[Federal Register: August 11, 1995 (Volume 60, Number 155)] [Notices] [Page 41621-41643] From the Federal Register Online via GPO Access [wais.access.gpo.gov] [Note: The official version of this document was published in the Federal Register from camera copy provided by the Food and Drug Administration (FDA). The graphic (TIFF) files are scanned images of those Federal Register Pages. This ASCII text version of the document (TEXT) is not an official copy and has not been certified as identical to the text published in the Federal Register. The ASCII text was provided by FDA at a later time solely to facilitate online access.] [[Page 41621]] B. INDUSTRY RESEARCH ON THE DRUG EFFECTS OF NICOTINE The tobacco industry has conducted and funded extensive research to characterize nicotine's addictive potential and properties. This research includes studies on nicotine's absorption into the bodies of tobacco users, its effects on behavior, and its effects on the brain and endocrine systems.240 Sections II.B., C., and D. detail the extensive research conducted and funded by the tobacco industry on: (1) nicotine's pharmacological effects, Sec. II.B., infra; (2) how consumers use tobacco products to obtain an adequate dose of nicotine, Sec. II.C., infra; and (3) how to manipulate nicotine delivery from tobacco to provide an adequate dose to consumers, Sec. II.D., infra.240a \240\ The long history of tobacco and nicotine use for pharmacological purposes is also well known to the tobacco industry. Larson PS, Silvette H. Medical uses of tobacco (past and present), (funded by a grant from the Tobacco Industry Research Committee and presented at industry-sponsored symposium). In: VonEuler, ed. Tobacco Alkaloids and Related Compounds. New York, NY: Pergamon Press; 1965:3-11. See also Cohen, note 183, supra, at p. 1. \240a\ The extent of the industry's research on nicotine pharmacology is very likely to be even greater than that reflected in this section. According to a recent report in the New York Times, Philip Morris conducted internal research on nicotine's pharmacological effects on smokers from the late 1960's to the mid- 1980's. The Times reported that Charles Wall, a Philip Morris lawyer, confirmed that company documents showed that Philip Morris carried out extensive research on nicotine over many years. Hilts PJ. ``Documents Disclose Philip Morris Studied Nicotine's Effect on Body.'' New York Times. June 8, 1995. Documents later disclosed by Congress provide detailed evidence of Philip Morris' long-term research on nicotine pharmacology, including studies to isolate and characterize nicotine receptors in the central nervous system, the effects of nicotine/smoking on the electrical activity of the brain, the effects of nicotine on human and animal behavior, self- administration of nicotine by rats, nicotine discrimination in rats, nicotine tolerance, and the effects of nicotine administration on human physiologic function, including the relationship between blood nicotine levels and central nervous system activity. 141 Cong. Rec. H7470-76 (daily ed. July 24, 1995); 141 Cong. Rec. H7646-83 (daily ed. July 25, 2995). Philip Morris has not contested the authenticity of these documents. R.J. Reynolds, too, appears to have conducted extensive research on nicotine pharmacology that is not fully reflected here. In response to questions about that company's research on nicotine, a spokeswoman for R.J. Reynolds Tobacco Company stated that ``[w]e've not only done research on the pharmacological effects of nicotine but we've published it in at least 250 peer-reviewed journals and symposia. We're extremely proud of the quality and number of the studies.'' Collins G. ``Legal Attack on Tobacco Intensifies.'' New York Times. June 9, 1995. [[Page 41622]] --------------------------------------------------------------------------- It is important to understand why the tobacco industry has conducted this research. Tobacco industry documents show that the industry research described in the following sections was undertaken because industry officials strongly suspected, more than 30 years ago, that nicotine's pharmacological effects were vital to the successful marketing of tobacco. For example, internal BATCO documents disclose that the major BATCO-sponsored nicotine studies completed or underway in the early 1960's were undertaken ``to elucidate the effects of nicotine as a beneficent alkaloid drug'' 241 because of the belief of Sir Charles Ellis, the leading BATCO scientist, that ``we are in a nicotine rather than a tobacco industry.'' 242 \241\ See Ellis, note 232, supra, at p. 16. On the same page Ellis describes upcoming research ``to investigate whether cigarette smoke produces effects on the central nervous system characteristic of tranquilising or stimulating drugs and, if so, to see if such activity is due solely to nicotine.'' \242\ Johnson RR. Comments on nicotine. June 30, 1963. Pages 10- 11. This document goes on to reveal that these studies on nicotine's pharmacological effects were part of a broader research initiative that was being conducted by the industry and included altering nicotine delivery: The Southampton group is going to be doing a large amount of work on nicotine, and for some good reasons. To summarize: Project ARIEL [a cigarette alternative developed by BATCO]--This is dormant for the moment. The first samples tried gave a tremendous kick, even though the nicotine delivery was quite small. It would appear that the project will be reinitiated within a few months. Dr. S.R. Evelyn is presently investigating the absorption of extractable and non-extractable nicotine in the mouth * * *. Dr. J.D. Backhurst is setting up an analysis for pH of whole smoke on a puff-by-puff basis. This correlates with his previous interest in extractable nicotine. Mr. H.G. Horsewell continues to work with alkaline filter additives which selectively increase nicotine delivery. --------------------------------------------------------------------------- Another nicotine study commissioned by BATCO in the early 1960's similarly reveals that industry research on nicotine's pharmacological effects was undertaken because of the industry's understanding that consumers use tobacco to obtain those effects: There is increasing evidence that nicotine is the key factor in controlling, through the central nervous system, a number of the beneficial effects of tobacco smoke * * *. Detailed knowledge of these effects of nicotine in the body [[Page 41623]] of a smoker is therefore of vital importance to the tobacco industry.243 \243\ Geissbuhler H, Haselbach C. The Fate of Nicotine in the Body. Battelle Memorial Institute. Geneva, Switzerland. May 1963. Page 1. Report prepared by Battelle for BATCO. (Hereafter cited as: BATCO. The Fate of Nicotine in the Body.). An annual report from the Council for Tobacco Research discloses that the research it funded on nicotine's pharmacology was designed to elucidate the effects of nicotine on the smoker's central nervous --------------------------------------------------------------------------- system: Most of the pharmacological studies currently being supported by The Council are concerned with the effects of nicotine and/or smoking on the central nervous system (the brain) with the object of learning more about why people like, want, or need to smoke.244 \244\ Report of the Scientific Director, 1969-1970. Council for Tobacco Research-U.S.A. Page 13. The studies of nicotine's pharmacokinetics and pharmacodynamics described in Sec. II.B., infra, were undertaken to assist the industry in marketing products that would satisfy tobacco users' nicotine requirements. This information relating to how nicotine acted in the body was needed by the industry for additional studies specifically designed to establish the dose of nicotine required by consumers, Sec. II.C., infra. As noted in the report of one study whose purpose was to validate a method for assaying nicotine and a metabolite in --------------------------------------------------------------------------- urine: It can be concluded from the comparative studies that analysis of nicotine and cotinine in urine is likely to be a good indicator of whole body nicotine dose in man. This technique has an immediate and direct relevance for * * * human behavioural studies in the assessment of an individuals' [sic] nicotine dose in response to modification in cigarette design. [Emphasis added.] 245 \245\ BATCO Group R&D Centre. Nicotine Studies: A Second Report. Estimation of Whole Body Nicotine Dose By Urinary Nicotine and Cotinine Measurement. Report No. RD.1792. March 31, 1981. Page 1. Industry documents related to other basic research studies on nicotine show a similar nexus with product development. For example, the report from a 1974 Brown and Williamson study of nicotine's brain effects states that: The development of new products and the modification of existing ones requires that we have some knowledge of the smoker toward whom these efforts are directed. The work described in this report is focused on the acute, or immediate physiological response of smokers. Brotzge RF, Kennedy JE. Brown and Williamson. Human Smoking Studies: Acute Effect of Cigarette Smoke on Brain Wave Alpha Rhythm--First Report. October 31, 1974. Report No. 74-20. Page 1. Similarly, a 1974 BATCO study on nicotine's effects on brain electrical activity was intended to ``help elucidate the mode of action of nicotine during smoking'' so as to better understand smoker behavior in response to nicotine. BATCO Group Research & Development. Comer AK, Thornton RE. Interaction of Smoke and the Smoker Part 3: The Effect of Cigarette Smoking on the Contingent Negative Variation. Report No. RD.1164-R. December 12, 1974. Page 2. [[Page 41624]] --------------------------------------------------------------------------- Thus, this research demonstrates the tobacco industry's fundamental interest in the dose of nicotine absorbed into the systemic circulation of the tobacco user (rather than simply the amount of nicotine necessary to deliver sensory effects to the mouth of the user.) The ultimate purpose of the tobacco industry's studies on nicotine was to better understand the nicotine requirements of tobacco users and to develop products that delivered the desired pharmacological effects of nicotine. Philip Morris officials stated that the rationale for the company's extensive research program on nicotine pharmacology was that the information would strengthen Philip Morris R&D capability in developing new and improved smoking products.245a \245a\ Memorandum from W.L. Dunn to T.S. Osdene-Plans and Objectives--1979. December 6, 1978. In 141 Cong. Rec. H7669 (daily ed. July 25, 1995). Accordingly, the industry-sponsored studies described in the following sections provide further evidence that tobacco manufacturers intend to market their products to deliver the pharmacological effects of nicotine to consumers.246 \246\ The full citations for the references in notes 247 through 279 can be found in Appendix 4. Entries under the heading ``OTHER'' include studies sponsored by the Smokeless Tobacco Research Council (whose members include U.S. tobacco companies), Swedish Tobacco Co. (which has corporate relationships with both Pinkerton and U.S. Tobacco Co.), Svenska Tobaks (a subsidiary of Swedish Tobacco Co.), the Tobacco Advisory Council and the Tobacco Research Council of the U.K. (whose members included British-American Tobacco Co.), Imperial Tobacco Co. (which has corporate relationships with British-American Tobacco Co., and manufactures cigarettes that are marketed in the U.S.), Carreras Rothmans Ltd. (whose affiliated companies manufacture cigarettes that are marketed in the U.S.), Swiss Association of Cigarette Manufacturers (whose members include affiliates of U.S. tobacco companies, and the Canadian Tobacco Manufacturers Council (whose members include affiliates of U.S. tobacco companies). [[Page 41625]] --------------------------------------------------------------------------- 1. Industry Research on Nicotine's Effects on the Brain The tobacco industry has extensively studied, in its own laboratories and through grants or contracts to other laboratories, the effects of nicotine on the brain and other parts of the central nervous system, including the sites in the brain on which nicotine acts.247 \247\ COUNCIL FOR TOBACCO RESEARCH-USA Abood. Comparison of the binding of optically pure (-)- and (+)- [3H] nicotine to rat brain membranes Abood. Electrophysiological, behavioral, and chemical evidence for a noncholinergic, stereospecific site for nicotine in rat brain Abood. Receptor binding characteristics of a 3H-labeled azetidine