National Institute on Drug Abuse
Director's Report to the National Advisory Council on Drug Abuse
September, 1998
Research Findings
Behavioral Research
Food Deprivation Enhances Drug Cues
It is known that food deprivation in animal models increases the self-administration of a variety of drugs that have high abuse liability in man. Some food deprivation conditions may actually enhance a relapse or "reinstatement" of drug self-administration following a priming dose of a drug. But can deprivation enhance the motivational and reinforcing properties of exteroceptive cues such as locations in which drugs are received? Dr. Richard Meisch and colleagues at the University of Texas Houston Health Science Center report in Psychopharmacology (131, pp. 1-8, 1997) that rats maintained at 80 percent free-feeding body weights preferred locations previously associated with intraperitoneal cocaine when given a choice between cocaine versus saline paired locations. The food deprivation condition also enhanced psychostimulant-induced locomotor activity and sensitization to this behavioral activation. Dr. Meisch suggests that the deprivation state may enhance HPA-axis activation of the central dopaminergic substrate for cocaine reinforcement, implicating neurobiological substrates for stress having an important role.
Circadian Shifts After Nicotine
Dr. Bruce O'Hara at Stanford University has found that nicotine is capable of causing phase shifts in the circadian rhythms of rodents, an effect that supports a role for cholinergic influences on the circadian system mediated by nicotinic acetylcholine receptors. Dr. O'Hara has previously found a dramatic sensitivity of the perinatal suprachiasmatic nucleus of the hypothalamus to nicotine. He postulates that such effects on the SCN may contribute to alterations caused by nicotine in other physiological systems, and may also contribute to nicotine's addictive properties through influences on arousal. O'Hara, Edgar, Cao, Wiler, Heller et al. Nicotine and Nicotinic Receptors in the Circadian System. Psychoneuroendocrinology, 23, pp. 161-173, 1998.
Cues Can Enhance Drug Taking
External stimuli paired with drugs may have more than one function: they may signal drug availability, and may also act as secondary reinforcers capable of strengthening behavior. Dr. Stanley Weiss at the American University in Washington, D.C. has been studying the effects of combining external stimuli, each of which has been paired with different reinforcing (e.g., food or cocaine) outcomes. A recent paper (Panlilio et al., Psychopharmacology, 135, pp. 70-74, 1998) found that animals' self-administration of single doses of cocaine (0.66mg/kg) doubled in the presence of two combined external stimuli that had each been paired with cocaine or food. Although administering primary reinforcers can attenuate drug selection behavior, as shown in other literature, it appears that cues which are associated with primary rewards can in fact enhance drug taking responses.
Assessing Effects of Drugs on Complex Motor Behavior
Measures of motor behavior in rodents are commonly used behavioral tools to assess the effects of a variety of experimental manipulations from the effects of drug challenges to evaluating differences in genetically altered mice (e.g., knock out mice). These methods are widely used because a variety of behaviors comprising motor behavior can be assessed with automated equipment and results are rapidly obtained. However, quantifying, and accurately characterizing what often appears to be random behavior is difficult. Researchers at the University of California at San Diego have addressed this problem and developed a mathematical technique to quantify motor behavior. The approach, which was derived from theoretical physics, takes into account the sequence, or pattern of movements, and the amount of motor activity displayed by the animal. Using this new mathematical approach, the researchers are able to uncover and quantify how drugs of abuse affect various aspects of motor behavior and can begin to determine how drugs of abuse act on various neurotransmitter systems to produce these effects. The mathematical tools developed by these researchers will allow for comprehensive studies of the effects of drugs of abuse on behavior. The ultimate goal is to predict behavioral changes and to identify the associated underlying neurochemical changes produced by drugs of abuse. Krebs-Thomson et al. Modulation of Phencyclidine (PCP)- induced Changes in Locomotor Activity and Patterns in Rats by Serotonin, European Journal of Pharmacology, 343, pp. 135-143, 1998.
High Rate of Passive Exposure to Crack/Cocaine in Infants
Researchers at the Yale Child Study Center prospectively obtained 124 urine samples from 122 children less than one year old for routine clinical indications from the Emergency Department at Yale-New Haven Hospital. Samples were analyzed by radioimmunoassay (RIA) for cocaine, with cross-reactivity for its major metabolite, benzoylecgogine (BE), using a threshold for detection of cocaine and BE that is lower than the current DHHS standard. The presence of cocaine or BE was presumed to indicate passive exposure to crack/cocaine. Of the 124 samples, 36.3 percent were positive (greater than or equal to 50ng/mL BE equivalents) for cocaine and/or BE. The positive samples were highly correlated with lower and upper respiratory symptoms and with seeking medical care more often. Lustbader, A.S., Mayes, L.C., McGee, B.A., Jatlow, P., and Roberts, W.L. Incidence of Passive Exposure to Crack/Cocaine and Clinical Findings in Infants Seen in an Outpatient Service, Pediatrics, (1 Part 1), E5, July 1998.
Pergolide Effects on Cocaine Craving and Self-Administration
Based on clinical evidence that pergolide, a D1/D2 dopamine receptor agonist, may be useful in maintaining cocaine abstinence, its effects were investigated in twelve inpatient volunteers who reported spending an average of $170 per week on cocaine. Subjects received pergolide (0.05mg BID) for eight days and placebo for eight days, with drug order balanced across subjects. Self-administration sessions occurred on the last four days of maintenance on each medication. A modified 7-trial progressive ratio choice procedure (0, 8, 16, 32 mg/70 kg cocaine vs. $5) was utilized with sessions consisting of: two sample trials wherein subjects responded to receive the dose and tokens available that day; and five choice trials wherein subjects chose between the available dose and tokens. Following each trial, the response requirement for the chosen option increased by 400. Maintenance on pergolide: decreased cocaine-induced increases in ratings of "High," "Stimulated," cocaine "Potency;" decreased estimates of street value; decreased heart rates; increased ratings of craving, i.e., "I want cocaine;" and had no effect on cocaine self-administration. According to the authors, the increased desire to use cocaine during pergolide maintenance suggests that it has limited treatment utility at this dose. However, given the finding of an attenuation of cocaine's subjective and cardiovascular effects, an investigation of a wide range of pergolide doses on cocaine self-administration and subjective effects may be warranted. Another finding of this research was that women reported lower ratings of "Stimulated" and dose quality, and had relatively smaller increases in systolic pressure following cocaine administration. Haney, M., Foltin, R.W., and Fischman, M.W. Effects of Pergolide on Intravenous Cocaine Self-Administration in Men and Women, Psychopharmacology, 137, pp. 15-24, 1998.
New Method for Studying Drug Reinforcement
Dr. Richard Meisch reports development of a new method for studying drug reinforcement using an alternative to intravenous (I.V.) self-administration and to oral self-administration. This procedure involves the animal, in this case the rat, responding under a long fixed-interval schedule. The reinforcer is delivery of a drug, in this case etonitazene, administered intraperitoneally (I.P.) by the experimenter. This procedure offers a number of practical advantages over the conventional I.V. route and the oral route of self-administration. Ahlgren-Beckendorf, J.A., Steward, R.B., Gomez, T.H., Silverman, P.B., and Meisch, R.A. Lever-press Responding Maintained by Contingent Intraperitoneal Administration of Etonitazene in Long Evans Hooded Rats, Journal of Neuroscience Methods, 80, pp. 149-154, 1998.
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