamie et & Thkmpie 90(4):462-465, August 1952. LEE, L.-Y., MORTON, R.F., HORD, A.H., FRAZIER, D.T. Reflex control of breathing following inhalation of cigarette smoke in conscious dogs. Journal of Applied Physiology: Respiratory, Environmental and Exercise Physiology 54(2):562-570, February 1983. LEHTOVIRTA, P., FORSS, M., RAURAMO, I., KARINIEMI, V. Acute effects of nicotine on fetal heart rate variability. British Journal of Obstetrics and Gynaecology 90(8):710-715, August 1983. LELCUK, S., THRELFALL, L., VALERIE, R., SHEPRO, D., HECHTMAN, H.B. Nicotine stimulates pulmonary parenchymal thromboxane synthesis. Surgety 100(5):836-840, November 1986. LINDNER, E. Untersuchungen/ber das Verhalten des N-(3'-phenyl-propy&?`&l,l- diphenyl-propyl-(3&amins (Segontin (I)) gegen/ber der Wirkungen des Noradrena- lins. Archives Znternationales de Pharmacodynamie et de Thkmpie 146475-484, December 1963. LOCKHART, L.P. Nicotine poisoning. (Letter.) British Medical Journal 1:246-247, February 11, 1933. LONGO, L.D. The biological effects of carbon monoxide on the pregnant woman, fetus, and newborn infant. American Journal of Obstetrics and Gynecology 129(1):69-103. September 1, 1977. LUNDBERG, J.M., MARTLING, C.-R., SARIA, A., FOLKERS, K., ROSELL, S. Cigarette smoke-induced airway oedema due to activation of capsaicin-sensitive vagal afferents and substance P release. Neuroscience 10(4):1361-1368, 1983. LUNDBERG, J.M., SARIA, A., MARTLING, C.R. Capsaicin pretreatment abolishes cigarette smoke-induced edema in rat trachea-bronchial mucosa. European Jour- nal of Pharmacology 86(2):317-318, December 24, 1982. MALIZIA, E., ANDREUCCI, G., ALFANI, F., SMERIGLIO, M., NICHOLAI, P. Acute intoxication with nicotine alkaloids and cannabinoids in children from ingestion of cigarettes. Human Toxicology 2(2):315-316, 1983. MANNING, F.A., FEYERABEND, C. Cigarette smoking and fetal breathing move men& British Journal of Obstetrics and Gynaecology 83(4):26%270, April 1976. MAOUAD, J., FERNANDEZ, F., BARRILLON, A., GERBAUX, A., GAY, J. Diffuse or segmental narrowing (spasm) of the coronary arteries during smoking demon- strated on angiography. American Journal of Cardiology 53(2):354-355, January 15, 1984. MARITZ, G. Pre- and postnatal carbohydrate metabolism of rat lung tissue: The effect of maternal nicotine exposure. Archives of Toxicology 5%2):89-93, July 1986. MARKS, M.H., BURCH, J.B., COLLINS, AC. Genetics of nicotine response in four inbred strains of mice. Journal of Pharmacology and Experimental Thempeutica 226(1):291-302, 1983. MARTIN, J.C., BECKER, R.F. The effects of maternal nicotine absorption or hypoxic episodes upon appetitive behavior of rat offspring. Developmental Psychobiology 4(2):133-147, 1971. MARTIN, J.C., MARTIN, D.D., RADOW, B., DAY, H.E. Life span and pathology in offspring following nicotine and methamphetamine exposure. Experimental Aging Research 5(4):509-522, August 1979. MARTIN, J.L., WILSON, J.R.. FERRARO, N., LASKEY, W.K., KLEAVELAND, J.P., HIRSHFELD, J. W. Jr. Acute coronary vasoconstrictive effects of cigarette smoking in coronary heart disease. American Journal of Cardiology 54(1):56-60, July 1, 1984. MASON, G.R., USZLER, J.M., EFFROS, R.M., REID, E. Rapidly reversible alterations of pulmonary epithelial permeability induced by smoking. Chest 83(1):&11, January 1983. 614 MAU, G., NETTER, P. Die auswirkungen des viaterlichen zigaretten kongums aug die perintale sterblichkeit und lie missbildungshaufigkeit. [The effects of paternal cigarette smoking on perinatal mortality and on incidence of malformations.] Deutsche Mediziniche Wockenshrift 99:113-l] 18, 1974. MCNALLY, W.D. A report of seven cases of nicotine poisoning. Journal of Laboratory and Clinical Medicine 8:83-85, 1923. McPHAUL, M.. PUNZI, H.A.. SANDY. A.. BORGANELLI, M., RUDE, R., KAPLAN, NM. Snuff-induced hypertension in pheochromocytoma. Journal of the American Medical Association 252(23,`301:2860-2862, 1984. MEHTA, J., MEHTA, P. Role of blood platelets and prostaglandins in coronary artery disease. American Journal of Cardio1og.v 48:36%373, August 1981. MENSCH, A.R., HOLDEN, M. Nicotine overdose after a single piece of nicotine gum. (Letter.) Chest 86(5):801-802, November 1984. MEYER, M.B., TONASCIA, J.A. Maternal smoking, pregnancy complications, and perinatal mortality. American Journal of Obstetrics and Gynecology 128(5):494-502, July 1. 1977. MEYERS, M.G., BENOWITZ. N.L.. DUBBIN, J.D.. HAYNES, R.B., SOLE, M.J. Cardiovascular effects of smoking in patients with ischemic heart disease. Chest 93(1):14-19, 1988. MINER, L.L., MARKS, M.H., COLLINS, A.C. Classical genetic analysis of nicotine- induced seizures and nicotine receptors. .Joumal of Pharmacology and Experimen- tal Therapeutics 231(31:545-554, December 1984. MOROSCO, G.J.. NIGHTINGALE, T.E.. FRASINEL, C.. GOERINGER, G.C. Pancreat- ic elastase activation as a possible indicator of the relative hazard of different cigarettes. Journal of Toxicology and Encironmenlal Health 8:89-94, 1981. MURTHY, S.N.S., DINOSO, V.P. Jr., CLEARFIELD, H.R., CHEY, W.Y. Simultaneous measurement of basal pancreatic, gastric acid secretion, plasma gastrin, and secretin during smoking. Gastroenterologv 73(41:758-761, 1977. MUSTARD, J.F., MURPHY, E.A. Effect of smoking on blood coagulation and platelet survival in man. British Medical Journal 1(5330):84&849, March 2, 1963. NAEYE, R.L. Effects of maternal cigarette smoking on the fetus and placenta. British Journal of Obstetrics and Gwmecology 85(101:732-737, October 1978. NAEYE, R.L., PETERS, E.C. Mental development of children whose mothers smoked during pregnancy. Obstetncs and G.vnecology 64(5X601-607, November 1984. NAKAMURA, M., HAGA. T., MIYANO, M., SASAKI. H., TAKISHIMA, T. Dose- response curves of central and peripheral airways to nicotine injections in dogs. Journal of Applied Physiolog? 61(51:1677-1685, 1986. NAKAMURA, M., HAGA, T., SASAKI, H., TAKISHIMA, T. Acute effects of cigarette smoke inhalation on peripheral airways in dogs. Journal of Applied Physiology 58(1):27-33, 1985. NICOD, P., REHR, R., WINNIFORD, M.D., CAMPBELL, W.B.. FIRTH, B.G., HILLIS, L.D. Acute systemic and coronary hemodynamic and serologic responses to cigarette smoking in long-term smokers with atherosclerotic coronary artery disease. Journal of the American College of Cardio1og.v 4(51:964-971, November 1984. NIEBURG, P., MARKS, J.S., McLAREN, N.M.. REMINGTON, P.L. The fetal tobacco syndrome. Journal o/* the American Medical Association 253(20):299%2999, May 24-31, 1985. NISHIMURA, H., NAKAI, K. Developmental anomalies in offspring of pregnant mice treated with nicotine. Science 127:877+78, 1958. PACKHAM. M.S., MUSTARD, J.F. The role of platelets in the development and complications of atherosclerosis. Seminars in Hematology 23(l)%-26, January 1986. 615 PALLADINO, G., BRUNNEjIANN, K.D., ADAMS, J.D.. HALEY. N.J., HOFFMANN, D. Snuff-dippmg in college students: A clinical profile. Military Medicine 151:342-346, June 1986 PETERS, M.A., NGAS. L.L.E. The effect of totigestational exposure to nicotine on pre- and posrnatai development in the rat. Archives Zntternationales et de Pharmacod,snamir 257(11:155-167, May 1982. PETERS, R.W., BENOWITZ. N.L., VALENTI, S., MODIN, G., FISHER, M.L. Electrophysiologic effects of cigarette smoking in patients with and without chronic beta-blocker therapy. nmerican Journal of Curdiology 60:1078-1082, 1987. PETI'ITI, D.B.. KLATSKY. A.L. Malignant hypertension in women aged 15 to 44 years and its relation to cigarette smoking and oral contraceptives. American Journal of Cardiology 52(3):297-298, August 1983. PHILIPP, K., PATEISKY, N., ENDLER, M. Effects of smoking on uteroplacental blood flow. Gpecologic and Obstetric Incestigation 17(4):179-182, April 1984. QUICK, C.R.G., COTTON, L.T. The measured effect of stopping smoking on intermittent claudication. British Journal of Surgery 6%Supplement): S24-S26, 1982. QUIMBY, G.F., BONNICE. C.A., BURSTEIN, S.H.. EASTWOOD, G.L. Active smoking depresses prostaglandin synthesis in human gastric mucosa. Annals of Internal Medicine 104(5):616-619, May 1986 RATTAN, S., GOYXL, R.K. Effect of nicotine on the lower esophageal sphincter. Studies on the mechanism of action. Gastmenterology 69(1):154-159, July 