analogue of nicotine Abood. Tritiated methylcarbamylcholine a new radioligand for studying brain nicotinic receptors Abood. Evidence for a noncholinergic site for nicotine's action in brain: Psychopharmacological, electrophysiological and receptor binding studies Abood. Acute and chronic effects of nicotine in rats and evidence for a non-cholinergic site of action Andersson. Involvement of D1 dopamine receptors in the nicotine- induced neuro-endocrine effects and depletion of diencephalic catecholamine stores in the male rat Andersson. Effects of acute central and peripheral administration of nicotine on hypothalamic catecholamine nerve terminal systems and on the secretion of adenohypophyseal hormones in the male rat Andersson. Interactions of nicotine and pentobarbitone in the regulation of telencephalic and hypothalamic catecholamine levels and turnover and of adenohypophyseal hormone secretion in the normal male rat Andersson. Effects of single injections of nicotine on the ascending dopamine pathways in the rat Andersson. Mecamylamine induced blockade of nicotine induced inhibition of gonadotrophin and TSH secretion and of nicotine induced increases of catecholamine turnover in the rat hypothalamus Andersson. Nicotine-induced increases of noradrenaline turnover in discrete noradrenaline nerve terminal systems of the hypothalamus and the median eminence of the rat and their relationship to changes in the secretion of adenohypophyseal hormones Andersson. Involvement of cholinergic nicotine-like receptors as modulators of amine turnover in various types of hypothalamic dopamine and noradrenaline nerve terminal systems and of prolactin, LH, FSH and TSH secretion in the castrated male rat Andersson. Effects of acute intermittent exposure to cigarette smoke on catecholamine levels and turnover in various types of hypothalamic DA and NA nerve terminal systems as well as on the secretion of adenohypophyseal hormones and corticosterone Andersson. 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 Andersson. Mecamylamine pretreatment counteracts cigarette smoke induced changes in hypothalamic catecholamine neuron systems and in anterior pituitary function Bhagat. Effects of chronic administration of nicotine on storage and synthesis of noradrenaline in rat brain Bhagat. Influence of chronic administration of nicotine on the turnover and metabolism of noradrenaline in the rat brain Bhagat. Effect of chronic administration of nicotine on the concentrations of adrenal enzymes involved in the synthesis and metabolism of adrenaline Bhattacharya. Influence of acute and chronic nicotine administration on EEG reactivity to drugs in rabbits: 2. Psychoactive agents Chance. A comparison of nicotine and structurally related compounds as discriminative stimuli Chang. Effect of chronic administration of nicotine on acetylcholinesterase activity in the hypothalamus and medulla oblongata of the rat brain An ultrastructural study Davies. Evidence for a noncholinergic nicotine receptor on human phagocytic leukocytes Domino. Electroencephalographic and behavioral arousal effects of small doses of nicotine: A neuropsychopharmacological study Erwin. Nicotine alters catecholamines and electrocortical activity in perfused mouse brain Essman. Changes in cholinergic activity and avoidance behavior by nicotine in differentially housed mice Fuxe. Increases in dopamine utilization in certain limbic dopamine terminal populations after a short period of intermittent exposure of male rats to cigarette smoke Fuxe. Neurochemical mechanisms underlying the neuroendocrine actions of nicotine: focus on the plasticity of central cholinergic nicotinic receptors Grenhoff. Selective stimulation of limbic dopamine activity by nicotine Grenhoff. Chronic continuous nicotine treatment causes decreased burst firing of nigral dopamine neurons in rats partially hemitransected at the meso-diencephalic junction Harfstrand. Distribution of nicotinic cholinergic receptors in the rat tel- and diencephalon: a quantitative receptor autoradiographical study using [3H]-acetylcholine, [alpha- 125I]bungarotoxin and [3H]nicotine Harsing. Dopamine efflux from striatum after chronic nicotine: evidence for autoreceptor desensitization Huganir. Phosphorylation of the nicotinic acetylcholine receptor regulates its rate of desensitization Kawamura. Differential actions of m and n cholinergic agonists on the brainstem activating system Knapp. Action of nicotine on the ascending reticular activating system Kramer. The effect of nicotine on catecholaminergic storage vesicles Lapin. Dopamine-like action of nicotine: lack of tolerance and reverse tolerance Lapin. Action of nicotine on accumbens dopamine and attenuation with repeated administration [[Page 41626]] Lindstrom. Structural and functional heterogeneity of nicotinic receptors London. Glucose metabolism: An index of nicotine action in the brain Lowy. Antagonism by cholinergic drugs of behavioural effects in cats of an anticholinergic psychotomimetic drug and enhancement by nicotine Lukas. Heterogeneity of high-affinity nicotinic [3H]acetylcholine binding sites Lukas. Pharmacological distinctions between functional nicotinic acetylcholine receptors on the PC12 rat pheochromocytoma and the TE671 human medulloblastoma Marks. Characterization of nicotine binding in mouse brain and comparison with the binding of alpha-bungarotoxin and quinuclidinyl benzilate Martin. Nicotine binding sites and their localization in the central nervous system Marty. Effects of nicotine on beta-endorphin, alpha MSH, and ACTH secretion by isolated perfused mouse brains and pituitary glands, in vitro Mitchell. Increases in tyrosine hydroxylase messenger RNA in the locus coeruleus after a single dose of nicotine are followed by time-dependent increases in enzyme activity and noradrenaline release Mitchell. Role of the locus coeruleus in the noradrenergic response to a systemic administration of nicotine Naftchi. Acute reduction of brain substance P induced by nicotine Nelsen. Chronic nicotine treatment in rats: 2. Electroencephalographic amplitude and variability changes occurring within and between structures Owman. Chronic nicotine treatment eliminates asymmetry in striatal glucose utilization following unilateral transection of the mesostriatal dopamine pathway in rats Pradhan. Effects of nicotine on self-stimulation in rats Rosecrans. Noncholinergic Mechanisms involved in the behavioral and stimulus effects of nicotine, and relationships to the process of nicotine dependence Rosecrans. Nicotine as a discriminative stimulus: a neurobehavioral approach to studying central cholinergic mechanisms Schaeppi. Nicotine treatment of selected areas of the cat brain: effects upon EEG and autonomic system Sershen. Effect of nicotine and amphetamine on the neurotoxicity of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice Sershen. Noncholinergic, saturable binding of (+/-)-[3H]nicotine to mouse brain Sershen. Nicotinic Binding Sites in the brain: properties, regulation, and putative endogenous ligands Siegel. Rapid and discrete changes in hypothalamic catecholamine nerve terminal systems induced by audiogenic stress, and their modulation by nicotine-relatinship to neuroendocrine function Silvette. The actions of nicotine on central nervous system functions Sorenson. The reducing agent dithiothreitol (DTT) does not abolish the inhibitory nicotinic response recorded from rat dorsolateral septal neurons Stadnicki. Nicotine changes in EEG and behavior after intravenous infusion in awake unrestrained cats Stadnicki. Nicotine infusion into the fourth ventricle of unrestrained cats: changes in EEG and behavior Stitzer. Effects of nicotine on fixed-interval behavior and their modification by cholinergic antagonists Sugiyama. [3H]Nicotine binding sites in developing fetal brains in rats Svensson. Effect of nicotine on dynamic function of brain catecholamine neurons Toth. Effect of nicotine on extracellular levels of neurotransmitters assessed by microdialysis in various brain regions: role of glutamic acid Toth. Effect of nicotine on levels of extracellular amino acids in regions of the rat brain in vivo Tung. Peripheral induction of burst firing in locus coeruleus neurons by nicotine mediated via excitatory amino acids Vincek. Synthesis of 4,4-ditritio-(+)-nicotine: comparative binding and distribution studies with natural enantiomer Westfall. Effect of nicotine and related substances upon amine levels in the brain Whiting. Expression of nicotinic acetylcholine receptor subtypes in brain and retina Wong. Pharmacology of nicotinic receptor-mediated inhibition in rat dorsolateral septal neurones Wong. A direct nicotinic receptor-mediated inhibition recorded intracellularly in vitro Yamamoto. Nicotine-induced EEG and behavioral arousal COUNCIL FOR TOBACCO RESEARCH--USA, Literature Review Edwards. Smoking, nicotine and electrocortical activity Fuxe. Neuroendocrine actions of nicotine and of exposure to cigarette smoke: medical implications PHILIP MORRIS TOBACCO COMPANY DeNoble. Behavioral effects of intraventricularly administered (-)-nicotine on fixed ratio schedules of food presentation in rats Sahley. Antinociceptive effects of central and systemic administrations of nicotine Vezina. The effect of acute and repeated nicotine injections on brain dopamine activation: Comparisons with morphine and amphetamine R.J. REYNOLDS COMPANY Bjercke. Anti-idiotypic antibody probes of neuronal nicotinic receptors Brazell. Effect of acute administration of nicotine on in vivo release of noradrenaline in the hippocampus of freely moving rats: a dose-response and antagonist study Collins. Modulation of Nicotine Receptors by Chronic Exposure to Nicotinic Agonists and Antagonists Gilbert. Effects of smoking/nicotine on anxiety, heart rate, and lateralization of EEG during a stressful movie Lippiello. The Role of Desensitization in CNS Nicotinic receptor function [[Page 41627]] Lippiello. Characterization of nicotinic receptors on cultured cortical neurons using anti-idiotypic antibodies and ligand binding Lippiello. The binding of L-[3H]nicotine to a single class of high affinity sites in rat brain membranes Lippiello. Identification of putative high affinity nicotinic receptors on cultured cortical neurons Lippiello. Kinetics and mechanism of L-[3H]nicotine binding to putative high affinity receptor sites in rat brain Marks. Downregulation of nicotinic receptor function after chronic nicotine infusion Mitchell. Nicotine-induced catecholamine synthesis after lesions to the dorsal or ventral noradrenergic bundle Mitchell. Regionally specific effects of acute and chronic nicotine on rates of catecholamine and 5-hydroxytryptamine synthesis in rat brain Prince. Actions of the general anesthetic propofol (2,6- diisopropylphenol) on the binding of [3H] nicotine to rat cortical membranes Pritchard. Flexible effects of quantified cigarette-smoke delivery on EEG dimensional complexity Smith. Effects of chronic and subchronic nicotine on tyrosine hydroxylase activity in noradrenergic and dopaminergic neurones in the rat brain Wonnacott. Presynaptic actions of nicotine in the CNS BROWN AND WILLIAMSON TOBACCO CORPORATION, Unpublished Brotzge. Human smoking studies: acute effect of cigarette smoke on brain wave alpha rhythm-first report BRITISH-AMERICAN TOBACCO COMPANY, LTD. Golding. Arousing and de-arousing effects of cigarette smoking under conditions of stress and mild sensory isolation Golding. Effects of cigarette smoking on resting EEG, visual evoked potentials and photic driving BRITISH-AMERICAN TOBACCO COMPANY, LTD., Unpublished Ayres. Notes from the GR & DC Nicotine Conference Comer. Interaction of smoke and the smoker part 3: the effect of cigarette smoking on the contingent negative variation BRITISH-AMERICAN TOBACCO COMPANY, LTD. Funded--Unpublished Battelle Studies Haselbach. Final report on project HIPPO II Haselbach. A tentative hypothesis on nicotine addiction Hersch. Final report on project HIPPO I Libert. Report no 1 regarding project HIPPO II Willey. Effects of nicotine on the central nervous system INDUSTRY SUPPORTED AMA/EDUCATIONAL AND RESEARCH FOUNDATION (ERF) STUDIES: Murphree. Elecroencephalographic changes in man following smoking Rosecrans. Brain area nicotine levels in male and female rats with different levels of spontaneous activity Rosecrans. Effects of nicotine on behavioral arousal and brain 5-hydroxytryptamine function in female rats selected for differences in activity Rosecrans. Brain area nicotine levels in male and female rats of two strains Schechter. Behavioral evidence for two types of cholinergic receptors in the C.N.S. Schechter. Effect of mecamylamine on discrimination