1975. REES, P.J.. CHOWIENCZYK, P.J., CLARK, T.J.H. Immediate response to cigarette smoke. Thorax 37(61:41i-422, June 1982. REES, T.D., LIVERE'IT, D.M., GUY, C.L. The effect of cigarette smoking on skin-flap survival in the face lift patient. Plastic Reconstructive Surgery 73(8):911-914, June 1984. RENAUD, S.. BLACHE, D.. DUMONT, E., THEVENON, C., WISSENDANGER, T. Platelet function after cigarette smoking in relation to nicotine and carbon monoxide. Clinical PharnacoZogJ and Therapeutics 36(3):389--395, September 1984. RESNICK, R.. BRINK, G.W.. WILKES, M. Catecho!amine-mediated reduction in uterine blood flow after nicotine infusion in the pregnant ewe. Journal of Clinical Znuestigation 63(61:1133-1136, June 1979. RIEBE, M., WESTPHAL, K. Studies of the induction of sister-chromatid exchanges in Chinese hamster ovary cells by various tobacco alkaloids. Mutation Research 124(3/4):281-286, December 1983. RIEBE. M., WESTPHAL, K., FORTNAGEL, P. Mutagenicity t.esting in bacterial test systems, of some constituents of tobacco. Mutntion Research 101(1):3943, March 1982. RIGOTTI. N.A., EAGLE, K.A. Arrial fibrillation while chewing nicotine gum. (Letter.) Journal of the Amerrcan Medtcal Association 255(8):1018, February 28, 1986. ROGERS, D.F.. WILLIAMS, D.A.. JEFFERY. P.K. Nicotine does not cause "bronchi- tis" in the rat. Clinical Science 7Q5k427-433. May 1986. SAXENA, K., SCHEMAN. A. Suicide plan by nicotine poisoning: A review of nicotine toxicity. Veterinary a& Human Toxicoiogy 27t61495497, December 1985. SCHMAHL. D.. OSSWALD. H. Fehlen einer carcinogenen Wirkung von cotinin bei Ratten. [The absence of a carcinogenic action of cotinine on rats.] Zeifschrift f/r Krebsforschrrng 71:198. 1968. SHEPHERD, R.J.. COLLINS. R.. SIL\`ERMAN, F. Responses of exercising subjects to acute "passive" cigarette smoke exposure. Enc~ironnlental Research 19:279-291, 1979. SHIONO, P.H., KLEBANOFF, M.A.. BERENDES, 1I.W. Congenital malformations and maternal smoking during pregnancy. Teratolog? 34(11:65-71. August 1986. SIESS. W., LORENZ, R.. ROTH, P.. WEBER, P.C. Plasma catecholamines, platelet aggregation and associated thrombosane formation after physical exercise, smoking or norepinephrine infusion. Czrculaliun 66(1):44-48, July 1982. SOLOMON, T.E., SOLOMON, N., SHANBOUR, L.L., JACOBSON, E.D. Direct and indirect effects of nicotine on rabbit pancreatic secretion. Gastroenlerology 67(21:276-283, August 1974. SONNENFELD, T.. WENNMAL.M. A. Inhibition by nicotine of the formation of prostacyclin-like activity in rabbit and human vascular tissue. British Journal of Pharmacology 71:609%613, 1980. SRIDHARAN, M.R.. FLOWERS. NC., HAND, R.C., HAND, J.W , HORAN, L.G. Effect of various regimens of chronic and acute nicotine exposure on myocardial infarct size in the dog. American Jaw-rraI of`curdiology 55(1):1407-1411. May 1, 1985. STANCILJ, C., BENNETT, J.R. Smoking and gastrooesophageal reflux. British hfedical Journal 3(58301:793-795, September 30. 1972. STEWART, P.M., CATTERALL. J.R. Chronic nicotine ingestion and atria1 fibrilla- tion. Brutish h'eart Journal 54(21,222-223, August 1985. STONE, P.J., CALORE. J.D., McGOWAS, S.E.. BERNARDO, J., SNIDER, G.L., FRANZBLAU, C. Functional a,-protease inhibitor in the lower respiratory tract of cigarette smokers is not decreased. Science 221:1187-1189, 1983. SUZUKI, K., HORIGUCHI. T., COMAS-URRUTIA. AC., MUELLER-HEUBACH, E., MORISHIMA. H.O.. ADAMSONS. K. Placental transfer and distribution of nicotine in the pregnant rhesus monkey. American Journal of Obstetrics and Gynecology 119(21:253-262, May 15, 1974. SZUTS. T.. OLSSON. S., LINDQUIST, N.G.. ULLBERG, S., PICOTTI. A., ENZELL, C. Long term fate of 14 C-nicotine in the mouse: Retention in the bronchi, melanin- containing tissues and urinary bladder wall. T<~zcolog~ 10(31:207-220, July 1978. THOMPSON, J.H., GEORGE, R. Chronic effects of nicotine on gastric secretion in rats with hypothalamic lesions. American Journal of Dig&ice Diswses 17(6):513-518, June 1972. THYBERG, J. Effects of nicotine on phenotypic modulation and initiation of DNA synthesis in cultured arterial smooth muscle cells. Virchows Archir; 52(1):25-32, 1986. TOTH, B. Effects of long term administration of nicotine hydrochloride and nicotinic acid in mice. Anticancer Research 2(1;21:71-73. January-April 1982. TO'ITI, N., McCUSKER, K.T., CAMPBELL, E.J.. GRIFFIN, G.L., SENIOR, R.M. Nicotine is chemotactic for neutrophils and enhances neutrophil responsiveness to chemotactic peptides. Science 223(4632):169-171, January 13, 1984. TRUHAUT, R., DE CLERCQ. M., LOISILLIER. F. Sur Ies toxicit& aiguti et chronique de la cotinine. et sur son effet can&rig&e chez le rat. Pathologic-Biologic 12:39-42, January 1964. TSUDA. M.. NIITSUMA, J., SATO, S., HIRAYAMA. T.. KAKIZOE, T.. SUGIMURA, T. Increase in the levels of N-nitrosoproline, N-nitrosothioproline, and N-nitroso-P- methylthioproline in human urine by cigarette smoking. Cancer Letters 30(2):117-124, 1986. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse- quences of Smoking for Women. A Report of-the Surgeon General. U.S. Department of Health and Human Services. Public Health Service, Office of the Assistant Secretary for Health. Office on Smoking and Health, 1980. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse- quences of Smoking: Cancer. A Report of the Surgeon General. U.S. Department of Health and Human Services, Public Health Service, Office on Smoking and Health. DHHS Publication No. (PHSl 82-50179. 1982 617 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Gmse- quences of Smoking: Cardiovascular Disease. A Report of the Surgeon General. U.S. Department of Health and Human Services, Public Health Service, Office on Smoking and Health. DHHS Publication No. (PHS) 84-50204, 1983. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse- quences of Smoking: Chronic Obstructive Lung Disease. A Report of the Surgeon General. U.S. Department of Health and Human Services, Public Health Service, Office on Smoking and Health. DHHS Publication No. (PHS) 84-50205, 1984. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse- quences of Smoking: Cancer and Chronic Lung Disease in the Workplace. A Report of the Surgeon General. U.S. Department of Health and Human Services, Public Health Service, Office on Smoking and Health. DHHS Publication No. (PHS) 85 50207, 1985. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse- quences of Involuntary Smoking. A Report of the Surgeon Geneml. US. Depart- ment of Health and Human Services, Public Health Service, Centers for Disease Control, Office on Smoking and Health. DHHS Publication No. (CDC) 87-8398, 1986. VALENZUELA, J.E., DEFILIPPI, C., CSENDES, A. Manometric studies on the human pyloric sphincter. Effect of cigarette smoking, metoclopramide, and atropine. Gastroenterology 7@4):481483, April 1976. WADDELL, W.J., MARLOWE, C. Localization of nicotine'%, cotinine-`*C, and nicotine-1'-N-oxide-"C in tissues of the mouse. Drug Metabolism and Disposition 4(6):530-539, November-December 1976. WALD, N.J., IDLE, M., BOREHAM, J., BAILEY, A., VAN VUNAKIS, H. Serum cotinine levels in pipe smokers: Evidence against nicotine as cause of coronary heart disease. Lancet 2(8250):775-777, October 10, 1981. WANG, N., CHEN, M., SCHRALJFNAGEL, D.E., YAO, Y. The cumulative scanning electron microscopic changes in baby mouse lungs following prenatal and postnatal exposures to nicotine. Journal of Pathology 144(2):89-100, October 1984. WELLS, D.G., RUSTICK, J.M. Hypertension from smokeless tobacco. (Letter.) Anesthesiology 65:339, 1986. WEIZENFCKER, R., DEAL, W.B. Tobacco cropper's sickness. Journal of the Florida Medical Association 57(X.1:13-14, December 1970. WERNER, B. Interviews with parents of 595 children with poisoning accidents International Conference of Poison Control, June 4, 1969. WINNIFORD, M.D., WHEELAN, K.R., KREMERS, MS., UGOLINI, V., VAN DEN BERG, E. Jr., NIGGEMANN, E.H., JANSEN, D.E., HILLIS, L.D. Smoking-induced coronary vasoconstriction in patients with atherosclerotic coronary artery disease: Evidence for adrenergically mediated alterations in coronary artery tone. Circula- tion 73(4):662-667, April 1986. WIRTH, W., GOSSWALD, R. Pharmacologische Untersuchungen in der Reihe der Diphenylcarbamidsaure-thioester: II Mitt&lung. Arch. Znt. Pharmacodyn. 