between nicotine- and arecoline- produced cues Schechter. Nicotine as a discriminative cue in rats: inability of related drugs to produce a nicotine-like cueing effect Schechter. Nicotine as a discriminative stimulus in rats depleted of norepinephrine or 5-hydroxytryptamine TOBACCO RESEARCH COUNCIL LABS., U.K. Armitage. Pharmacological basis for the tobacco smoking habit Armitage. Some recent observations relating to the absorption of nicotine from tobacco smoke Armitage. Effects of nicotine on electrocortical activity and acetylcholine release from the cat cerebral cortex Armitage. Nicotine, Smoking and cortical activation Armitage. The effects of nicotine on the electrocorticogram and spontaneous release of acetylcholine from the cerebral cortex of the cat Armitage. Effects of nicotine and some nicotine-like compounds injected into the cerebral ventricles of the cat Armitage. Further evidence relating to the mode of action of nicotine in the central nervous system Balfour. A possible role for the pituitary-adrenal system in the effects of nicotine on avoidance behaviour Bhagat. The effects of nicotine and other drugs on the release of injected 3H-norepinephrine and on endogenous norepinephrine levels in the rat brain Hall. Effects of nicotine and tobacco smoke on the electrical activity of the cerebral cortex and olfactory bulb Morrison. A comparison of the effects of nicotine and physostigmine on a measure of activity in the rat Wesnes. Effects of scopolamine and nicotine on human rapid information processing performance Wesnes. The separate and combined effects of scopolamine and nicotine on human information processing OTHER Adem. Distribution of nicotinic receptors in human thalamus as visualized by 3H-nicotine and 3H-acetylcholine receptor autoradiography Adem. Quantitative autoradiography of nicotinic receptors in large cryosections of human brain hemispheres Andersson. Effects of acute central and peripheral administration of nicotine on ascending dopamine pathways in the male rat brain Evidence for nicotine induced increases of dopamine turnover in various telencephalic dopamine nerve terminal systems Cohen. Monograph on the pharmacology and toxicology of nicotine and its role in tobacco smoking Copeland. A comparison of the binding of nicotine and nornicotine stereoisomers to nicotinic binding sites in rat brain cortex Falkeborn. Chronic nicotine exposure in rat: a behavioural and biochemical study of tolerance Fuxe. On the action of nicotine and cotinine on central 5- hydroxytryptamine Fuxe. Reduction of [3H]nicotine binding in hypothalamic and cortical membranes by dopamine D1 receptors Fuxe. Regulation of endocrine function by the nicotinic cholinergic receptor Grenhoff. Nicotinic effects on the firing pattern of midbrain dopamine neurons Hasenfratz. Smoking-related subjective and physiological changes: pre- to postpuff and pre- to post cigarette Hasenfratz. Post-lunch smoking for pleasure seeking or arousal maintenance? Knott. Effects of cigarette smoking on subjective and brain evoked responses to electrical pain stimulationLarsson. Comparative analysis of nicotine-like receptor-ligand interactions in rodent brain homogenate Larsson. In vitro binding of 3H-acetylcholine to nicotinic receptors in rodent and human brain Nisell. Systemic nicotine-induced dopamine release in the rat nucleus accumbens is regulated by nicotinic receptors in the ventral tegmental area Nordberg. Effect of long-term nicotine treatment on [3H]nicotine binding sites in the rats brain Nordberg. Effect of acute and subchronic nicotine treatment on cortical acetylcholine release and on nicotinic receptors in rats and guinea-pigs Nordberg. Studies of muscarinic and nicotinic binding sites in brain Perez de la Mora. Neurochemical effects of nicotine on glutamate and GABA mechanisms in the rat brain Slotkin. Developmental Effects of Nicotine Slotkin. Effects of prenatal nicotine exposure on neuronal development: selective actions on central and peripheral catecholaminergic pathways Svensson. Effect of nicotine on single cell activity in the noradrenergic nucleus locus coeruleus Zhang. Effects of chronic treatment with (+)- and (-)- nicotine on nicotinic acetylcholine receptors and N-methyl-D-aspartate receptors in rat brain OTHER, Literature Review Edwards. Smoking, nicotine and electrocortical activity [[Page 41628]] --------------------------------------------------------------------------- Mechanisms of action: receptors, neurotransmitters, and hormones. The tobacco industry has supported sophisticated studies to identify the sites and mechanisms of nicotine's actions, as well as how the structure of the brain itself is altered by nicotine's effects on nicotinic receptors. These studies have identified the receptors in the central nervous system on which nicotine acts; shown that nicotinic receptors present in the brain of both animals and man mediate the behavioral effects of nicotine; and sought to define the location and functional properties of these nicotinic receptors in the central nervous system.248 \248\ COUNCIL FOR TOBACCO RESEARCH-USA Abood. Comparison of the binding of optically pure (-)- and (+)- [3H]nicotine to rat brain membranes Abood. Electrophysiological, behavioral, and chemical evidence for a noncholinergic, stereospecific site for nicotine in rat brain Abood. Evidence for a noncholinergic site for nicotine's action in brain: Psychopharmacological, electrophysiological and receptor binding studies Abood. Tritiated methylcarbamylcholine a new radioligand for studying brain nicotinic receptors Andersson. Intravenous injections of nicotine induce very rapid and discrete reductions of hypothalamic catecholamine levels associated with increases of ACTH, vasopressin and prolactin secretion Andersson. Effects of acute central and peripheral administration of nicotine on hypothalamic catecholamine nerve terminal systems and on the secretion of adenohypophyseal hormones in the male rat Andersson. Nicotine-induced increases of noradrenaline turnover in discrete noradrenaline nerve terminal systems of the hypothalamus and the median eminence of the rat and their relationship to changes in the secretion of adenohypophyseal hormones Andersson. Effects of single injections of nicotine on the ascending dopamine pathways in the rat Evidence for increases of dopamine turnover in the mesostriatal and mesolimbic dopamine neurons Andersson. Effects of acute central and peripheral administration of nicotine on ascending dopamine pathways in the male rat brain Evidence for nicotine induced increases of dopamine turnover in various telencephalic dopamine nerve terminal systems Britto. Immunohistochemical localization of nicotinic acetylcholine receptor subunits in the mesencephalon and diencephalon of the chick (Gallus gallus) Chance. A comparison of nicotine and structurally related compounds as discriminative stimuli Davies. Evidence for a noncholinergic nicotine receptor on human phagocytic leukocytes Fuxe. Neuroendocrine actions of nicotine and of exposure to cigarette smoke: medical implications Fuxe. Neurochemical mechanisms underlying the neuroendocrine actions of nicotine: focus on the plasticity of central cholinergic nicotinic receptors Harfstand. Distribution of nicotinic cholinergic receptors in the rat tel- and diencephalon: a quantitative receptor autoradiographical study using [3H]-acetylcholine, [alpha- 125I]bungarotoxin and [3H]nicotine Huganir. Phosphorylation of the nicotinic acetylcholine receptor regulates its rate of desensitization [[Page 41629]] Lapin. Action of nicotine on accumbens dopamine and attenuation with repeated administration Lindstrom. Structural and functional heterogeneity of nicotinic receptors Lukas. Heterogeneity of high-affinity nicotinic [3H]acetylcholine binding sites Lukas. Pharmacological distinctions between functional nicotinic acetylcholine receptors on the PC12 rat pheochromocytoma and the TE671 human medulloblastoma Marks. Characterization of nicotine binding in mouse brain and comparison with the binding of alpha-bungarotoxin and quinuclidinyl benzilate Martin. Nicotine binding sites and their localization in the central nervous system Mitchell. Increases in tyrosine hydroxylase messenger RNA in the locus coeruleus after a single dose of nicotine are followed by time- dependent increases in enzyme activity and noradrenaline release Mitchell. Role of the locus coeruleus in the noradrenergic response to a systemic administration of nicotine Owman. Chronic nicotine treatment eliminates asymmetry in striatal glucose utilization following unilateral transection of the mesostriatal dopamine pathway in rats Pradhan. Effects of nicotine on self-stimulation in rats Rosecrans. Nicotine as a discriminative stimulus: a neurobehavioral approach to studying central cholinergic mechanisms Rosecrans. Noncholinergic Mechanisms involved in the behavioral and stimulus effects of nicotine, and relationships to the process of nicotine dependence Schaeppi. Nicotine treatment of selected areas of the cat brain: effects upon EEG and autonomic system Sershen. Nicotinic Binding Sites in the brain: properties, regulation, and putative endogenous ligands Sershen. Noncholinergic, saturable binding of (+/-)-[3H]nicotine to mouse brain Sorenson. The reducing agent dithiothreitol (DTT) does not abolish the inhibitory nicotinic response recorded from rat dorsolateral septal neurons Stitzer. Effects of nicotine on fixed-interval behavior and their modification by cholinergic antagonists Sugiyama. [3H]Nicotine binding sites in developing fetal brains in rats Svensson. Effect of nicotine on dynamic function of brain catecholamine neurons Toth. Effect of nicotine on levels of extracellular amino acids in regions of the rat brain in vivo Whiting. Expression of nicotinic acetylcholine receptor subtypes in brain and retina Wong. A direct nicotinic receptor-mediated inhibition recorded intracellularly in vitro Wong. Pharmacology of nicotinic receptor-mediated inhibition in rat dorsolateral septal neurones COUNCIL FOR TOBACCO RESEARCH--USA, Literature Review Fuxe. Effects of Nicotine and exposure to cigarette smoke on discrete dopamine and noradrenaline nerve terminal systems of the telencephalon and diencephalon of the rat: Relationship to reward mechanisms and neuroendocrine functions and distribution of nicotinic binding sites in brain R.J. REYNOLDS COMPANY Bjercke. Anti-idiotypic antibody probes of neuronal nicotinic receptors Collins. Modulation of Nicotine Receptors by Chronic Exposure to Nicotinic Agonists and Antagonists Lippiello. The Role of Desensitization in CNS Nicotinic receptor function Lippiello. Characterization of nicotinic receptors on cultured cortical neurons using anti-idiotypic antibodies and ligand binding Lippiello. Identification of putative high affinity nicotinic receptors on cultured cortical neurons Lippiello. Properties of putative nicotine receptors identified on cultured cortical neurons Lippiello. Kinetics and mechanism of L-[3H]nicotine binding to putative high affinity receptor sites in rat brain Lippiello. The binding of L-[3H]nicotine to a single class of high affinity sites in rat brain membranes Marks. Downregulation of nicotinic receptor function after chronic nicotine infusion Prince. Actions of the general anesthetic propofol (2,6- diisopropylphenol) on the binding of [3H] nicotine to rat cortical membranes BRITISH-AMERICAN TOBACCO COMPANY, LTD. Unpublished Ayres. Notes from the GR & DC Nicotine Conference PHILIP MORRIS TOBACCO COMPANY, Unpublished DeNoble. Brain Sites Involved in the Mediation of the Behavioral Effects of Intraventricularly Administered (-)-nicotine DeNoble. Manuscript--Brain Sites Involved in the Mediation of the Behavioral Effects of Intraventricularly Administered (-)- nicotine INDUSTRY SUPPORTED AMA/ERF STUDIES Hirschhorn. Studies on the time course and the effect of cholinergic and adrenergic receptor blockers on the stimulus effect of nicotine Schechter. Behavioral evidence for two types of cholinergic receptors in the CNS Schechter. Effect of mecamylamine on discrimination between nicotine- and arecoline- produced cues Schechter. Nicotine as a discriminative stimulus in rats depleted of norepinephrine or 5-hydroxytryptamine TOBACCO RESEARCH COUNCIL LABS., U.K. Wesnes. The separate and combined effects of scopolamine and nicotine on human information processing Wesnes. Effects of scopolamine and nicotine on human rapid information processing performance OTHER Adem. Quantitative autoradiography of nicotinic receptors in large cryosections of human brain hemispheres Adem. Distribution of nicotinic receptors in human thalamus as visualized by 3H-nicotine and 3H-acetylcholine receptor autoradiography Copeland. A comparison of the binding of nicotine and nornicotine stereoisomers to nicotinic binding sites in rat brain cortex Fuxe. On the action of nicotine and cotinine on central 5- hydroxytryptamine Fuxe. Reduction of [3H]nicotine binding in hypothalamic and cortical membranes by dopamine D1 receptors Larsson. In vitro binding of 3H-acetylcholine to nicotinic receptors in rodent and human brain Larsson. Comparative analysis of nicotine-like receptor-ligand interactions in rodent brain homogenate Nisell. Systemic nicotine-induced dopamine release in the rat nucleus accumbens is regulated by nicotinic receptors in the ventral tegmental area Nordberg. Effect of long-term nicotine treatment on [3H]nicotine binding sites in the rats brain Nordberg. Effect of acute and subchronic nicotine treatment on cortical acetylcholine release and on nicotinic receptors in rats and guinea-pigs Nordberg. Studies of muscarinic and nicotinic binding sites in brain Slotkin. Developmental Effects of Nicotine Svensson. Effect of nicotine on single cell activity in the noradrenergic nucleus Zhang. Effects of chronic treatment with (+)- and (-)- nicotine on nicotinic acetylcholine receptors and N-methyl-D-aspartate receptors in rat brain [[Page 41630]] --------------------------------------------------------------------------- Neurotransmitters. Tobacco industry studies have shown that nicotine and its metabolites produce neurochemical and metabolic effects in the brain.249 \249\ COUNCIL FOR TOBACCO RESEARCH-USA Andersson. Effects of acute central and peripheral administration. of nicotine on ascending dopamine pathways in the male rat brain. Evidence for nicotine induced increases of dopamine turnover in various telencephalic dopamine nerve terminal systems Andersson. Mecamylamine pretreatment counteracts cigarette smoke induced changes in hypothalamic catecholamine neuron systems and in anterior pituitary function Andersson. Intravenous injections of nicotine induce very rapid and discrete reductions of hypothalamic catecholamine levels associated with increases of ACTH, vasopressin and prolactin secretion Andersson. Involvement of cholinergic nicotine-like receptors as modulators of amine turnover in various types of hypothalamic dopamine and noradrenaline nerve terminal systems and of prolactin, LH, FSH and TSH secretion in the castrated male rat Andersson. Interactions of nicotine and pentobarbitone in the regulation of telencephalic and hypothalamic catecholamine levels and turnover and of adenohypophyseal hormone secretion in the normal male rat Andersson. Effects of acute central and peripheral administration of nicotine on hypothalamic catecholamine nerve terminal systems and on the secretion of adenohypophyseal hormones in the male rat Andersson. Effects of single injections of nicotine on the ascending dopamine pathways in the rat: Evidence for increases of dopamine turnover in the mesostriatal and mesolimbic dopamine neurons Andersson. Nicotine-induced increases of noradrenaline turnover in discrete noradrenaline nerve terminal systems of the hypothalamus and the median eminence of the rat and their relationship to changes in the secretion of adenohypophyseal hormones Andersson. Mecamylamine induced blockade of nicotine induced inhibition of gonadotrophin and TSH secretion and of nicotine induced increases of catecholamine turnover in the rat hypthalamus Andersson. Effects of acute intermittent exposure to cigarette smoke on catecholamine levels and turnover in various types of hypothalamic DA and NA nerve terminal systems as well as on the secretion of adenohypophyseal hormones and corticosterone Andersson. 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 Bhagat. Influence of chronic administration of nicotine on the turnover and metabolism of noradrenaline in the rat brain Bhagat. Effect of chronic administration of nicotine on the concentrations of adrenal enzymes involved in the synthesis and metabolism of adrenaline Bhagat. Effects of chronic administration of nicotine on storage and synthesis of noradrenaline in rat brain Chang. Effect of chronic administration of nicotine on acetylcholinesterase activity in the hypothalamus and medulla oblongata of the rat brain An ultrastructural study Chiou. The ability of various nicotinic agents to release acetylcholine from synaptic vesicles Erwin. Nicotine alters catecholamines and electrocortical activity in perfused mouse brain Essman. Changes in cholinergic activity and avoidance behavior by nicotine in differentially housed mice Fuxe. Increases in dopamine utilization in certain limbic dopamine terminal populations after a short period of intermittent exposure of male rats to cigarette smoke Grenhoff. Chronic continuous nicotine treatment causes decreased burst firing of nigral dopamine neurons in rats partially hemitransected at the meso-diencephalic junction Grenhoff. Selective stimulation of limbic dopamine activity by nicotine Harsing. Dopamine efflux from striatum after chronic nicotine: evidence for autoreceptor desensitization Knapp. Action of nicotine on the ascending reticular activating system Lapin. Dopamine-like action of nicotine: lack of tolerance and reverse tolerance Lapin. Action of nicotine on accumbens dopamine and attenuation with repeated administration Lowy. Antagonism by cholinergic drugs of behavioural effects in cats of an anticholinergic psychotomimetic drug and enhancement by nicotine Marty. Effects of nicotine on beta-endorphin, alpha MSH, and ACTH secretion by isolated perfused mouse brains and pituitary glands, in vitro Mitchell. Increases in tyrosine hydroxylase messenger RNA in the locus coeruleus after a single dose of nicotine are followed by time-dependent increases in enzyme activity and noradrenaline release Mitchell. Role of the locus coeruleus in the noradrenergic response to a systemic administration of nicotine Naftchi. Acute reduction of brain substance P induced by nicotine Siegel. Rapid and discrete changes in hypothalamic catecholamine nerve terminal systems induced by audiogenic stress, and their modulation by nicotine-relatinship to neuroendocrine function Toth. Effect of nicotine on extracellular levels of neurotransmitters assessed by microdialysis in various brain regions: role of glutamic acid Toth. Effect of nicotine on levels of extracellular amino acids in regions of the rat brain in vivo Tung. Peripheral induction of burst firing in locus coeruleus neurons by nicotine mediated via excitatory amino acids Westfall. Effect of nicotine and related substances upon amine levels in the brain Westfall. Effect of nicotine and other drugs on the release of 3H-norepinephrine and 3H-dopamine from rat brain slices R.J. REYNOLDS COMPANY Brazell. Effect of acute administration of nicotine on in vivo release of noradrenaline in the hippocampus of freely moving rats: a dose-response and antagonist study Mitchell. Nicotine-induced catecholamine synthesis after lesions to the dorsal or ventral noradrenergic bundle Mitchell. Regionally specific effects of acute and chronic nicotine onrates of catecholamine and 5-hydroxytryptamine synthesis in rat brain Smith. Effects of chronic and subchronic nicotine on tyrosine hydroxylase activity in noradrenergic and dopaminergic neurones in the rat brain BRITISH-AMERICAN TOBACCO COMPANY, LTD. Unpublished Haselbach. Tentative Hypothesis on Nicotine Addiction Haselbach. Final Report on Project HIPPO II INDUSTRY SUPPORTED SYMPOSIA Joseph. Possible mechanisms underlying beneficial effects of nicotine in cognitive function Nordberg. Assessment of cholinergic neuronal activity in the brain INDUSTRY SUPPORTED AMA/ERF STUDIES Rosecrans. Effects of nicotine on behavioral arousal and brain 5-hydroxytryptamine function in female rats selected for differences in activity Schechter. Nicotine as a discriminative stimulus in rats depleted of norepinephrine or 5-hydroxytryptamine TOBACCO RESEARCH COUNCIL LABS., U.K. Armitage. Effects of nicotine on electrocortical activity and acetylcholine release from the cat cerebral cortex Armitage. The effects of nicotine on the electrocorticogram and spontaneous release of acetylcholine from the cerebral cortex of the cat Armitage. Further evidence relating to the mode of action of nicotine in the central nervous system Balfour. A possible role for the pituitary-adrenal system in the effects of nicotine on avoidance behaviour Bhagat. The effects of nicotine and other drugs on the release of injected 3H-norepinephrine and on endogenous norepinephrine levels in the rat brain OTHER Fuxe. Regulation of endocrine function by the nicotinic cholinergic receptor Fuxe. On the action of nicotine and cotinine on central 5- hydroxytryptamine neurons Grenhoff. Nicotinic effects on the firing pattern of midbrain dopamine neurons Nisell. Systemic nicotine-induced dopamine release in the rat nucleus accumbens is regulated by nicotinic receptors in the ventral tegmental area Nordberg. Effect of acute and subchronic nicotine treatment on cortical acetylcholine release and on nicotinic receptors in rats and guinea-pigs Perez de la Mora. Neurochemical effects of nicotine on glutamate and GABA mechanisms in the rat brain Slotkin. Effects of prenatal nicotine exposure on neuronal development: selective actions on central and peripheral catecholaminergic pathways OTHER, Literature Review Edwards. Smoking, nicotine and electrocortical activity [[Page 41631]] --------------------------------------------------------------------------- These studies show that nicotine exerts its behavior modifying effects, in part, through the cascade of effects that are produced through nicotine's actions on existing brain chemicals. Industry- supported studies show that nicotine, like other addictive drugs, acts on dopaminergic receptors 250 in the mesolimbic system to release [[Page 41632]] dopamine, a chemical in the brain associated with pleasurable feelings. \250\ COUNCIL FOR TOBACCO RESEARCH-U.S.A Abood. Receptor binding characteristics of a 3H-labeled azetidine analogue of nicotine Andersson. Mecamylamine induced blockade of nicotine induced inhibition of gonadotrophin and TSH secretion and of nicotine induced increases of catecholamine turnover in the rat hypothalmus Andersson. Effects of acute intermittent exposure to cigarette smoke on catecholamine levels and turnover in various types of hypothalamic DA and NA nerve terminal systems as well as on the secretion of adenohypophyseal hormones and corticosterone Andersson. Effects of single injections of nicotine on the ascending dopamine pathways in the rat. Evidence for increases of dopamine turnover in the mesostriatal and mesolimbic dopamine neurons Andersson. Involvement of cholinergic nicotine-like receptors as modulators of amine turnover in various types of hypothalamic dopamine and noradrenaline nerve terminal systems and of prolactin, LH, FSH and TSH secretion in the castrated male rat Andersson. Interactions of nicotine and pentobarbitone in the regulation of telencephalic and hypothalamic catecholamine levels and turnover and of adenohypophyseal hormone secretion in the normal male rat Andersson. Effects of acute central and peripheral administration of nicotine on hypothalamic catecholamine nerve terminal systems and on the secretion of adenohypophyseal hormones in the male rat Erwin. Nicotine alters catecholamines and electrocortical activity in perfused mouse brain Fuxe. Increases in dopamine utilization in certain limbic dopamine terminal populations after a short period of intermittent exposure of male rats to cigarette smoke Grenhoff. Selective stimulation of limbic dopamine activity by nicotine Harsing. N-type calcium channels are involved in the dopamine releasing effect of nicotine Lapin. Action of nicotine on accumbens dopamine and attenuation with repeated administration Lapin. Dopamine-like action of nicotine: lack of tolerance and reverse tolerance Westfall. Effect of nicotine and other drugs on the release of 3H-norepinephrine and 3H-dopamine from rat brain slices R.J. REYNOLDS COMPANY Lippiello. The role of desensitization in CNS nicotinic receptor function Marks. Downregulation of nicotinic receptor function after chronic nicotine infusion INDUSTRY SUPPORTED SYMPOSIA Joseph. Possible mechanisms underlying beneficial effects of nicotine in cognitive function OTHER Adem. Quantitative autoradiography of nicotinic receptors in large cryosections of human brain hemispheres Andersson. Effects of acute central and peripheral administration of nicotine on ascending dopamine pathways in the male rat brain. Evidence for nicotine-induced increases of dopamine turnover in various telencephalic dopamine nerve terminal systems