155:393-417, 1965. (Cited in Larson, P.S., Silvette, H. Z'obacco: Experimental and Clinical Studies, Supplement II. Baltimore, Maryland: Williams and Wilkins Co., 1971, p. 198.) YAMATAKE, Y., SASAGAWA, S., YANAURA, S. Drug responses of canine trachea, bronchus and bronchiole. Chemical and Pharmaceutical Bulletin 26:318-320, January 1978. YOSHINAGA, K., RICE, C., KRENN, J., PILOT, R.L. Effects of nicotine on early pregnancy in the rat. Biology of Reproduction 20(2):294-303, March 1979. 618 INDEX ABSORPTION buccal, 29 chewing tobacco, 281 cigarette smoke, 29, 281 lung, 29 nicotine polacrilex gum, 281 other tobacco expoeure, 29 smoking behavior, 153 ABSTINENCE (See also CESSATION OF SMOK- MG; DEPRIVATION; WITH- DRAWAL SYMPTOMS; WITH- DRAWAL SYNDROME) aggression, 203 spontaneous withdrawal assessment, 293 weight gain, relapse predictor, 440 withdrawal syndrome, reinforce- ment, 197 ACBTYLCHOLINE desynchronisation of electroenceph- alograms, 110 high-affinity binding sites, 90, 92 nicotinic cholinergic agonista, 81 receptor measurement, 53 release in cerebral cortex, 96 turnover in hippocampus and fron- tal cortex, 98 ADDICTION definitions, 7, 149, 247-248, 249- 25(x296 effecta of selected drugs, 299-303 identification of hazardous drugs, 304 nicotine and tobacco, 6, 8 perceived functions of smoking, 397 relationship to physical dependence, 296 ADOLIBCENTS epidemiological studies, 261-262 initiation of use, 259-265 multidrug use, 259265 ADOLESCENTS-ConM. negative- and positive-affect regula- tion, smoking, 399 perceptions of stress, 121 smoking prevalence, 573-577 vulnerability factors, 266-267 weight control and smoking, 438 ADVERTISING increased drug use, 365 low-yield cigarettes, health risks, 566 AGE FACTORS body weight effects, 415, 41-18, 424, 431 relapse, 316 smoking cessation, 580-581 smoking prevalence, 569, 579 ALCOHOL aversive stimuli, 286 discriminative effects, 272 multidrug use, 261-264 place conditioning, 285 prohibition and decreased use, 365 reinforcement, 282 ALCOHOL CONSUMPTION abuse, smoking as risk factor, 401 body weight, smokers vs. nonsmok- ers, 417-418, 431 cigarette consumption effects, 167 smoking prevalence among alcohol- ics, 402 ALKALOIDS, TOBACCO 2,3'dipyridyl, structure, 27 G'oxoanabasine. structure, 27 anabaseine, structure, 27 anabasine, structure, 27, 28 anatabine, structure, 27, 28 metanicotine, structure, 27 myosmine, structure, 27, 28 N-formyl-nornicotine, content, 28 N'-methylanabasine, structure, 27 N'-methylanatabine, structure, 27 619 INDEX ALKALOIDS, TOBACCO-Contd. N'-nitrosonornicotine, structure, 27 nicotine N-oxide, structure, 27 nicotyrine, structure, 27 nornicotine, structure, 27, 28 nornicotyrine, structure, 27 pharmacologic effects, 56 pseudooxynicotine, structure, 27 AMPHEH'AMINES cigarette consumption effects, 167 discrimination, 172, 275-276 ANABASINE content, 28 discrimination, nicotine-trained ani- mals, 172 respiratory and cardiovascular ef- fects, 57 structure, 27 ANTAGONISTS mecamylamine, 484-485 naloxoneprecipitated withdrawal syndrome, 297 nicotine effects in brain, reinforce ment, 192 precipitated withdrawal syndrome, 293 pretreatment, smoke intake, 166 ANIURTY consumption increases, 404 deprivation, 405 neuroticism and adult smoking habit, 402 pain thresholds, abstinence vs. high-nicotine cigarettes, 406-407 reduction, affect regulation, smok- ing, 396, 397 reduction, cognitive appraisal, 411- 412 weight gain, smokers vs. nonsmok- ers and ex-smokers, 422 withdrawal symptom, 199, 201, 204 withdrawal symptom, with nicotine polacrilex gum, 208, 210 ARBCOLINE discriminative stimulus, 172, 175 hippocampal theta activity, 109 ATROPINE discrimination, nicotine-trained ani- mals, 174 effects on desynchronixation, 109 effects on radioligand binding, 90 620 ATROPINB-Contd. low dependence potential, 285 AUDITION amplitude decreases, withdrawal symptom, 204 auditory evoked response during smoking abstinence, 202 information task, smoking effects, 385 psychological enhancement and sensory gratification, 413 vigilance tasks, smoking effects, 383 AUTONOMIC NERVOUS SYSTEM myenteric plexus, 96 peripheral cholinergic neuron stim- ulation, 79 phasic increases, emotional stimula- tion, 411 AVERSIVE THERAPY contingency contracting, 494-495 covert sensitization, 488 directed smoking, 488 less severe techniques, 492-493 rapid smoking, 501 relaxation training, 49W94 unpleasant conditions, 501 BEHAVIOR, ANIMAL associated stimuli, 309 drug seeking, 309 food intake and body weight, nic- otine administration, 434 negative-affect-reducing properties of nicotine, 407 physical activity, nicotine adminis- tration and cessation, 435 place preference or aversion, 194- 195 reinforcing drug effects, 279 self-administration of drugs, 279 BEHAVIOR, HUMAN classically conditioned, 307 cocaine deprivation, 310 compulsive drug use, 250 counseling, 502-503 drug seeking, 310 nicotine self-administration, nega- tive reinforcement, 193-194 nicotine self-administration, re sponse rates, 192 operant, 307 INDEX BEHAVIOR, HUMAN-ConM. repetitive and stereotypic drug use, 8 respondent, 367 treatment strategies, 487-503 BELGIUM body weight, smokers vs. nonsmok- ers and ex-smokers, 419, 420 BIOASSAYS cotinine and nicotine, 4243 enzyme-linked immunosorbent as- my, 43 gas chromatography, 43 mass spectrometry, 43 radioimmunoassay, 43 BIOCHEMICAL MARKERS blood cotinine, 38, 42 blood nicotine, 42 carboxyhemoglobin, 42, 514 cotinine, 515 metabolism of nicotine, 41 salivary cotinine levels, 42 thiocyanate, 514-515 urinary cotinine levels, 42 BLACK AMERICANS (See also ETHNIC GROUPS) cessation motivation and success, 510 cessation of smoking, 508-509 church and fraternal roles, 511512 coronary risk trial, 511 health care access, 569 physician influence, 511 quit-smoking treatments, 511512 smoking and quitting patterns, 510 social norms and advertising, 509- 510 sociodemographic factors, 509 BLOCKADE THERAPY mecamylamine, 484-485 opioid dependence, 484 tobacco dependence, 484-485 BLOOD carboxyhemoglobin, 39 cotinine, 38 nicotine, 30-33, 38-39 pH and nicotine measures, 41 wound healing, 600 BLOOD PRESSURE changes during abstinence or re- lapse, 202, 205 BLOOD PRBSSURE-Contd. hypertension relationship to smok- ing, 600-601 stress and nicotine, 409 BODY HEIGHT smokers vs. nonsmokers and ex- smokers, 416, 418 BODY TEMPERATURE changes, withdrawal symptom, 202 skin, changes during abstinence or relapse, 202, 205 BODY WEIGHT adipose tissue, relative nicotine lev- el, 32 carbohydrate metabolism and smok- ing, 107 changes during abstinence or re lapse, 205 control, smoking and nicotine ef- fects, 381 gains after nicotine cessation, ani- mals, 432 hypothalamic consummatory drive model, nicotine, 412-413 nicotine administration, animals, with food intake, 434 nicotine polacrilex gum, effects, 432 smokers vs. nonsmokers and ex- smokers, 414-441 smoking cessation effects, 199, 202, 439 weight loss and nicotine, animals, 432 BRAIN alpha, beta, and theta power, with smoking, Ill-112 anteroventral thalamic nucleus, 86, 94 blood-brain barrier, nicotine isome thonium penetration, 57 caudate nucleus, 94 central grey matter, 86-87 cerebellum, 94 cerebral cortex, 94 chemical mediation of nicotine, 8 cortical arousal, withdrawal symp tom, 202, 204 cortical electric potentials, with- drawal symptom, 206 cortical evoked potentials, with- drawal symptoms with nicotine polacrilex gum, 208 621 INDEX BRAINAontd. dentate gyrus, 94 electrocortical effects of nicotine, 107-l 12 expectancy and orienting waves, 115 frontoparietal cortex, 86-87 glucose utilization, nicotine stimula tion, 81, 86-88 hippocampus, 94, 99-100, 109 homovanillic acid levels after nic- otine exposure, 110 hypothalamus, 94, 97 interanteromedial thalamic nucleus, 86 interpeduncular nucleus, 86, 94, 95 interpeduncular nucleus and medi- al habenula, SH-labeled nicotine, 81 lateral geniculate body, 86 lateral habenulae, 86 lateralized affective processors mod- el, stressful conditions, 412 locus coeruleus, 95 medial habenulae, 86, 94, 95 metabolism, binding sites, 85-86 nerve cells, nicotine concentrations, 85 nicotine concentrations, animals, 82-85 nicotine levels, discrimination stim- ulus, 174 nicotine polacrilex gum, 111-112 nicotine-induced