Fuxe. Regulation of endocrine function by the nicotinic cholinergic receptor Grenhoff. Nicotinic effects on the firing pattern of midbrain dopamine neurons Nisell. Systemic nicotine-induced dopamine release in the rat nucleus accumbens is regulated by nicotinic receptors in the ventral tegmental area --------------------------------------------------------------------------- Mood modification and EEG effects. In tobacco industry-sponsored trials, nicotine has been shown to induce both behavioral arousal and calming effects.251 These effects have been correlated with [[Page 41633]] electroencephalogram/electrocorticogram changes in electrical activity in the brain.252 Whether nicotine provides a stimulating or calming effect depends on the dose of nicotine taken, the time elapsed since the last dose, and other factors.253 \251\ COUNCIL FOR TOBACCO RESEARCH-USA Domino. Electroencephalographic and behavioral arousal effects of small doses of nicotine: A neuropsychopharmacological study Heimstra. The effects of deprivation of cigarette smoking on psychomotor performance Marks. Genetics of nicotine response in four inbred strains of mice Nelsen. Improvement of performance on an attention task with chronic nicotine treatment in rats Pradhan. Effects of nicotine on several schedules of behavior in rats Schaeppi. Nicotine treatment of selected areas of the cat brain: effects upon EEG and autonomic system Stadnicki. Nicotine infusion into the fourth ventricle of unrestrained cats: changes in EEG and behavior Stadnicki. Nicotinic changes in EEG and behavior after intravenous infusion in awake unrestrained cats Yamamoto. Nicotine-induced EEG and behavioral arousal COUNCIL FOR TOBACCO RESEARCH-USA, Literature Review Silvette. The actions of nicotine on central nervous system functions R.J. REYNOLDS COMPANY Lippiello. Properties of putative nicotine receptors identified on cultured cortical neurons Pritchard. Electroencephalographic effects of cigarette smoking Robinson. The role of nicotine in tobacco use BRITISH-AMERICAN TOBACCO COMPANY, LTD. Golding. Arousing and de-arousing effects of cigarette smoking under conditions of stress and mild sensory isolation Mangan. The effects of cigarette smoking on vigilance performance BRITISH-AMERICAN TOBACCO COMPANY, LTD. Unpublished Comer. Interaction of Smoke and the Smoker Part 3: The Effect of Cigarette Smoking on the Contingent Negative Variation Thornton. Some ``Benefits'' of Smoking INDUSTRY SUPPORTED SYMPOSIA Joseph. Possible mechanisms underlying beneficial effects of nicotine in cognitive function Wesnes. The effects of cigarette smoking and nicotine tablets upon human attention INDUSTRY SUPPORTED AMA/ERF STUDIES Rosecrans. Effects of nicotine on behavioral arousal and brain 5-hydroxytryptamine function in female rats selected for differences in activity TOBACCO RESEARCH COUNCIL LABS., U.K. Armitage. Effects of nicotine on electrocortical activity and acetylcholine release from the cat cerebral cortex Armitage. Nicotine, smoking and cortical activation Hall. Effects of nicotine and tobacco smoke on the electrical activity of the cerebral cortex and olfactory bulb Morrison. Antagonism by antimuscarinic and ganglion-blocking drugs of some of the behavioural effects of nicotine Morrison. The occurrence of tolerance to a central depressant effect of nicotine Warwick. Experimental studies of the behavioural effects of nicotine OTHER Cohen. Monograph on the ``Pharmacology and Toxicology of Nicotine and its Role in Tobacco Smoking Draft Edwards. Evidence of more rapid stimulus evaluation following cigarette smoking Golding. Effects of cigarette smoking on measures of arousal, response suppression, and excitation/inhibition balance Nordberg. Effect of nicotine on passive avoidance behaviour and motoric activity in mice \252\ COUNCIL FOR TOBACCO RESEARCH-USA Domino. Electroencephalographic and behavioral arousal effects of small doses of nicotine: A neuropsychopharmacological study Erwin. Nicotine alters catecholamines and electrocortical activity in perfused mouse brain Kawamura. Differential actions of m and n cholinergic agonists on the brainstem activating system Marty. Effects of nicotine on beta-endorphin, alpha MSH, and ACTH secretion by isolated perfused mouse brains and pituitary glands, in vitro Nelsen. Chronic nicotine treatment in rats 2 Electroencephalographic amplitude and variability changes occurring within and between structures Schaeppi. Nicotine treatment of selected areas of the cat brain: effects upon EEG and autonomic system Stadnicki. Nicotine infusion into the fourth ventricle of unrestrained cats: changes in EEG and behavior Stadnicki. Nicotinic changes in EEG and behavior after intravenous infusion in awake unrestrained cats Yamamoto. Nicotine-induced EEG and behavioral arousal COUNCIL FOR TOBACCO RESEARCH-USA, Literature Review Silvette. The actions of nicotine on central nervous system functions PHILIP MORRIS TOBACCO COMPANY Mangan. Relationships between photic driving, nicotine and memory (One Philip Morris document explains why the company decided to conduct nicotine-related EEG research: ``We are establishing an EEG laboratory in search of the reinforcing event. Brain waves are neuro-physiological phenomena, but they are legitimate subject matter for us in that brain events underlie behavioral events. Smoke-related changes in brain waves can give us clues as to smoke- related psychological changes.'' Philip Morris employee (almost certainly W.L. Dunn). Smoker Psychology Program Review. October 19, 1977. Page 9.) R.J. REYNOLDS COMPANY Gilbert. Effects of smoking/nicotine on anxiety, heart rate, and lateralization of EEG during a stressful movie Pritchard. Flexible effects of quantified cigarette-smoke delivery on EEG dimensional complexity Pritchard. Electroencephalographic effects of cigarette smoking Robinson. Psychopharmacological effects of smoking a cigarette with typical ``tar'' and carbon monoxide yields but minimal nicotine BROWN AND WILLIAMSON TOBACCO CORPORATION, Unpublished Brotzge. Human smoking studies: acute effect of cigarette smoke on brain wave alpha rhythm-first report BRITISH-AMERICAN TOBACCO COMPANY, LTD. Golding. Effects of cigarette smoking on resting EEG, visual evoked potentials and photic driving Golding. Arousing and de-arousing effects of cigarette smoking under conditions of stress and mild sensory isolation Golding. Effects of cigarette smoking on measures of arousal, response suppression, and excitation/inhibition balance BRITISH-AMERICAN TOBACCO COMPANY, LTD. Unpublished Comer. Interaction of smoke and the smoker. Part 3: The effect of cigarette smoking on the contingent negative variation Willey. Effects of nicotine on the central nervous system INDUSTRY SUPPORTED AMA/ERF STUDIES Murphree. Elecroencephalographic changes in man following smoking TOBACCO RESEARCH COUNCIL LABS., U.K. Armitage. Effects of nicotine on electrocortical activity and acetylcholine release from the cat cerebral cortex Armitage. The effects of nicotine on the electrocorticogram and spontaneous release of acetylcholine from the cerebral cortex of the cat Armitage. Pharmacological basis for the tobacco smoking habit Ashton. The use of event-related slow potentials of the brain as a means to analyse the effects of cigarette smoking and nicotine in humans Hall. Effects of nicotine and tobacco smoke on the electrical activity of the cerebral cortex and olfactory bulb OTHER Edwards. Smoking, nicotine and electrocortical activity Knott. Effects of cigarette smoking on subjective and brain evoked responses to electrical pain stimulation Knott. Reaction time, noise distraction and autonomic responsivity in smokers and non-smokers \253\ INDUSTRY SUPPORTED AMA/ERF STUDIES Rosecrans. Effects of nicotine on behavioral arousal and brain 5-hydroxytryptamine function in female rats selected for differences in activity R.J. REYNOLDS COMPANY Robinson. Psychopharmacological effects of smoking a cigarette with typical ``tar'' and carbon monoxide yields but minimal nicotine BRITISH-AMERICAN TOBACCO COMPANY, LTD. Mangan. The effects of cigarette smoking on vigilence performance COUNCIL FOR TOBACCO RESEARCH-USA Domino. Electroencephalographic and behavioral arousal effects of small doses of nicotine: A neuropsychopharmacological study Marks. Genetics of nicotine response in four inbred strains of mice Pradhan. Effects of nicotine on several schedules of behavior in rats Yamamoto. Nicotine-induced EEG and behavioral arousal TOBACCO RESEARCH COUNCIL LABS, U.K. Warwick. Experimental studies of the behavioral effects of nicotine [[Page 41634]] --------------------------------------------------------------------------- Effects on performance and behavior. Industry-funded scientists have conducted research to characterize nicotine's effects on behavioral performance and cognitive function.254 \254\ COUNCIL FOR TOBACCO RESEARCH-USA Bhagat. Effect of nicotine on the swimming endurance of rats Heimstra. The effects of deprivation of cigarette smoking on psychomotor performance Levin. Memory enhancing effects of nicotine Marks. Genetics of nicotine response in four inbred strains of mice Nelsen. Chronic nicotine treatment in rats Nelsen. Protection by nicotine from behavioral disruption caused by reticular formation stimulation in the rat Nelsen. Improvement of performance on an attention task with chronic nicotine treatment in rats COUNCIL FOR TOBACCO RESEARCH-USA, Literature Reviews Essman. Drug effects and learning and memory processes Silvette. The actions of nicotine on central nervous system functions PHILIP MORRIS TOBACCO COMPANY Colrain. Effects of post-learning smoking on memory consolidation.DeNoble. Behavioral effects of intraventricularly administered (-)-nicotine on fixed ratio schedules of food presentation in rats Mangan. Relationships between photic driving, nicotine and memory Woodson. Effects of nicotine on the visual evoked response R.J. REYNOLDS COMPANY Pritchard. Enhancement of continuous performance task reaction time by smoking in non-deprived smokers Pritchard. Electroencephalographic effects of cigarette smoking BRITISH-AMERICAN TOBACCO COMPANY, LTD. Mangan. The effects of cigarette smoking on vigilance performance Mangan. The effects of smoking on memory consolidation INDUSTRY SUPPORTED AMA/ERF STUDIES Schechter. C.N.S. effect of nicotine as the discriminative stimulus for the rat in a T-maze TOBACCO RESEARCH COUNCIL LABS., U.K. Armitage. Pharmacological basis for the tobacco smoking habit Balfour. A possible role for the pituitary-adrenal system in the effects of nicotine on avoidance behaviour Morrison. Effects of nicotine on motor co-ordination and spontaneous activity in mice Morrison. The effects of nicotine on punished behaviour Warwick. Experimental studies of the behavioral effects of nicotine Wesnes. Effects of nicotine on stimulus sensitivity and response bias in a visual vigilance task Wesnes. The separate and combined effects of scopolamine and nicotine on human information processing Wesnes. Effects of scopolamine and nicotine on human rapid information processing performance Wesnes. Effects of smoking on rapid information processing performance TOBACCO RESEARCH COUNCIL, UK, Literature Reviews Hall. New evidence for a relationship between tobacco smoking, nicotine dependence, and stress Wesnes. Smoking, nicotine and human performance OTHER Andersson. Effects of cigarette smoking on incidental memory Battig. The effect of pre- and post-trial application of nicotine on the 12 problems of the Hebb-Williams-test in the rat Driscoll. Effects of nicotine on the shuttlebox behavior of trained guinea pigs Hasenfratz. Action profiles of smoking and caffeine: Stoop effect, EEG, and peripheral physiology Hasenfratz. Can smoking increase attention in rapid information processing during noise? Knott. Reaction time, noise distraction and autonomic responsivity in smokers and non-smokers Knott. Noise and task induced distraction effects on information processing: Sex differences in smokers and non-smokers Nordberg. Effect of nicotine on passive avoidance behaviour and motoric activity in mice Roth. Smoking deprivation in ``early'' and ``late'' smokers and memory functions Wesnes. The effects of cigarettes of varying yield on rapid information processing [[Page 41635]] --------------------------------------------------------------------------- Neuroendocrine effects. Tobacco industry-supported studies have demonstrated that nicotine affects hormone secretion and several endocrine functions involved in modulation of mood and behavior. These studies showed that nicotine stimulates the secretion of corticosteroids and catecholamines and decreases the secretion of thyroid stimulating