desynchronization, 109 physiological effects of nicotine in- jections, 9697 presubiculum, 94 putamen, 94 rapid nicotine uptake, 32-33 rat cerebellum, nicotine effects, 92- 93 relative nicotine level, 32 retrosplenial cortex, 86 substantia nigra pars compacta, 94 superior colliculus, 86, 94 ventral tegmental area, 86-88, 94 BUNGAROTOXIN binding sites, 47 binding studies, mammalian brain, 91-94 nicotinic choline@ receptors, 88- 89 622 BUNGAROTOXIN-ConM. receptor measurement, 53 CAFFBINE cigarette consumption effects, 167 nonreinforcer, 281 CANADA body weight, smokers vs. nonsmok- ers and ex-smokers, 417 CARBON MONOXIDE carboxyhemoglobin content, 59 smoking behavior, 154 toxicity, 59 visual information processing task, smoking effects, 384 CARBOXYHBMOGLOBIN carbon monoxide exposure, 59 concentration, 39 CARCINOGENBSIS benzofa)pyrene-tetradecanoyl phor- bol acetate, 604 bladder, 604 respiratory tract, 664 tobacco cigarettes vs. nicotine pola- crilex gum, 215 CARDIOVASCULAR SYSTEM (See also CORONARY HEART DIS- EASE) acute tolerance, 48, 49 atherosclerosis, 596598 body weight, smokers vs. nonsmok- ers and ex-smokers, 417, 422, 427 carbon monoxide effects, 596 cardiomyopathy, 599-666 contribution of nicotine, 56 coronary artery disease, 598 lowdensity lipoproteins, 596 nicotine and carbon monoxide, 116- 117 nicotine effects, 596601 stress and smoking, 118 Surgeon General's Report, 12 thrombosis, 597-598 very low-density lipoproteins, 596 CATECHOLAMINBS amniotic fluid, 603 nicotine effects on central neurons, 100 release from extra-adrenal chromaf- iin tissues, 97-98 INDEX CELLS nerve, nicotine concentrations, 85 CENTRAL NERVOUS SYSTEM nicotine concentrations, 83-84 nicotine isomethonium, 57 nicotinic cholinergic receptors, 89 pre or postsynaptic release of ace- tylcholine, 95 psychoactive drugs, 267 tranquilization effects of nicotine, 409 CESSATION OF SMOKING f&e also ABSTINENCE; DEPRIVA- TION; WITHDRAWAL SYMP- TOMS; WITHDRAWAL SYN- DROME) blacks vs. whites, 572 criteria, 516 heavy vs. light smokers, success rates, 577 males vs. females, 580, 581 measurements, 576, 580 men, neuroticism, 402 physical activity changes, 435 program development, nicotine ad- diction, 6 quit attempts, 150 quit difficulty and daily consump tion, 206 quit ratios by age and sax, 1965 to 1985, 531 relapse and psychophysiological re activity, 120 spontaneous remission, 255-259 stages, 518 Surgeon General's Report, 12 trials, 489-496 weight gain, 414, 416, 422, 423, 424, 425, 431, 439-440 CESSATION OF SMOKING, METHODS (See also NICOTINE DELIVERY, ALTERNATE; NICOTINE POLA- CRILEX GUM; NICOTINE RE PLACEMENT; TREATMENT) acupuncture, 564 contingency contracting, 494-495 hypnosis, 504 nicotine addiction, 8-9 nicotine fading, 497-499 nicotine vapor inhaler, 212 selfefflcacy, 497 CESSATION OF SMOKING, MEI'HODS-ConM. similarity to methods for other drugs, 467 stimulus control, 497 CHEMICAL DETECTION biological samples, 256, 259 interpretation, 259 sensitivity, 259 specificity, 259 CHEMICAL STRUCTURE nicotine, 27 nicotine metabolites, 35 tobacco alkaloids, minor, 27 CHEWING TOBACCO nicotine absorption, 29, 31 nicotine levels, 38 CHILDREN negative- and positive-affect regula- tion, smoking, 399 smoking and body weight beliefs, 438 CHOLINERGIC AGENTS acetylcholine release, 81 interaction with biogenic amine pathways, 98 nicotine effects on central and pe ripheral nervous systems, 96-97 CIGAR SMOKING body weight, smokers vs. nonsmok- ers, 417, 419 nicotine levels, 38 prevalence, men, 1964 to 1986, 580, 582 Surgeon General's Report, 12 CIGARIWlXS, HIGH-NICOTINE affect modulation, 405 blood nicotine levels, 39 brand loyalty, 567 carboxyhemoglobin levels, 39 effects on recall, 389 emphysema, 604 knee-jerk reflex, 45 visual information processing task, smoking effects, 384 yields of nicotine, 26 CIGARETTES, HIGH-TAR brand loyalty, 567 visual information processing task, smoking effects, 384 623 INDEX CIGARETTES, HIGH-YIELD carbon monoxide, 59 heart rate, partial tolerance, 55-56 smoking behavior, 163 CIGARETTES, LOW-NICOTINE affect modulation, 405 effects on recall, 389 emphysema, 604 knee-jerk reflex, 45 Surgeon General's Report, 12 visual information processing task, smoking effects. 3,84 CIGARETTES, LOW-TAR Surgeon General's Report, 12 visual information processing task, smoking effects, 364 CIGARETTES, LOW-YIELD carbon monoxide, 59 consumption. health risks, 566 heart rate, partial tolerance, 5.%56 vented, smoke concentration, 159- 161 COCAINE cost, 283-284 crack, 281 increase in use, 305306 multidrug use, 261-264 place conditioning, 285 starter drug, 278 COFFEE CONSUMPTION smokers vs. nonsmokers, 437 COGNITION concentration difficulty, withdrawal symptom 199 201, 204. 205. 1 1 208, 210 euphoria and dysphoria. 117 oral contraceptive use, response to stress, 118-119 stressor response among women, 118 task performance, 394 CONDITIONING behavioral tolerance, 269 cues to smoke, 465 drug use as learned behavior, 307- 309 drug-opposite response, 289 nicotine addiction 465 pharmacologic and psychological factors, 465 physiological reactions, 466 624 CONDITIONING-Contd. place preference and aversion, 194, 284 placebo effects, 309 taste aversion, 194 CONSUMPTION adolescents, 260 adolescents, stress factor, 400 adults, effects of stress, 401 body weight effects, 415, 416, 417, 419, 420, 423, 426, 431 children, smoking and body weight beliefs, 438 frequency and multiple drugs, 263- 264 heavy smokers, stress, 403 heavy vs. light smokers, smoking cessation success, 577 high-yield cigarettes, 163 multiple drugs, 260 occasional tobacco use, 253-254 prediction, 262-263 progression of drug use, 261-263 race, age, and gender factors, 579 severity of withdrawal symptoms, 206 United States, 1973 to 1987, 567 United States, estimation through taxes, 565 United States, per capita decline, 565-566 CONTROLLED SMOKING compensatory behavior, 499-500 outcomes, 499-500 parameters, 499 prospects for abstinence, 500 COPING STRATEGIES cognitive versus behavioral tech- niques, 530-531 retrospective bias, 531 self-punitive cognitions, 531 short- and long-term effects, 496 skill-based treatment, 532 skills training, 496 stimulus control, 530-531 stress and smoking habit, 402 willpower, 531 CORONARY HEART DISEASE !See also CARDIOVASCULAR SYS TEM! ischemia, mortality myocardial infarct, 598-599 INDEX CORONARY HEART DISEASE+ Contd. myocardial infarct, weight gain af- ter smoking cessation or continu- ation, 426 pharmacodynamic aspects, nicotine, 56 risk, 598 stress and smoking, 118 Surgeon General's Report, 11 CORTICOSTEROIDS corticosterone and tolerance, 52 plasma corticosterone levels, 100- 101, 103 plasma levels and cigarette smok- ing, 104-106 COST alternate nicotine delivery systems, 214 individual and social, 252 positive and negative incentives, 284 required work, 2KJ-284 time, 283 COTINmE bioassay comparison, -0 biochemical detection, 515 blood levels with nicotine polacri- lex gum, withdrawal symptoms, 209 content, 28 daily cigarette consumption, 160 discrimination, nicotine-trained ani- mals, 172 levels and severity of withdrawal symptoms, 206-207 metabolites, 34 nicotine metabolite, 34-36 structure, 27 tobacco-use marker, 36, 40 CRAVING abstinence, 205 definitions, 295 gender difference, 523 measurement problems, 211 mecamylamine effects, 485 nicotine polacrilex gum, -209, 210, 475 plasma nicotine levels, 211 precipitating factors, 211 recurrent and persistent, absti- nence, 8 relapse, 205, 523 CRAVING-ConM. sensory stimuli, 211 smokeless tobacco withdrawal symptom, 207 withdrawal symptom, 199, 201, 204 CYTISINE discrimination, nicotine-trained ani- mals, 172-173 respiratory and cardiovascular ef- fects, 57 DEMOGRAPHIC FACTORS 6'eg~) SOCIOECONOMIC FAG cigarettes and smokeless tobacco, 306 marital status, 571 smoking prevalence, 569, 571 women and youth, 396 DENMARK body weight, smokers vs. nonsmok- ers and ex-smokers, 418 DEPENDENCE aversive limits, 266 behavioral effects, 286 cross-tolerance, 292 definitions, 7, 198, 247-246, 245- 250 drug use, 12 interoceptive drug effects, 266 levels, 253 neuroadaptation, 266 physiological effects, 286 positive reinforcement, 266 potential testing, 269-270, 285-286 progression, 253 unconditioned stimuli, 266 DEPRESSION Navy men, cigarette consumption, 404 nicotine polacrilex gum, 208-210 withdrawal symptom, 201 DEPRIVATION (See also ABSTINENCE; CRSSA- TION OF SMOKING; WITH- DRAWAL SYMPTOMS; WITH- DRAWAL SYNDROME) attention span of smokers, 366 effects on memory, 336 negative affect, 405, 406 smoking rates and behavior, 164 stress, relapse, 402 625 INDEX DIAZEPAM nicotine-induced antagonism, 175 withdrawal syndrome, 297 DIET alkaline, smoking behavior, 163- 164 changes during abstinence or re- lapse, 205, 206, 433-434 changes, smokeless tobacco with- drawal symptom, 207 food intake and appetite, withdraw- al symptom, 202 food intake and smoking-related energy imbalance, 434 hunger, hypothalamic consummate ry drive model, nicotine, 412-413 hunger, withdrawal symptom with nicotine polacrilex gum, 209, 210 sweet food intake and weight gain after smoking cessation, 433-434 DISCRIMINATION behavior, 274 drug similarity, 274 generalization. 