hormone, leutinizing hormone, and prolactin.255 \255\ COUNCIL FOR TOBACCO RESEARCH-USA Andersson. Involvement of D1 dopamine receptors in the nicotine- induced neuro-endocrine effects and depletion of diencephalic catecholamine stores in the male rat Andersson. Effects of withdrawal from chronic exposure to cigarette smoke on hypothalamic and preoptic catecholamine nerve terminal systems and on the secretion of pituitary hormones in the male rat Andersson. Nicotine-induced increases of noradrenaline turnover in discrete noradrenaline nerve terminal systems of the hypothalamus and the median eminence of the rat and their relationship to changes in the secretion of adenohypophyseal hormones Andersson. Mecamylamine induced blockade of nicotine induced inhibition of gonadotrophin and TSH secretion and of nicotine induced increases of catecholamine turnover in the rat hypothalamus Andersson. Effects of acute intermittent exposure to cigarette smoke on catecholamine levels and turnover in various types of hypothalamic DA and NA nerve terminal systems as well as on the secretion of adenohypophyseal hormones and corticosterone Andersson. Involvement of cholinergic nicotine-like receptors as modulators of amine turnover in various types of hypothalamic dopamine and noradrenaline nerve terminal systems and of prolactin, LH, FSH and TSH secretion in the castrated male rat Andersson. Effects of acute central and peripheral administration of nicotine on hypothalamic catecholamine nerve terminal systems and on the secretion of adenohypophyseal hormones in the male rat Fuxe. Neuroendocrine actions of nicotine and of exposure to cigarette smoke: medical implications Fuxe. Neurochemical mechanisms underlying the neuroendocrine actions of nicotine: focus on the plasticity of central cholinergic nicotinic receptors Fuxe. Effects of Nicotine and exposure to cigarette smoke on discrete dopamine and noradrenaline nerve terminal systems of the telencephalon and diencephalon of the rat: Relationship to reward mechanisms and neuroendocrine functions and distribution of nicotinic binding sites in brain Marty. Effects of nicotine on beta-endorphin, alpha MSH, and ACTH secretion by isolated perfused mouse brains and pituitary glands, in vitro Rubin. Nicotine-induced stimulation of steroidogenesis in adrenocortical cells of the cat Siegel. Rapid and discrete changes in hypothalamic catecholamine nerve terminal systems induced by audiogenic stress, and their modulation by nicotine-relatinship to neuroendocrine function Westfall. Effect of 4.4'-biphenylenebis-[(2-oxoethylene)-bis- (2,2'-diethoxyethyl)] dimethylammonium dibromide (DMAE) on accumulation and nicotine-induced release of norepinephrine in the heart Westfall. Specificity of blockade of the nicotine-induced release of 3H-norepinephrine from adrenergic neurons of the guinea- pig heart by various pharmacological agents R.J. REYNOLDS COMPANY Mitchell. Regionally specific effects of acute and chronic nicotine on rates of catecholamine and 5-hydroxytryptamine synthesis in rat brain TOBACCO RESEARCH COUNCIL LABS., U.K. Balfour. A possible role for the pituitary-adrenal system in the effects of nicotine on avoidance behaviour OTHER Fuxe. Regulation of endocrine function by the nicotinic cholinergic receptor --------------------------------------------------------------------------- 2. Industry Research on Nicotine Delivery to the Blood and Brain The tobacco industry has studied the bioavailability of nicotine in tobacco products and how nicotine is distributed throughout the body, after absorption into the bloodstream. This has led to the industry's development of sophisticated techniques for determining, quantitatively and qualitatively, the presence of nicotine and its metabolites in body fluids.256 \256\ AMERICAN TOBACCO COMPANY Castro. Nicotine antibodies: comparison of ligand specificities of antibodies produced against two nicotine conjugates COUNCIL FOR TOBACCO RESEARCH-USA Castro. Nicotine enzyme immunoassay Castro. Radioimmunoassays of drugs of abuse in humans: a review Haines. Radioimmunoassay of plasma nicotine in habituated and naive smokers McNiven. Determination of nicotine in smokers' urine by gas chromatography Monji. Plasma nicotine pharmacokinetics in dogs after intravenous administration: determination by radioimmunassay R.J. REYNOLDS COMPANY Caldwell. Characterization of the glucuronide conjugate of cotinine: a previously unidentified major metabolite of nicotine in smokers' urine Davis. The determination of nicotine and cotinine in plasma Kyerematen. Radiometric high performance liquid chromatographic assay for nicotine and twelve of its metabolites Kyerematen. Pharmacokinetics of nicotine and 12 metabolites in the rat Langone. Idiotype-anti-idiotype hapten immunoassays: assay for cotinine McManus. A new quantitative thermospray LC-MS method for nicotine and its metabolites in biological fluids BRITISH-AMERICAN TOBACCO COMPANY, Unpublished Backhurst. Further work on extractable nicotine Isaac. The absorption and effects of nicotine from inhaled tobacco smoke Read. Method for nicotine and cotinine in blood and urine Read. Nicotine studies: A second report. Estimation of whose body nicotine dose by urinary nicotine and contine measurement BRITISH-AMERICAN TOBACCO COMPANY, LTD. Funded--Battelle Unpublished Studies Geissbuhler. The fate of nicotine in the body Haselbach. A tentative hypothesis on nicotine addiction TOBACCO RESEARCH COUNCIL LABS., U.K. Armitage. The transfer of endogenous and exogenous radioisotopically labelled nicotine to mainstream cigarette smoke and its absorption into the blood of anaesthetized cats Beckett. Analysis of nicotine-1-N-oxide in urine, in the presence of nicotine and cotinine, and its application to the study of in vivo nicotine metabolism in man OTHER Biber. Determination of nicotine and cotinine in human serum and urine: an interlaboratory study Isaac. Cigarette smoking and plasma levels of nicotine Schievelbein. Nicotine Workshop Schmiterlow. Distribution of Nicotine in the Central Nervous System Schmiterlow. Tissue distribution of C14-nicotine and Related Compounds Szuts. Long-term fate of [14C]nicotine in the mouse: retention in the bronchi, melanin-containing tissues and urinary bladder wall [[Page 41636]] --------------------------------------------------------------------------- Nicotine pharmacokinetics. Numerous publications document the tobacco industry's involvement in investigating all aspects of the pharmacokinetics of nicotine. (Pharmacokinetics is the study of the absorption, distribution, metabolism, and elimination of drugs in the body.) Areas that the industry has researched include: general pharmacokinetics of nicotine (absorption, distribution, metabolism, elimination); 257 \257\ COUNCIL FOR TOBACCO RESEARCH-USA Becker. Studies on nicotine absorption during pregnancy Haines. Radioimmunoassay of plasma nicotine in habituated and naive smokers Hibberd. Enzymology of the metabolic pathway from nicotine to cotinine, in vitro Kershbaum. Cigarette, cigar, and pipe smoking. Some differences in biochemical effects Monji. Plasma nicotine pharmacokinetics in dogs after intravenous administration: determination by radioimmunoassay Rama. Distribution and Retention of nicotine and its major metabolite cotinine in the rat as a function of time COUNCIL FOR TOBACCO RESEARCH-USA, Literature Reviews Larson. Tobacco--Experimental and Clinical Studies Larson. Tobacco--Experimental and Clinical Studies--A Comprehensive Account of the World Literature--Supplement I Larson. Tobacco--Experimental and Clinical Studies--A Comprehensive Account of the World Literature--Supplement II Larson. Tobacco--Experimental and Clinical Studies--A Comprehensive Account of the World Literature --Supplement III AMERICAN TOBACCO COMPANY Haag. Studies on the fate of nicotine in the body I: The effect of pH on the urinary excretion of nicotine by tobacco smokers Larson. Studies on the fate of nicotine in the body VI: Observations on the relative rate of elimination of nicotine by the dog, cat, rabbit and mouse Larson. Studies on the fate of nicotine in the body II: On the fate of nicotine in the dog Larson. Studies on the fate of nicotine in the body IV: Observations on the chemical structure of an end product of nicotine metabolism McKennis. N-methylation of nicotine and cotinine in vivo Owen. Studies on the fate of nicotine in the animal body. VIII: Observations on the number and chemical nature of nicotine metabolites in the dog and cat Weatherby. Rate of elimination of nicotine by the rabbit R.J. REYNOLDS COMPANY Caldwell. Characterization of the glucuronide conjugate of cotinine: a previously unidentified major metabolite of nicotine in smokers' urine Caldwell. Intragastric nitrosation of nicotine is not a significant contributor to nitrosamine exposure deBethizy. Chemical and biological studies of a cigarette that heats rather than burns tobacco deBethizy. Absorption of nicotine from a cigarette that does not burn tobacco Hammond. Metabolism of nicotine by rat liver cytochromes P-450: Assessment utilizing monoclonal antibodies to nicotine and cotinine Kyerematen. Pharmacokinetics of nicotine and 12 metabolites in the rat Kyerematen. Disposition of nicotine and eight metabolites in smokers and nonsmokers: Identification in Smokers of two metabolites that are longer lived than cotinine BROWN AND WILLIAMSON TOBACCO CORPORATION, Unpublished Brotzge. Human smoking studies: acute effect of cigarette smoke on brain wave alpha rhythm--first report BRITISH-AMERICAN TOBACCO COMPANY, LTD., Funded--Unpublished Battelle Studies Geissbuhler. The fate of nicotine in the body TOBACCO RESEARCH COUNCIL LABS., U.K. Armitage. Absorption and metabolism of nicotine from cigarettes Armitage. Absorption of nicotine in cigarette and cigar smoke through the oral mucosa Armitage. The transfer of endogenous and exogenous radioisotopically labelled nicotine to mainstream cigarette smoke and its absorption into the blood of anaesthetized cats Beckett. Effect of smoking on nicotine metabolism in vivo in man Beckett. Analysis of nicotine-1-N-oxide in urine, in the presence of nicotine and cotinine, and its application to the study of in vivo nicotine metabolism in man Beckett. Buccal absorption of basic drugs and its application as an in vivo model of passive drug transfer through lipid membranes Jenner. Species variation in the metabolism of R-(+)- and S-(-)- nicotine by alpha-C- and N-oxidation in vitro Jenner. Factors affecting the in vitro metabolism of R-(+)- and S-(-)-nicotine by guinea-pig liver preparations OTHER Cholerton. Sources of inter-individual variability in nicotine pharmacokinetics Cohen. Monograph on the Pharmacology and Toxicology of Nicotine and its Role in Tobacco Smoking Hasenfratz. Development of central and peripheral smoking effects over time Pilotti. Studies on the identification of tobacco alkaloids, their mammalian metabolites and related compounds by gas chromatography- -mass spectrometry Schievelbein. Nicotine Workshop Schmiterlow. Tissue distribution of C14-nicotine Schmiterlow. Distribution of nicotine in the central nervous system Szuts. Long-term fate of [14C]nicotine in the mouse: retention in the bronchi, melanin-containing tissues and urinary bladder wall --------------------------------------------------------------------------- factors affecting the absorption of nicotine into the bloodstream, including route of administration; 258 \258\ COUNCIL FOR TOBACCO RESEARCH-USA Haines. Radioimmunoassay of plasma nicotine in habituated and naive smokers Kershbaum. Cigarette, cigar, and pipe smoking. Some differences in biochemical effects R.J. REYNOLDS COMPANY deBethizy. Chemical and biological studies of a cigarette that heats rather than burns tobacco deBethizy. Absorption of nicotine from a cigarette that does not burn tobacco BRITISH-AMERICAN TOBACCO COMPANY, LTD. Unpublished Backhurst. Further Work on Extractable Nicotine Evelyn. Retention of nicotine and phenols in the human mouth Evelyn. Transfer of nicotine from smoke into blood using a perfused canine lung Evelyn. Absorption of nicotine via the mouth: studies using animal models Isaac. The absorption and effects of nicotine from inhaled tobacco smoke TOBACCO RESEARCH COUNCIL LABS., U.K. Armitage. Absorption of nicotine by man during cigar smoking [proceedings] Armitage. Absorption of nicotine from small cigars Armitage. The transfer of endogenous and exogenous radioisotopically labelled nicotine to mainstream cigarette smoke and its absorption into the blood of anaesthetized cats Armitage. Absorption of nicotine in cigarette and cigar smoke through the oral mucosa OTHER Hasenfratz. Development of central and peripheral smoking effects over time Schievelbein. Nicotine workshop: Absorption of nicotine under various conditions (an introductory review) [[Page 41637]] --------------------------------------------------------------------------- distribution of nicotine to the brain; 259 and \259\ COUNCIL FOR TOBACCO RESEARCH-USA Hatchell. The influence of genotype and sex on behavioral sensitivity to nicotine in mice Vincek. Synthesis of 4,4-ditritio-(+)-nicotine: comparative binding and distribution studies with natural enantiomer BRITISH-AMERICAN TOBACCO COMPANY, LTD. Unpublished Creighton. Relative contributions of nicotine and carbon monoxide to human physiological response Creighton. Further studies on the effect of nicotine on human physiological response Isaac. The Absorption and Effects of Nicotine from Inhaled Tobacco Smoke INDUSTRY SUPPORTED AMA/ERF STUDIES Rosecrans. Brain area nicotine levels in male and female rats with different levels of spontaneous activity Rosecrans. Brain area nicotine levels in male and female rats of two strains OTHER Cholerton. Sources of inter-individual variability in nicotine pharmacokinetics Schmiterlow. Distribution of Nicotine in the Central Nervous System OTHER, Literature Review Edwards. Smoking, nicotine and electrocortical activity [[Page 41638]] --------------------------------------------------------------------------- plasma profiles of nicotine and its metabolites.260 \260\ COUNCIL FOR TOBACCO RESEARCH-USA Castro. Nicotine enzyme immunoassay Haines. Radioimmunoassay of plasma nicotine in habituated and naive smokers Monji. A Plasma nicotine pharmacokinetics in dogs after intravenous administration: Determination by radioimunassay Rama. Distribution and Retention of nicotine and its major metabolite cotinine, in the rat as a function of time AMERICAN TOBACCO COMPANY Castro. Nicotine antibodies: comparison of ligand specificities of antibodies produced against two nicotine conjugates R.J. REYNOLDS COMPANY Davis. The determination of nicotine and cotinine in plasma deBethizy. Absorption of nicotine from a cigarette that does not burn tobacco Kyerematen. Pharmacokinetics of nicotine and 12 metabolites in the rat Application of a new radiometric high performance liquid chromatography assay Kyerematen. Radiometric high performance liquid chromatographic assay for nicotine and twelve of its metabolites BRITISH-AMERICAN TOBACCO COMPANY, LTD. Unpublished Isaac. The absorption and effects of nicotine from inhaled tobacco smoke TOBACCO RESEARCH COUNCIL LABS., U.K. Armitage. Absorption and metabolism of nicotine from cigarettes Armitage. Absorption of nicotine by man during cigar smoking [proceedings] Armitage. Absorption of nicotine from small cigars Armitage. The transfer of endogenous and exogenous radioisotopically labelled nicotine to mainstream cigarette smoke and its absorption into the blood of anaesthetized catsStepney. Behavioural regulation of nicotine intake in cigarette smokers presented with a `shortened' cigarette [proceedings] OTHER Isaac. Cigarette smoking and plasma levels of nicotine Isaac. Blood levels of nicotine and physiological effects after inhalation of tobacco smokeIsaac. Blood levels of nicotine and physiological effects after inhalation of tobacco smoke Schievelbein. Nicotine Workshop --------------------------------------------------------------------------- Nicotine metabolism. The industry has investigated the metabolic fate of nicotine, including the metabolites (breakdown products) of nicotine.261 Studies have also been done on the enzymatic systems involved in nicotine [[Page 41639]] metabolism.262 Industry-supported research shows that smokers metabolize nicotine faster than non-smokers because one or more of the substances in cigarette smoke increases the production of the enzymes that metabolize nicotine.263 Industry-funded studies have also shown that there may be gender differences in the metabolism of nicotine.264 \261\ COUNCIL FOR TOBACCO RESEARCH-U.S.A Abood. Specific binding and metabolism of (-)- and (+)-[3H]- nicotine in isolated rat hepatocytes and hepatocyte membranes Hibberd. Nicotine delta 1' (5)' iminium ion: a reactive intermediate in nicotine metabolism Vincek. Synthesis of 4,4-ditritio-(+)-nicotine: comparative binding and distribution studies with natural enantiomer AMERICAN TOBACCO COMPANY Bowman. Studies on the metabolism of (-)-cotinine in the human Bowman. Disposition and fate of (-)-cotinine-H3 in the mouse Hucker. Studies on the metabolism of nornicotine in the dog Larson. Studies on the fate of nicotine in the body III: On the pharmacology of some methylated and demethylated derivatives of nicotine Larson. Studies on the fate of nicotine in the body IV: Observations on the chemical structure of an end product of nicotine metabolism McKennis. Gamma-(3-pyridyl)-gamma-methylaminobutyric acid as a urinary metabolite of nicotine McKennis. The excretion and metabolism of nicotine McKennis. Mammalian degradation of (-)-nicotine to 3- pyridylacetic acid and other compounds McKennis. Demethylation in the metabolism of (-)-nicotine McKennis. Metabolic release of methyl groups from a series of N- methylpyridinium compounds McKennis. Metabolism of nicotine to (+)-gamma-(3-pyridyl)-gamma- methylaminobutyric acid McKennis. Demethylation of cotinine in vivo McKennis. Metabolites of nicotine and a synthesis of nornicotine McKennis. Demethylation in the metabolism of (-)-nicotine in vivo McKennis. N-methylation of nicotine and cotinine in vivo McKennis. The Metabolic Formation of Gamma-(3-Pyridyl)-Gamma- Hydroxybutyric Acid and Its Possible Intermediary Role in the Mammalian Metabolism of Nicotine McKennis. The isolation and structure of a ketoamide formed in the metabolism of nicotine Meacham. Additional routes in the metabolism of nicotine to 3- pyridylacetate Miller. Observations on the metabolism of nicotine by tissue slices Owen. Studies on the fate of nicotine in the animal body VIII: Observations on the nubmer and chemical nature of nicotine metabolites in the dog and cat Schwartz. Studies on the degradation of the pyrrolidine ring of (-)-nicotine in vivo Schwartz. Mammalian degradation of (-)-demethylcotinine R.J. REYNOLDS COMPANY Caldwell. Characterization of the glucuronide conjugate of cotinine: a previously unidentified major metabolite of nicotine in smokers' urine Kyerematen. Disposition of nicotine and eight metabolites in smokers and nonsmokers: Identification in smokers of two metabolites that are longer lived than cotinine TOBACCO RESEARCH COUNCIL LABS., U.K. Jenner. Factors affecting the in vitro metabolism of R-(+)- and S-(-)-nicotine by guinea-pig liver preparations Jenner. Species variation in the metabolism of R-(+)- and S-(-)- nicotine by alpha-C- and N-oxidation in vitro OTHER Fuxe. On the action of nicotine and cotinine on central 5- hydroxytryptamine \262\ COUNCIL FOR TOBACCO RESEARCH-U.S.A Hibberd. Enzymology of the metabolic pathway from nicotine to cotinine, in vitro Wilson. Nicotine-like actions of cis-metanicotine and trans- metanicotine R.J. REYNOLDS COMPANY Hammond. Metabolism of nicotine by rat liver cytochromes P-450: Assessment utilizing monclonal antibodies to nicotine and cotinine \263\ COUNCIL FOR TOBACCO RESEARCH-U.S.A Hatchell. The influence of genotype and sex on behavioral sensitivity to nicotine in mice Jusko. Role of tobacco smoking in pharmacokinetics TOBACCO RESEARCH COUNCIL LABS., U.K. Beckett. The effect of smoking on nicotine metabolism in vivo in man \264\ COUNCIL FOR TOBACCO RESEARCH-U.S.A Jusko. Role of tobacco smoking in pharmacokinetics TOBACCO RESEARCH COUNCIL LABS., U.K. Beckett. The effect of smoking on nicotine metabolism in vivo in man OTHER Cohen. Monograph on the Pharmacology and Toxicology of Nicotine and its Role in Tobacco Smoking --------------------------------------------------------------------------- Nicotine pharmacodynamics. The tobacco industry has studied a wide range of factors related to the pharmacodynamics of nicotine and nicotine delivery systems. (Pharmacodynamics is the study of a drug's effects on the body over time. A pharmacodynamic study would involve, for example, administering a drug and then evaluating its behavioral and physiological effects over time.) The industry has funded research on: factors affecting the onset and duration of nicotine's physiological effects on the body; 265 \265\ COUNCIL FOR TOBACCO RESEARCH-USA Domino. Electroencephalographic and behavioral arousal effects of small doses of nicotine: A neuropsychopharmacological study Hoff. Neurophysiological aspects of the action of nicotine Lapin. Dopamine-like action of nicotine: lack of tolerance and reverse tolerance Stitzer. Effects of nicotine on fixed-interval behavior and their modification by cholinergic antagonists TOBACCO RESEARCH COUNCIL LABS., U.K. Armitage. Absorption of nicotine in cigarette and cigar smoke through the oral mucosa COUNCIL FOR TOBACCO RESEARCH-USA, Literature Reviews Larson. Tobacco--Experimental and Clinical Studies--A Comprehensive Account of the World Literature--Supplement I Larson. Tobacco--Experimental and Clinical Studies--A Comprehensive Account of the World Literature--Supplement II Larson. Tobacco--Experimental and Clinical Studies--A Comprehensive Account of the World Literature--Supplement III OTHER Battig. Smoke yield of cigarettes and puffing behavior in men and women Nordberg. Pharmacodynamic effects of nicotine and acetylcholine biosynthesis in mouse brain [[Page 41640]] --------------------------------------------------------------------------- the relationship of nicotine's physiological effects on the body to nicotine blood levels; 266 and \266\ COUNCIL FOR TOBACCO RESEARCH-U.S.A Hatchell. The influence of genotype and sex on behavioral sensitivity to nicotine in mice Westfall. Influence of nicotine on catecholamine metabolism in the rat R.J. REYNOLDS COMPANY Pritchard. Flexible effects of quantified cigarette-smoke delivery on EEG dimensional complexity BRITISH-AMERICAN TOBACCO COMPANY, LTD. Unpublished Isaac. The absorption and effects of nicotine from inhaled tobacco smoke OTHER Isaac. Blood levels of nicotine and physiological effects after inhalation of tobacco smoke --------------------------------------------------------------------------- physiological effects of nicotine on the brain and their time-course.267 \267\ COUNCIL FOR TOBACCO RESEARCH-U.S.A Abood. Comparison of the binding of optically pure (-)- and (+)- [3H]nicotine to rat brain membranes Andersson. Effects of withdrawal from chronic exposure to cigarette smoke on hypothalamic and preoptic catecholamine nerve terminal systems and on the secretion of pituitary hormones in the male Andersson. Effects of acute intermittent exposure to cigarette smoke on catecholamine levels and turnover in various types of hypothalamic DA and NA nerve terminal systems as well as on the secretion of adenohypophyseal hormones and corticosterone Bhagat. Influence of chronic administration of nicotine on the turnover and metabolism of noradrenaline in the rat brain Fuxe. Increases in dopamine utilization in certain limbic dopamine terminal populations after a short period of intermittent exposure of male rats to cigarette smoke Fuxe. Effects of Nicotine and exposure to cigarette smoke on discrete dopamine and noradrenaline nerve terminal systems of the telencephalon and diencephalon of the rat: Relationship to reward mechanisms and neuroendocrine functions and distribution of nicotinic binding sites in brain Tung. Peripheral induction of burst firing in locus coeruleus neurons by nicotine mediated via excitatory amino acids Wong. Pharmacology of nicotinic receptor-mediated inhibition in rat dorsolateral septal neurones Yamamoto. Nicotine-induced EEG and behavioral arousal R.J. REYNOLDS COMPANY Byrd. Evidence for urinary excretion of glucuronide conjugates of nicotine, cotinine, and trans-3'-hydroxycotinine in smokers INDUSTRY SUPPORTED SYMPOSIA Binnie. The effect of cigarette smoking on the contingent negative variation (CNV) and eye movement INDUSTRY SUPPORTED AMA/ERF STUDIES Hirschhorn. Studies on the time course and the effect of cholinergic and adrenergic receptor blockers on the stimulus effect of nicotine Rosecrans. Brain area nicotine levels in male and female rats with different levels of spontaneous activity TOBACCO RESEARCH COUNCIL LABS., U.K. Armitage. The effects of nicotine on the electrocorticogram and spontaneous release of acetylcholine from the cerebral cortex of the cat Wesnes. Smoking, nicotine and human performance OTHER Fuxe. On the action of nicotine and cotinine on central 5- hydroxytryptamine neurons Hasenfratz. Development of central and peripheral smoking effects over time Hasenfratz. Can