274 intravenous nicotine administration, humans, 176177 metrazol, animals, 175 nicotine, administration method, animals, 171-172 nicotine, humans, 176-177 nicotine, pentolinium pretreatment. 176-177 nicotine vs. 3-methyl-pyridylpyrolli- dine, 173 specificity, 275276 testing, 274-277 DIZZINESS acute sensitivity, 45, 47 tobacco poisoning, 595 DOPAMINE control over acetylcholine turnover, 98 cue properties of nicotine, 97 nicotine agonists, 54 stimulation by nicotine, 54 turnover and release, 100-101 DOSE CONTROL brand switching, 162 consistent nicotine intake, 158 function of time, 164 nicotine reinforcement, animals, 189-190 626 DOSE CONTROWonM. ventilated cigarette holders, 159 DOSE-RESPONSE amphetamines, 282 aversive limits, 282 biphasic effects, 44 compensatory nicotine intake, 283 heart rate changes, 56 psychoactivity, 272 self-administration and reinforce- ment, 282 self-reported effects, 274 titration-studies, nicotine, 282-283 tobacco smoke, 282 withdrawal reactions, 293 DRUG ABUSE adolescents, smoking as risk factor, 400-401 liability factors, 304 DYSPHORIA nicotine dose increases, 178 EDUCATION high school dropouts, smoking prevalence, 574 smoking prevalence, 1985, 571 ELECTROENCEPHALOGRAPHY activating effects of nicotine, 81-82 activity in rats, 52 changes during abstinence or re- lapse, 205, 206 distinct central nervous system ef- fects, 108-109 history of nicotine studies, 108-109 nicotine-induced desynchronization, 112 parallels with self-reports, 274 power spectral analysis, 110 withdrawal symptoms with nicotine polacrilex gum, 208 ELIMINATION acid loading, 40-41 alkaline loading, 4041 kinetics, 38 measurement of smoke intake, 152 renal nicotine, 4Wl tolerance measure, 289 urinary tract, 33, 34, 36, 37 EMPHYSEMA Surgeon General's Report, 11 weight gain, smokers vs. nonsmok- ers. 426 INDEX ENDOCRINE adrenal cortex, 104-106 follicle-stimulating hormone, 100- 102 growth hormone, 101 luteinizing hormone, 100-102 nicotine effects, 96 prolactin, 100-102 thyroid, 104 thyroid-stimulating hormone, 100- 102 ENVIRONMENTAL FACTORS conditioned responses, 306 contingent reinforcement, 306 drug costs, 306 economic factors, 266 individual reactions, 529 negative affect, 530 other smokers, 529-530 parental drug use, 266 peer smoking, 526 place conditioning, 284-285 relationship to direct drug effects, 308, 309 smoking cues, 526, 529-530 spousal smoking, 526-527 stimulus control, 497 stress, 536 withdrawal effects, 204, 310-311 EF'INEPHRINE levels during abstinence or relapse, 204, 205 serum concentrations, 97 JWI-INIC GROUPS (see also BLACK AMERICANS; HISPANIC AMERICANS) black Americans, 508-512 black vs. white males, smoking prevalence, 569 black vs. white pregnant smokers vs. nonsmokers, body weight, 418, 424 blacks, smokers vs. nonsmokers and ex-smokers, body weight, 419 blacks vs. whites, cigarette con- sumption, 577 blacks vs. whites, smoking preva- lence, 572, 579 Hispanic Americans, 512-513 Hispanic, smoking prevalence, 569- 570 Oriental alcoholism, 290 ETHNIC GROUPS-Contd. Oriental aversion to alcohol, 290 =-SMOKERS body weight, vs. smokers and non- smokers, 416430 spontaneous remission, 466 withdrawal symptoms, 199-200 EYES nicotine concentrations, 83 pupil enlargement after nicotine use, 274 pupillary constriction from opioids, 291 visual evoked response during smoking abstinence, 202 FINLAND body weight, smokers vs. nonsmok- ers and ex-smokers, 429 FRANCE body weight, smokers vs. nonsmok- ers and ex-smokers, 422 GANGLIA localization of nicotine, animals, 85 peripheral cholinergic neuron stim- ulation, 79 GASTROINTWTiNAL SYSTEM heartburn, 607 peptic ulcer, 605607 relative nicotine level, 32 small bowel, nicotine reabsorption, 33 stomach, nicotine concentrations, 82-83 GENETIC PREDISPOSITION adolescent drug use, 266267 vulnerability factors, 266 HAIR nicotine recovery, 33 HEADACHE acute sensitivity, 45, 47 tobacco poisoning, 595 HEART acute nicotine tolerance, 48, 49 arrhythmia, 599 nicotine concentrations, animals, 84 relative nicotine level, 32 HEART RATE abstinence or relapse, 122-123. 202, 204. 205, 206 627 INDEX HEART RATE-Co&d. acute tolerance, 48, 49 drug and environmental effects, 308 nicotine-induced tachycardia, 291 smokeless tobacco withdrawal symptom, 207 stress and nicotine, 409 stress and smoking, 118 tachycardia, 492-493 withdrawal symptom, 199, 201 withdrawal symptom with nicotine polacrilex gum, 210 HEROIN cigarette consumption effects, 167 methadone effect, 236 HEXAMETHONIUM acetylcholine release blocked, 81 attenuated amine release, 98 discrimination, nicotine-trained ani- mals, 174 inhibiting effects on nicotine, 88, 92-93 smoke-induced edema, 179 HISPANIC AMERICANS (See also ETHNIC GROUPS) gender difference, 512 physician influence, 513 prevalence of smoking, 512 smoking cessation, 512-513 smoking correlates, 512-513 HISTORICAL PERSPECTIVE addictive behavior, 269 discovery of nicotine, 10 medicinal vs. harmful effects, 9-10 nicotine addiction, 16-11 nicotine pharmacology, 10-11 tobacco use, 9 HORMONES adrenocorticotropic, acetylcholine effects, 97 adrenocorticotropic, nicotine effects, 100-103, 105-106 androgen, testosterone levels, and smoking, 106 . argmme vasopressin, nicotine- induced release, 102-103 estrogen production and metabo- lism, smoking effects, 106 pro-opiomelanocortin, acetylcholine effects, 97 628 HORMONES--Contd. pro-opiomelanocortin, factors influ- encing release, 103-104 prolactin, luteinizing, and follicle stimulating, 52 HYPOTHALAMUS consummatory drive model, nic- otine, 412-413 neuroendocrine function, 52 HYPOXEMIA fetal development, 603 subsequent behavioral abnormali- ties, 603 IMPATIENCE nicotine polacrilex gum, 210 withdrawal symptom, 199, 201 INHALATION PARAMETERS measurement techniques, 152 published values, 156-157 INITIATION aversive reactions, 264-265 dependence, cigarettes vs. nicotine polacrilex gum, 215 drug classes, 259, 261-265 environmental motivations, 278 experimental use, 265 smokeless tobacco, 265, 564 social and pharmacologic factors, 264-265 stress and early smoking onset, 399 Surgeon General's Report, 12 weight control and smoking, 436 women, neuroticism, 402 INTEROCEPTIVE EFFECTS definition, 170 dependence potential testing, 270- 271 mood and feeling, 270 morning withdrawal cues, 307-306 perception, smoke and nicotine, 179 subjective pleasure, 308 taste, airway irritation, 179 IRRITABILITY changes during abstinence or re- lapse, 205, 206 nicotine polacrilex gum, 208, 210 withdrawal symptom, 199, 201 JAPAN body weight, smokers vs. nonsmok- ers and ex-smokers, 420 INDEX KIDNEYS nicotine concentrations, 82-84 nicotine elimination, 33, 37 relative nicotine level, 32 MAINTENANCE OF SMOKINWntd. weight control, 438 LEARNING behavioral tolerance, 289 letter-digit substitution task, smok- ing effects, 386-387 nicotine and smoking effects, hu- mans and animals, 386 paired-associated, smoking effects, 387, 388 serial, retention, smoking effects, 388 state-dependent, definition, 389 verbal rote, smoking effects, 387- 388 MARIJUANA SMOKING cigarette consumption effects, 168 multidrug use, 261-264 smoking as risk factor, 401 LIVER drug detoxification and tolerance, 290 nicotine concentrations, 83-84 nicotine metabolism, 37 relative nicotine level, 32 LOBELINE discrimination, nicotine-trained ani- mals, 173 respiratory and cardiovascular ef- fects, 57 LOCOMOTOR ACTIVITY decreases with nicotine, 49, 51 nicotine induced, 53 MECAMYLAMINE brain and spinal cord effects, 89 discrimination, nicotine-trained ani- mals, 173-174 dose-response, 93 effects on desynchronization, 109 local cerebral glucose utilization, 86-88 nicotine conditioning taste aversion, 196 nicotine-induced antagonism, 175 nicotinic receptors blocked, 81 place preference, nicotine effects, 195 pretreatment, effect on conditioned reinforcer, 191 pretreatment, harshness ratings of smoke, 179 pretreatment, negative nicotine re- inforcement, 193 pretreatment, nicotine discrimina- tion, 176-177 pretreatment, nicotine polacrilex gum, discrimination, 178 pretreatment, smoke intake, 166 LUNG DISEASES bronchoconstriction, 664 cancer, Surgeon General's Report, 11 chronic bronchial wall inflamma- tion, 663 emphysema, 663 nicotine toxicity, 603604 pulmonary epithelial permeability, 604 Surgeon General's Report, 12 MEMORY (See also RECALL) delayed, smoking effects, 388 immediate, smoking effects, 388 nicotine and smoking effects, hu- mans and animals, 386 recognition study, state-dependent, 390 task performance, 394 verbal, smoking and nicotine ef- fects, 389 LUNGS afferent neuron stimulation, 116 nicotine concentrations, animals, 84 relative nicotine level, 32 LYSERGIC ACID DIETHYLAMIDE (LSD) nonreinforcer, 281, 282, 285 MAINTENANCE OF SMOKING Surgeon General's Report, 12 words and order, smoking effects, 389 METABOLISM (See also PHYSICAL ACTIVITY) animal, body weight, smoke expo- sure or nicotine administration, 436 body weight and smoking, 434, 435437 629 INDEX METABOLISM-Contd. decreased, withdrawal symptom, 263 nicotine clearance, 40 nicotine metabolites, 34, 35, 36 rate, 37 smokers vs. nonsmokers, 53 smoking cessation effects, 433, 436 METHADONE cigarette consumption effects, 167 effect on heroin use, 266 efficacy, 296 MOOD changes during abstinence or re- lapee, 205-206 hedonic systems model, negative af- fect, 411 regulation, smoking and drug use, 401 regulation, subjective well-being, smoking effects, 394-399 MORPHINE discrimination, 275-276 euphoria and self-administration, 277 physical dependence, withdrawal, 294 place conditioning, 265 MOTIVATION behavioral tolerance, 239 gender differences, 506 self-perceived reasons for smoking, 398 treatment enhancement, 332-334 MOTOR BEHAVIOR alcohol-induced muscle relaxation, 291 smoking and nicotine effects, 392 393 task performance, 394 MUCOUS MEMBRANES cardiovascular effects of nicotine, 596 MUSCLES alcohol-induced relaxation, 291 N-methylnicotinium ion, pressor and neuromuscular effects, 57 relative nicotine level, 32 tonic and phasic muscular activity, nicotine effects, 410 630 MUTAGENESIS Salmonella typhimurium assays, 605 NALOXONE cigarette consumption effects, 168 opioid withdrawal, 297 NAUSEA acute sensitivity, 45, 47 tobacco poisoning, 595 TI-IE NETHERLANDS body weight, smokers vs. nonsmok- ers and ex-smokers, 430 NEUROENDOCRINE FUNCTION nicotine effects, 95-96 NEW YORK smokeless tobacco use, 1966, 561 NEW ZEALAND body weight, smokers vs. nonsmok- ers and ex-smokers, 421 NICOTINE content, different tobaccoa, 26 intake, 40 place conditioning, 285 sensitivity, ti7 structure, 27 MCOTINE AEROSOLS respiratory sensations, plasma nic- otine levels, 179-180 tobacco-like sensations, cessation method, 166 NICOTINE CONTENT cigarettes vs. chewing tobacco, snuff, 26 high-yield cigarettes, 26 low-yield cigarettes, 26 NICOTINE DELIVERY, ALTER- NATE Bee also CESSATION OF SMOK- ING, METHODS; NICOTINE POLACRILEX GUM; NICOTINE REPLACEMENT; TREATMEN'I'l chewable product, FDA ruling, 212-213 dependence potential, 214 nicotine polacrilex gum, depen- dence and withdrawal, 20'7-206 potential for abuse with concurrent tobacco use, 213-214 tobacco cigarettes vs. nicotine pola- crilex gum, 215 INDEX NICOTINE DELIVERY, ALTERNATE-Contd. tolerance, physical dependence, withdrawal symptom alleviation, 212 toothpaste-like formulation, FDA review, 212 toxic effects, convenience, depen- dence potential, 213 NICOTINE FADING combination with self-monitoring, 498 definition, 497 low-tar and -nicotine brands, 497- 498 outcomes, 49S.499 NICOTINE MEX'ABOLISM nicotine-l'-N-oxide, 36 pathways, 34-37 tachyphylaxis, 50 NICOTINE PHARMACOLOGY addictive properties, 6 discrimination effecta, 272 pharmacokinetics, 25, 32 stimulant and depressant effects, 79 tobacco cigarettes vs. nicotine pola- crilex gum, 215 NICOTINE POLACRILEX GUM (See also CESSATION OF SMOK- ING, METHODS; NICOTINE DELIVERY, ALTERNATE; NIC- OTINE REPLACEMENT; TREATMENT) absorption, 29, 31 affect modulation, 405 blood levels of nicotine, 472 body weight effects, 432 combined with behavioral therapy, 476 coronary heart disease, 599 craving reduction, 475 dose-patient relationship, 478-479 duration of use, 478 efficacy trials, 473-474, 475-478, 486 fetal development, 60243 followup, 477 mood regulation during smoking cessation, 406 physical dependence, 210 physician trials, 476-477 poststimulus components, 115 NICOTINE POLACRILEX GUM- Gmtd. pretreatment, smoking behavior, 165 relapse, 477478 safety vs. cigarettes, 214-215 stimulus effects, 178 temporary treatment aid, 214 toxicity, 213 weight gain, 423 withdrawal symptom alleviation, 207, 208, 472 NICOTINE REPLACEMENT (See also CESSATION OF SMOK- ING, METHODS; NICOTINE DELIVERY, ALTERNATE; NIC- OTINE POLACRILEX GUM; TREATMENT) addiction treatment, 7 aerosols, 480 comparisons of preparations, 46O- 481 dependence, 481 forms and rationale, 471 nasal solutions, 479 polacrilex gum, 471-479 side effects, 480 transdermal patches, 479-480 NITROSAMINES American snuff, 605 chemical structure, 606 mainstream tobacco smoke, 605 NOREPINEPHRINE levels during abstinence or relapse, 205 neuroendocrine activity, 101 nicotine effects, 100-101 release in hypothalamus, 97 NORNICOTINE content, 28 discrimination, nicotine-trained ani- mals, 172 structure, 27 NORWAY body weight, smokers vs. nonsmok- ers and ex-smokers, 417, 418, 421, 426 OCCUPATIONS asbestos workers, 422 civil servants, 422 factory workers, 419 farm workers, 594 631 INDEX OCCUPATIONS-Contd. government workers, 418 insurance company employees, 416 manufacturing company employees, 419 nurses, 439 physicians, 438 steei workers, 419 telephone company employees, 420, 423 OPIOIDS addiction, 247 addictive patterns, 282 chipping, 253 discriminative effects, 272 fetal syndrome, 251-252 physical dependence potential, 286- 287 protracted withdrawal, 253 tolerance, 287 withdrawal, 291-294 OXOTREMORINE discrimination, nicotine-trained ani- mals, 172 muscarinic cholinergic agonist, 52 PANCREAS body weight and smoking, 107 PASSIVE SMOKING Surgeon General's Report, 12 PEER GROUPS relapse, 321-322 treatment, 334 PENTOBARBITAL depressant, cigarette consumption effects, 167 discrimination, 275-276 PERFORMANCE impairment, withdrawal symptom, 204, 205, 206 nicotine polacrilex gum, 203, 208 problem solving, attention, and memory, 391 PERIPHERAL EFFECTS OF NIC- OTINE discriminative stimulus, 173 overview, 79 PHARMACODYNAMICS cardiovascular changes, 55-56 daily smoking patterns, 55 definition, 25 dose-response, 44 632 PHARMACODYNAMICS-Contd. tolerance, 44-46 PHARMACOLOGIC TREATMENT alprazolam, 482 blockade therapy, 328 clonidine, 328329, 482-483 deterrents, 329 drug replacement therapy, 326-328 mood changes, 483-484 relief from withdrawal symptoms, 327 symptomatic treatment, 328, 481- 483 PHYSICAL ACTIVITY (See also METABOLISM) body weight differences, smokers vs. nonsmokers, 434 body weight, smoking cessation, 435 decreased energy expenditure, with- drawal symptom, 203 exercise tolerance, 600 smokers vs. nonsmokers, 435 PIPE SMOKING body weight, smokers vs. nonsmok- ers, 417, 419 coronary heart disease, 598 nicotine levels, 38 prevalence, men, 1964 to 1986, 580, 582 Surgeon General's Report, 12 POLAND body weight, smokers vs. nonsmok- ers and ex-smokers, 420 POLYDRUG DEPENDENCE adolescents, 259-260 frequency of use, 263-264 initiation of cigarette and other drug use, 259-260 prediction, 262-263 preference tests, 272-273 progression of use, 261-263 tobacco-opioids-alcohol-stimulants, 254 POTENTIALS, SENSORY EVENT- RELATED auditory function and nicotine, 112-113 contingent negative variation, 114- 115 INDEX POTENTIALS, SENSORY EVENT- RELATED--Co&d. visual function and nicotine, 11% 114 PREGNANCY amniotic fluid, nicotine recovery, 33 body weight, smokers vs. nonsmok- ers, 416, 418, 424, 426, 429 breast-milk fluid, nicotine levels, 33 low birth weight, 602 nicotine effects on animals. 