smoking increase attention in rapid information processing during noise? Electrocortical, physiological and behavioral effects Perez de la Mora. Neurochemical effects of nicotine on glutamate and GABA mechanisms in the rat brain OTHER, Literature Review Edwards. Smoking, nicotine and electrocortical activity --------------------------------------------------------------------------- 3. Industry Research Establishes That Nicotine Produces Pharmacological Effects Similar to Those of Other Addictive Drugs The tobacco industry has conducted or sponsored studies which demonstrate that nicotine produces pharmacological effects similar to those of other addictive substances. See FINDINGS Sec. I.B., supra, for a discussion of the properties of addictive substances. Indeed, a number of industry-funded studies state that [[Page 41641]] nicotine is an addictive/dependence-producing drug.268 \268\ COUNCIL FOR TOBACCO RESEARCH-U.S.A Bosse. Age and addiction to smoking Martin. Tobacco Smoking and Nicotine: A Neurobiological Approach Rosecrans. Noncholinergic Mechanisms involved in the behavioral and stimulus effects of nicotine, and relationships to the process of nicotine dependence Rosecrans. Nicotine as a discriminative stimulus: a neurobehavioral approach to studying central cholinergic mechanisms Svensson. Effect of nicotine on dynamic function of brain catecholamine neurons Tung. Peripheral induction of burst firing in locus coeruleus neurons by nicotine mediated via excitatory amino acids Williams. Stability of a factor-analytic description of smoking behavior TOBACCO RESEARCH COUNCIL LABS., U.K. Hall. New evidence for a relationship between tobacco smoking, nicotine dependence, and stress OTHER Andersson. Effects of acute central and peripheral administration of nicotine on ascending dopamine pathways in the male rat brain. Evidence for nicotine-induced increases of dopamine turnover in various telencephalic dopamine nerve terminal systems Nisell. Systemic nicotine-induced dopamine release in the rat nucleus accumbens is regulated by nicotinic receptors in the ventral tegmental area --------------------------------------------------------------------------- Nicotine psychoactivity and discrimination studies. Industry studies have shown that nicotine is psychoactive and produces clearly discriminable stimulus effects 269 in both animals and humans.270 \269\ These effects are evaluated in animals using drug discrimination techniques which enable direct comparisons of the effects of different drugs. Such studies evaluate whether an animal experiences a psychoactive effect from a drug and facilitate comparisons of the effect of the study drug with the effect of other psychoactive drugs. Industry-funded studies have shown that animals can distinguish (discriminate) nicotine from other drugs or a placebo, and can communicate their identification of nicotine (as distinct from other drugs) to the investigator by pressing a bar or providing other behavioral signals. These studies also provide information on the similarity of nicotine's effects to effects of other dependence-producing drugs, including the degree to which nicotine mimics the psychoactive effects of those other drugs. See p. 95. \270\ INDUSTRY SUPPORTED AMA/ERF STUDIES Hirschhorn. Studies on the time course and the effect of cholinergic and adrenergic receptor blockers on the stimulus effect of nicotine Schechter. Behavioral evidence for two types of cholinergic receptors in the C.N.S. Schechter. Behavioral tolerance to an effect of nicotine in the rat Schechter. Effect of mecamylamine on discrimination between nicotine- and arecoline- produced cues Schechter. Nicotine as a discriminative cue in rats: inability of related drugs to produce a nicotine-like cueing effect Schechter. Nicotine as a discriminative stimulus in rats depleted of norepinephrine or 5-hydroxytryptamine Schechter. C.N.S. effect of nicotine as the discriminative stimulus for the rat in a T-maze COUNCIL FOR TOBACCO RESEARCH-U.S.A Chance. A comparison of nicotine and structurally related compounds as discriminative stimuli Rosecrans. Nicotine as a discriminative stimulus: a neurobehavioral approach to studying central cholinergic mechanisms PHILIP MORRIS TOBACCO COMPANY Kallman. Nicotine as a discriminative stimulus in human subjects TOBACCO RESEARCH COUNCIL LABS., U.K. Morrison. Nicotine injections as the conditioned stimulus in discrimination learning --------------------------------------------------------------------------- Nicotine reinforcement/self-administration studies. The industry has examined nicotine's ability to serve as a positive reinforcer in self-administration studies involving rats and monkeys. For example, Philip Morris conducted studies in rats demonstrating that nicotine is self-administered by rats and has other hallmark properties of addictive susbstances.271 The industry-supported research on monkeys led prominent drug addiction researchers Deneau and Inoki to conclude in a paper published in 1967 that nicotine ``may be one of [[Page 41642]] the substances in tobacco smoke which is responsible for man's use of tobacco.'' 272 The industry has also funded studies demonstrating that nicotine could enhance the rewarding effects of electrical brain stimulation.273 A book resulting from The International Smoking Behaviour Conference held at Chelwood Vachery, Sussex, England, in 1978, which was edited by a senior scientist at British-American Tobacco, included a ``Conference Overview'' stating: ``At this stage, we hypothesize that nicotine (possible [sic] interacting with tar) is the main reinforcing agent in cigarettes * * *.'' 274 Moreover, as noted earlier, the industry has conducted studies showing that nicotine is active in the same dopaminergic pathways that modulate cocaine's effects. These studies are relevant to understanding how nicotine causes addiction. \271\ PHILIP MORRIS TOBACCO COMPANY, Unpublished DeNoble. Manuscript: Nicotine as a Positive Reinforcer for Rats: Effects of Infusion Dose and Fixed Ratio Size See also pp. 278-79, infra. INDUSTRY SUPPORTED AMA/ERF STUDIES Deneau. Nicotine self-administration in monkeys \272\ INDUSTRY SUPPORTED AMA/ERF STUDIES Deneau. Nicotine self-administration in monkeys \273\ COUNCIL FOR TOBACCO RESEARCH-U.S.A. Olds. Comparision of muscarinic and nicotinic cholinergic agonists on self-stimulation behavior Pradan. Effects of nicotine on self-stimulation in rats \274\ INDUSTRY SUPPORTED SYMPOSIA Jarvik. Smoking Behaviour--Physiological and psychological influences. 31. Conference overview --------------------------------------------------------------------------- Tolerance to nicotine. Tolerance to the physiological and behavioral effects of nicotine has been thoroughly studied by the tobacco industry and has been demonstrated to occur in animals as a result of nicotine use.275 \275\ COUNCIL FOR TOBACCO RESEARCH-U.S.A Abood. Acute and chronic effects of nicotine in rats and evidence for a non-cholinergic site of action Abood. Behavioral and biochemical studies in rats after chronic exposure to nicotine Andersson. Effects of withdrawal from chronic exposure to cigarette smoke on hypothalamic and preoptic catecholamine nerve terminal systems and on the secretion of pituitary hormones in the male Cronan. Effects of chronically administered nicotine and saline on motor activity in rats Domino. Tolerance to the effects of daily nicotine on rat bar pressing behavior for water reinforcement Fuxe. Effects of nicotine and exposure to cigarette smoke on discrete dopamine and noradrenaline nerve terminal systems of the telencephalon and diencephalon of the rat: Relationship to reward mechanisms and neuroendocrine functions and distribution of nicotinic binding sites in brain Lapin. Dopamine-like action of nicotine: lack of tolerance and reverse tolerance Nelsen. Improvement of performance on an attention task with chronic nicotine treatment in rats and stimulus effects of nicotine, and relationships to the process of nicotine dependence Stitzer. Effects of nicotine on fixed-interval behavior and their modification by cholinergic antagonists Wenzel. Studies on the acute and chronic depressor actions of nicotine in the rat Westfall. Studies on the mechanism of tolerance to nicotine- induced elevations of urinary catecholamines R.J. REYNOLDS COMPANY Bjercke. Anti-idiotypic antibody probes of neuronal nicotinic receptors Collins. Modulation of nicotine receptors by chronic exposure to nicotinic agonists and antagonists Marks. Downregulation of nicotinic receptor function after chronic nicotine infusion PHILIP MORRIS TOBACCO COMPANY, Unpublished DeNoble. Manuscript: Development of behavioral tolerance following chronic nicotine administration. INDUSTRY SUPPORTED AMA/ERF STUDIES Schechter. Behavioral tolerance to an effect of nicotine in the rat TOBACCO RESEARCH COUNCIL LABS., U.K. Morrison. The occurrence of tolerance to a central depressant effect of nicotine OTHER Larsson. Subchronic treatment of rats with nicotine: effects on tolerance and on [3H]acetylcholine and [3H]nicotine binding in the brain Nordberg. Effect of acute and subchronic nicotine treatment on cortical acetylcholine release and on nicotinic receptors in rats and guinea-pigs Nordberg. Effect of long-term nicotine treatment on [3H]nicotine binding sites in the rats brain [[Page 41643]] --------------------------------------------------------------------------- Nicotine's withdrawal effects. Scientists funded by the tobacco industry have conducted research on various aspects of withdrawal, including potential neurochemical mechanisms 276 and the effects of withdrawal on performance.277 Symptoms of withdrawal may include craving, irritability, nervousness, tension, emotional strain, depression, inability to concentrate, sleep disturbance, sweating, gastrointestinal changes, drop in blood pressure and pulse rate, impaired performance, and changes in the electroencephalogram.278 \276\ COUNCIL FOR TOBACCO RESEARCH-U.S.A Andersson. Effects of withdrawal from chronic exposure to cigarette smoke on hypothalamic and preoptic catecholamine nerve terminal systems and on the secretion of pituitary hormones in the male Fuxe. Effects of Nicotine and exposure to cigarette smoke on discrete dopamine and noradrenaline nerve terminal systems of the telencephalon and diencephalon of the rat: Relationship to reward mechanisms and neuroendocrine functions and distribution of nicotinic binding sites in brain Rosecrans. Noncholinergic Mechanisms involved in the behavioral and stimulus effects of nicotine, and relatinships to the process of nicotine dependence COUNCIL FOR TOBACCO RESEARCH-U.S.A., Literature Reviews Larson. Tobacco--Experimental and Clinical Studies--A Comprehensive Account of the World Literature--Supplement II Larson. Tobacco--Experimental and Clinical Studies--A Comprehensive Account of the World Literature--Supplement III AMERICAN TOBACCO COMPANY Finnegan. The role of nicotine in the cigarette habit \277\ COUNCIL FOR TOBACCO RESEARCH-U.S.A Heimstra. The effects of deprivation of cigarette smoking on psychomotor performance Heimstra. Effects of smoking upon sustained performance in a simulated driving task COUNCIL FOR TOBACCO RESEARCH-U.S.A., Literature Reviews Fuxe. Neuroendocrine actions of nicotine and of exposure to cigarette smoke: medical implications Larson. Tobacco--Experimental and Clinical Studies--A Comprehensive Account of the World Literature--Supplement III OTHER Hasenfratz. Psychophysiological reactions during active and passive stress coping following smoking cessation \278\ COUNCIL FOR TOBACCO RESEARCH-U.S.A., Literature Reviews Larson. Tobacco--Experimental and Clinical Studies--A Comprehensive Account of the World Literature--Supplement II Larson. Tobacco--Experimental and Clinical Studies--A Comprehensive Account of the World Literature--Supplement III AMERICAN TOBACCO COMPANY Finnegan. The role of nicotine in the cigarette habit --------------------------------------------------------------------------- The industry has also funded studies showing that tobacco users report ``craving'' for tobacco.279 Continued use of tobacco despite attempts to quit. As described in Sec. II.C.4., infra, the tobacco industry has conducted a number of studies documenting the large percentage of tobacco users who have attempted to quit using tobacco and the very small percentage who have succeeded. \279\ R.J. REYNOLDS COMPANY Robinson. The meaning of addiction: reply to West OTHER Hasenfratz. Development of central and peripheral smoking effects over time Hasenfratz. Post-lunch smoking for pleasure seeking or arousal maintenance? ---------------------------------------------------------------------------