602 perinatal mortality, 602 placenta, carbon monoxide and nic- otine, 602 placenta, nicotine penetration, 33 prematurity, 602 spontaneous abortion, 602 PRETREATMENT lidocaine, airway sensations, 169 nicotine, smoking behavior, 165-166 pentolinium, nicotine discrimina- tion, 176-177 pimozide, taste aversion, 196 PREVENTION OF SMOKING aversive smoking, 501-502 program development, nicotine ad- diction, 6 skills training, 501 PSEUDOOXYNICOTINE structure, 27 PSYCHIATRIC DISORDERS multiple diagnosis, 254 negative affect of smoking, 403 neuroticism, 401-402 tobacco-nicotine dependence and withdrawal, 12 PSYCHOACTIVITY drug classification, 269-270 interoceptive effects, 270 mood and feeling, 270-271 tobacco cigarettes vs. nicotine pola- crilex gum, 215 PSYCHOMOTOR PERFORMANCE letter crossing tests, smoking ef- fects, 384 smoking abstinence vs. nicotine po- lacrilex gum, 203 smoking and nicotine effects, 381 smoking effects, methodological lim- itations, 382 PSYCHOMOTOR PERFORMANCE- Contd. Stroop test, nicotine effects, 385- 386 sustained attention tasks, defini- tion, 382 PUFFING PARAMETERS definitions, 153 frequency, duration, volume, inter- puff interval, 153-154 interdependent relationships among measures, 153 measurement techniques. 151-152 published values, 156-157 visual information processing, smoking effects, 384 within-cigarette changes, nicotine dose, 155158 RAPID SMOKING aversive smoking cessation therapy, 196-197 cardiovascular and pulmonary risks, 493 comparison with other techniques, 492493 conditioned aversive response, 492 rapid puffing, 501-503 single and multicomponent proce- dures, 491492 stress, 494 tachycardia, 492-493 REACTION TIME simple and complex, smoking ef- fects, 392-393 smoking abstinence vs. nicotine polacrilex gum, 203 visual and auditory, smoking ef- fects, 385 visual information processing, smoking effects, 384 visual, smoking effects, 383 RECALL (See also MEMORY) immediate, nicotine effects, 388 short- and long-term, nicotine tab- lets, 390 state-dependent, smoking vs. no- smoking conditions, 390 verbal rote learning, smoking ef- fects, 387-388 RECEPTORS adaption to drug, 289 binding sites. minor alkaloids. 56 633 INDEX RECEPTORS-Contd. constitutional tolerance, 290 dihydro-beta-erythroidine, rat brain, 91 disuifoton, 3H-nicotine binding, 54 functional or pharmacodynamic tol- erance, 289 RECEPTORS, CHOLINERGIC distribution of `H-acetylcholine and 3H-nicotine, 80 neuron stimulation, 79 regulation of 3H-nicotine sites in mice, 80 RECEPTORS, NICOTINIC aversive effects of nicotine injec- tions, 193 binding sites, 53 chronic tolerance, 53 ganglionic and neuromuscular types, a-439 high-affinity sites, 90, 92-94 locomotor activity, 53 low-affinity sites, 90-91 peripheral nervous system, 88-89 primary and secondary binding sites, 86 radioligand binding studies, 89-92 tolerance, 54 REINFORCEMENT evaluation, 279-281 negative, behavior modification, 193 negative, nicotine injection, 193 nicotine addiction, 6 positive, continuous, intravenous nicotine, 182 positive, intermittent, intravenous nicotine, 189, 190-191 positive, nicotine, review, 183-168 potential of various drugs, 305 self-administration, 276-279 stimulus effects, 268 tobacco cigarettes vs. nicotine pola- crilex gum, 215 REINFORCERS cocaine vs. nicotine, 189-190 definition, 170 positive, biobehavioral mechanism, dependence-producing drugs, 181-182 psychoactive drugs, 8 634 RELAPSE Gee also SPONTANEOUS REMIS SION) abstinence violation effect, 532 age factors, 316 alcohol and opioid dependencies, 316 attribution theory, 525-526 biochemical detection, 313 correlates, 315, 317-319 definition, 312, 518 demographics, 520 drug dependence severity, 315-316 drug use, 8 family support, 321, 324 frequency of smoking, 521 gender differences, 520 high-risk factors, 519, 529-530 long-term abstinence difficulties, 311 measurement, 313 negative emotions, 322-324 peer drug use, 321-322 prevention skills, 330-331 psychiatric impairment, 316 quitting history, 312, 522 rates by drug class, 313-314 self-efficacy, 524-525 sensory cues, 121-123 smoking history, 521 social learning theory, 519 treatment effectiveness, 315, 320- 321 treatment modalities, 312-313 typologies, 521-522 weight gain, risk factor, 440, 523- 524 withdrawal and dependence, 522- 523 withdrawal symptom alleviation, 205 work and leisure activities, 322, 324 RESEARCH METHODS biochemical markers, 514-515 carbon monoxide, 514 carboxyhemoglobin, 514 confounding design factors, 119-120 cotinine assays, 515 nicotine dosage control, 119 self-reports, 515 study design, 513-514 suspect data, 514 R-NESS changes during abstinence or re- lapse, 205 nicotine polacrilex gum, 208, 210 withdrawal symptom, 199, 201 SEROTONIN intemeuronal communication sys- tern, 98 pharmacological effects of nicotine, 99-100 ROLLYOUR-OWN prevalence, men, 1964 to 1986, 580, 562 SEX RATIO adolescents, weight control and smoking, 438 SALIVA nicotine secretion, 33 tobacco poisoning, 595 body weight, smokers vs. nonamok- em, 415, 417, 421, 431 cessation and relapse rates, 505- 508 SATIATION comparison with comprehensive procedure, 501-502 single and multicomponent proce- dures, 488, 491 education, 506507 heavy vs. light smokers, 577 high school seniors, smoking preva- lence, 574-576 Hispanics, smoking prevalence, 569-570 SELF-ADMINISTRATION abstinence symptoms, 310 adjunctive, schedule-induced behav- ior, 278-279 alcohol, 278, 281 amphetamine, 278, 281 animal research methods, 27%Z%O behavioral process, 158 cocaine, 278-281 compulsive use, 149 drive state, 277 drug substitution, 278 environmental pressure, 278 free sampling, 277 graduation, 277-278 human and animal studies, 276 277 human research methods, LB&281 initiation, 277 intravenous nicotine, response rates, humans, 192 morphine, 278, 281 nicotine, 278-281 pentobarbiti, 278, 281 positive reinforcement, 276-277, 279 reinforcing effects, 279-280 reinitiation of drug use, 310 voluntary conditions, 279 motivation to quit, 506 neuroticism and adult smoking habit, 402 smokeless tobacco use, 1970 to 1986, 580, 583 smoking cessation rates, 580, 581 smoking prevalence, 569, 572, 573, 579 social support, 508 social values and beliefs, 507 stress and smoking, 118, 508 weight gain after smoking cessa- tion, 416, 433, 507-506 SENSATION environmental stimulus, condi- tioned reinforcers, 191 place conditioning, 284 psychological enhancement and sensory gratification, 413 INDEX SLEEP disturbances, nicotine polacrilex gum, 208, 210 disturbances, smokeless tobacco withdrawal symptom, 207 disturbances, withdrawal symptom, 202, 204, 205, 206 SMELL aversion to alcohol, 230 environmental stimulus, condi- tioned reinforcers, 191 receptors, 58-59 tobacco grade and type, 53-59 tobacco smoke, place conditioning, 285 SMOKE CONSTITUENTS acetaldehyde effects, 60 benxo(a)pyrene, 604 brand switching, 162 nonnicotine, tracheobronchial sensa- tions, 168-169 635 INDEX SMOKE INHALATION, ANIMAL lungs, spleen, intestine, and brain, nicotine concentrations, 84 SMOKELESS TOBACCO (See also SNUFF) addiction, with nicotine, 13 demographic changes, 306 nicotine dependence, 214 starter products, 265 withdrawal symptoms, 207 SMOKELESS TOBACCO USE gum and mouth diseases and neo- plasms, 213 prevalence, 1970 to 1986, 580, 583 SMOKING ANTECEDENTS anxious, aggressive, and neurotic personality traits, 402 personality measures, 402 stress, adolescents, 400 SMOKING ARTICLES ventilated cigarette holders, 159 SMOKING BEHAVIOR biochemical and behavioral mea- sures, 154 carbon monoxide intake, 154 cigarette length, 161 consistent patterns, 155 measurement techniques, 150-152 perceived functions of smoking, 397 Surgeon General's Report, 12 switching cigarette brands, 161-162 taste and smell, 58-59 SMOKING CONTROL PROGRAMS multicomponent, smoking cessation, 501-503 Surgeon General's Report, 12 SMOKING HABIT negative- and positive-affect regula- tion, 399 smoking-related disease diagnosis, 150 United States, adults, prevalence, 565-567 young adults, prevalence and con- sumption, 578 SMOKING SURVEYS adolescents, 573-577 Adult Use of Tobacco Survey, 572 Behavioral Risk Factor Surveil- lance System, 573 Current Population Survey, 573 636 SMOKING SURVEYS-Contd. Hispanic Health and Nutrition Ex- amination Survey, 569-570 National Health Interview Surveys, 56.%566, 568569, 572 self-reported smoking status, un- derreporting, 567-568 tobacco use trends, 9 SNUFF (See also SMOKELESS TOBACCO) angina pectoris, 600 dipping prevalence, 1970 to 1986, 580, 583 nicotine absorption, 29-31 nicotine levels, 38 paroxysmal hypertension, 600 SOCIAL SUPPORT buddy system, 495 gender differences, 508 global support, 527 partner support, 527-528 smoking cessation. 526-527 spouse, 495 SOCIOECONOMIC FACTORS (See also DEMOGRAPHIC FAG TORS) body weight, smokers vs. nonsmok- em, 420, 428 ethnic, class, gender differences, 505 smoking prevalence, 1985, 571 treatment and prevalence, 467 SPONTANEOUS REMISSION (See also RELAPSE) comparison by drug class, 255-259 contributing factors, 255-259 studies, 257-258 STATEDEPENDENT LEARNING abstinence vs. smoking, 393-394 definition, nicotine, humans, 181, 389 nicotine effects, 387 STATISTICAL ANALYSIS Addiction Research Center Invento- ry, 271-272 discrimination procedures, 271 Morphine Benzedrine Group scale, 271-273 overlap of drug classes, 271 STIMULANTS addiction, 247 INDEX STIMULAmnM. addictive patterns, 282 discriminative effects, 272 nicotine, 177 STRESS abstaining and coping, 528-529 adult cigarette consumption, 401 affect modulation, smoking and nic- otine effects, 405-408 affect regulation, smoking, 395-399 consumption increases, 404 elimination of nicotine, 41 Hassles Scale, 528 hedonic systems model, negative af- fect, 411 initiation and consumption risk, 413-414 lateralized affective processors mod- el, 412 low- vs. high-nicotine cigarettes, 405 management skills, 332 Navy men, smoking habit, 403-404 nicotine polacrilex gum, 405 nicotine withdrawal, conditioned re- sponses, 408 nurses, smoking habit, 403 perceived stress, 528 perceptual and painendurance thresholds, nicotine effects, 410 psychophysiological reactivity, 117- 122 reduction, gender differences, 508, 528 reduction, neurochemical role of nicotine, 408-409 reduction, smokers vs. nonsmokers, 407 relationship to relapse, 528529 risk factor for adolescent smokjng, 399-401 smoking and nicotine effects, 381 smoking cessation relapse, 402, 528 subjective well-being, smoking ef- fects, 394-395 STUDENTS high school boys, body weight and smoking, 438 high school seniors, smoking preva- lence, 574-576 junior and senior high school, stress and smoking initiation, 400 SWEDEN body weight, smokers vs. nonsmok- ers and ex-smokers, 426 SYMPATHETIC NERVOUS SYS- TEM arousal regulation with nicotine, 409 TAR CONTENT sales-weighted average yield, 566 smoking maintenance, 58 tobacco taste characteristics, 58 TASTE environmental stimulus, condi- tioned reinforcers, 191 iirst cigarette of day, 47 menthol popularity among black Americans, 510 receptors, 58 tobacco cigarettes vs. nicotine pola- crilex gum, 215 tobacco grade and type, 58 tobacco smoke, place conditioning, 285 TASTE AVERSION alcohol, 280 apomorphine vs. nicotine, 196 chlorisondomine, 196 nicotine conditioning, animals, 196 196 TAXATION reflection of cigarette consumption, 565 TERATOGBNICITY animals, 601 humans, 601-602 THERAPY approved drug uses, 298 deterrent, silver acetate, 485A86 replacement, 326323 symptomatic, 328 TOBACCO CONSTITUENTS beta-carbolines, pharmacologic ef- fects, 60 TOBACCO SUBSTITUTES smoke condensate, sensory effects, 169 TOLERANCE acquired reaction, 289 acute, tachyphylaxis, 44, 47-50 animal and human studies, 251 637 INDEX TOLERANCE-4ont.d. behavioral, 44 behavioral and physiological re- sponses to nicotine, 197 chronic, 44, 50-54 constitutional reaction, 290 cross-tolerance, 288, 292 dependence potential testing, 286 dose escalation, 50, 51 intoxication, 251 limits on escalation, 286-287 measures, 288 mechanisms, 288-290 nicotine addiction, 6 nicotine uptake, 8 pharmacodynamic, functional, 44 pharmacokinetic. dispositional, 44 toxic effects, 45 TOXICITY acute, 593-596 acute sensitivity, 45, 46 children, 595 chronic, 596 nicotine polacrilex gum, 595-596 physiological and psychological, 252 TREATMENT (See dso CESSATION OF SMOK- ING, METHODS; NICOTINE DELIVERY, ALTERNATE; NIC OTINE PGLACRILEX GUM; NICOTINE REPLACEMENT) abstinence maintenance, 503 behavioral strategies, 329-334 blockade therapy, 328 clonidine, 328-329 family support, 333 goals, 325 leisure activity skills, 331-332 loss of control, 325 methodology, 513-516 motivation enhancement, 332-334 nicotine polacrilex gum, maintain- ing physical dependence, 210 overview, 465470 peer suppcrt, 334 pharmacologic approaches, 326-329 professional contact, 333 relapse prevention skills, 330-331 relief from withdrawal symptoms, 327 replacement therapy, 326328 stress management skills, 332 symptomatic therapy, 328 638 TREMOR hand, changes during abstinence or relapse, 205 smoking effects, 392 TWINS body weight, smokers vs. nonsmok- ers, 417 TYROSINE HYDROXYLASE IN- HIBITOR histofluorescence studies, 100 UNITED KINGDOM Wales, body weight, smokers vs. nonsmokers and ex-smokers, 416 URINE acidification and cigarette consump tion, 163 cotinine, 36, 37 nicotine isomethonium, 57 nicotine-N-oxide, 36, 37 pH and stress, 41 unchanged nicotine content, 33 VISION conditioned reinforcer, nicotine de livery, 191 environmental stimulus, 191 information processing tank, smok- ing effects, 384 peripheral vision monitoring, smok- ing effects, 385 place conditioning, tobacco smoke, 285 psychological enhancement and sensory gratification, 413 rapid visual information task, smoking effects, 385 vigilance tasks, nicotine tablet ef- fects, 383 vigilance tasks, smoking effecta, 383 WEST VIRGINL4 smokeless tobacco use, 1986, 581 WITHDRAWAL SYMPTOMS (See also ABSTINENCE; CESSA- TION OF SMOKING; DEPRIVA- TION; WITHDRAWAL SYN- DROME) aggression, 203 anxiety, 199, 201, 204, 208, 210 behavioral and physiological seque- lae, 251 biting, animals, 204-205 INDEX WITHDRAWAL SYMPTOMS-Contd body temperature changes, 202 concentration difficulty, 199, 201, 204, 205, 208, 210 conditioned drug seeking, 310 craving, 199, 201, 204, 208-209, 210 depression, 201, 208-210 electroencephalography changes, 208 environmental and pharmacologic factors, 198 environmental stimuli, 310 fatigue, 201, 202, 205 further drug intake, 8 hearing amplitude decreases, 204 hunger, food intake, 202, 207, 209, 210, 412-413, 434 hypothalamic consummatory drive model, nicotine, 412413 identified, 198-199 increased heart rate, 210 irritability, impatience, 199, 201, 208, 210 measurements and techniques, 199- 200 metabolism changes, 203, 433, 436 negative affect reduction, nicotine, 408 nervousness, 199, 201 nicotine blood levels with nicotine polacrilex gum, 209 nicotine polacrilex gum, 207, 208, 472 opioids, 291, 292 performance, 208 physical complaints, 199, 201, 208 plasma nicotine levels and symp tom severity, 206207 rebound phenomena, 204 respiration rate decrease, 202 restlessness, 199, 201, 208, 210 sleep disturbances, 202, 204, 205, 206, 207, 208 stress, 402, 408, 528, 529 WITHDRAWAL SYMPTOMSXontd. tobacco cigarettes vs. nicotine pola- crilex gum, 215 weight gain, 414, 416, 422, 423, 424, 425, 431, 438, 439-440, 523 WITHDRAWAL SYNDROME (See also ABSTINENCE; CESSA- TION OF SMOKING; DEPRIVA- TION; WITHDRAWAL SYMP- TOMS) American Psychiatric Association, recognition, 295 autonomic measures, 291 behavioral, 291 dependence potential testing, 286 distinctive signs, 296-297 evidence of addiction, 6, 294295 precipitated responses, 293 protracted, 253 somatomotor measures, 291 spontaneous reactions, opioids and depressants, 292 variability, 294-295 WOMEN black, smoking prevalence, 569 body weight, smokers vs. nonsmok- ers, 420 education, 506507 electroencephalograms of neonates from smokers, 112 prolactin and breast feeding, smok- ing effects, 102 smoking prevalence, 569 social factors, 507508 stress and smoking, 400, 508 Surgeon General's Report, 12 treatment programs, 467 weight control, 439, 507-508 weight gain, 523 WORKPLACE Surgeon General's Report, 12 YUGOSLAVIA body weight, smokers vs. nonsmok- ers and ex-smokers, 425 639 f? U.S. GOVERNMENT PRINTING OFFICE: 19&3- 2 2 3 - 6 7 2 , 0