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National Institute on Drug Abuse

Director's Report to the National Advisory Council on Drug Abuse

September, 1999

Research Findings

Behavioral Research

Laboratory Measurement of Adaptive Behavior Change in Humans with a History of Substance Dependence

Dr. Scott Lane and colleagues at the University of Texas Health Science Center examined components of behavioral adaptation to changes in environmental conditions in human subjects with and without a history of substance dependence. Over a two-day period, volunteers were rewarded for changing their patterns of response. On the first day, they earned monetary rewards for producing high response rates. However, on the second day they were required to wait ten seconds between each response, producing low response rates. Volunteers meeting DSM-IV criteria for past substance dependence and having histories of substance dependence longer than ten years adjusted poorly to the required transition in responding, exhibiting high rates of responding on both days. Because of their inability to change to a slower response rate, subjects with long substance abuse histories earned few if any monetary rewards on the second day. These results were unrelated to age, attention, impulsiveness, or general intellectual aptitude and suggest a deficiency in adaptive behavior change. Whether this deficiency predated or was a consequence of drug abuse is unclear. Lane, S.D., Cherek, D.R., Dougherty, D.M., and Moeller, F.G. Drug and Alcohol Dependence, 51, pp. 239-252, 1998.

Luteinizing Hormone-Releasing Hormone Affects Plasma Cocaine Levels in Rhesus Monkeys

Considerable evidence points to the role of the brain neurotransmitter dopamine in the reinforcing effects of cocaine. Cocaine binds to the dopamine transporter, thus blocking the reuptake of dopamine and resulting in increased levels of dopamine at the synapse between neurons in the brain. Harvard researchers Drs. Jack Mendelson, Nancy Mello, and Stevens Negus noted structural similarities between the dopamine transporter and luteinizing hormone (LH), a gonadatropin hormone released by the anterior pituitary. They hypothesized that LH bound to cocaine and thereby decreased cocaine levels. They report that when they administered synthetic LH-releasing hormone (LHRH) to male and female rhesus monkeys prior to the administration of cocaine, LH secretion significantly increased and peak plasma levels of cocaine significantly decreased in both males and females. In males, but not females, there was an inverse relationship between levels of LHRH-stimulated LH immediately prior to cocaine injection and peak plasma cocaine levels two minutes following cocaine injection. There were also gender differences in the levels of LH required, 70ng/ml in males versus 45 ng/ml in females, to decrease plasma cocaine levels. This research raises the possibility of developing LH or an LH-like molecule as medications that will bind to cocaine for use in the treatment of cocaine addiction. Mendelson, J.H., Mello, N.K., and Negus, S. Journal of Pharmacology and Experimental Therapeutics, 289, pp. 791-799, 1999.

Cocaine Pharmacokinetics in Male and Female Rhesus Monkeys and in Humans

Several studies, both animal and human, have shown greater cocaine toxicity in males than in females. There has been little research focus however, on the study of sex differences in pharmacokinetics and the relation it may have to cocaine's greater toxicity in males. In the course of their research on the effects of luteinizing hormone-releasing hormone on plasma cocaine levels in rhesus monkeys (see above), Dr. Jack Mendelson and colleagues compared the pharmacokinetics of plasma cocaine in males and females following the intravenous administration of 0.8 mg/kg cocaine. Females were tested during the follicular phase of the menstrual cycle, six to eight days after the onset of menstruation. Pharmacokinetic analyses indicated that although females had significantly lower plasma cocaine levels than males ten minutes after injection, males and females did not differ in peak levels of cocaine, time to reach peak levels of cocaine in plasma, the elimination half life, or the area under the curve. These findings in rhesus monkeys are consistent with results obtained by Dr. Mendelson and Dr. Nancy Mello and their colleagues following intravenous cocaine administration (0.2 and 0.4 mg/kg) in humans. No sex differences in peak plasma cocaine levels, elimination half-life, or area of the curve were observed, nor were sex differences observed in cardiovascular effects on heart rate and blood pressure or in the subjective report of feeling "high." In females, both the pharmacokinetic and pharmacodynamic measures were similar in the follicular and mid-luteal phases of the cycle. The single significant difference observed in the pharmacokinetic parameters was that the time to reach peak plasma levels was significantly lower in the follicular phase women (four minutes) than in the luteal phase women (6.7 minutes) or in males (eight minutes). The authors conclude that pharmacokinetic factors alone do not account for sex differences observed in cocaine toxicity and they recommend exploring neuroendocrine and other factors. Mendelson, J.H., Mello, N.K., and Negus, S. Journal of Pharmacology and Experimental Therapeutics, 289, pp. 791-799, 1999. Mendelson, J.H., Mello, N.K., Sholar, M.B., Siegel, A.J., Kaufman, M.J., Levin, J.M., Renshaw, P.F., and Cohen, B.M. Neuropsychopharmacology, 21, pp. 294-303, 1999.

Female Rats Acquire Self-Administration of Cocaine and Heroin Faster than Male Rats

Animal studies of the locomotor response to psychostimulants have shown greater responsivity in female as compared to male rats. Studies of the self-administration of drugs including cocaine, caffeine, alcohol, morphine, and fentanyl have shown higher levels of intake in females than males. Less research attention, however, has been paid to sex differences in the acquisition of drug self-administration. Drs. Wendy Lynch and Marilyn Carroll at the University of Minnesota report significantly faster acquisition of intravenous cocaine and heroin self-administration for female as compared to male rats. Females acquired cocaine self-administration in a mean of 7.57 sessions as compared to 16.67 sessions for males. Females acquired heroin self-administration in a mean of 8.7 sessions as compared to 13 sessions for males. For cocaine, but not heroin, significantly more females than males met the acquisition criterion within the 30-day maximum. Seventy percent of the females, but only 30 percent of the males met the acquisition criterion for cocaine self-administration. For heroin self-administration, 90 percent of the females and 91.7 percent of the males met the criterion. Following the acquisition of drug self-administration, the level of self-administered cocaine and heroin was higher in females than in males, but was significant only for cocaine. Lynch, W.J. and Carroll, M.E. Psychopharmacology, 144, pp. 77-82, 1999.

New Techniques for Measuring Inhalant Effects in Animals

Dr. Robert Balster at the Medical College of Virginia has been investigating the effects of inhaled solvents for the past twenty years using animal models that incorporate multiple behavioral assessments. These are compounds that are found in typical household products and have been demonstrated to have abuse potential in humans. Typically, pharmacological investigations with behavioral endpoints are useful for establishing dose-response relationships, and for determining thresholds and dosing midpoints for behavioral effects. However, dose-orderly effects on complex responses in operant behavioral paradigms have been difficult to establish for compounds administered via the inhalation route. Recently, Dr. Balster has developed a novel "adjusting" procedure for delivering compounds in the inhalation chamber to mice. Animals are trained to press a lever for milk as solvent concentrations in the chamber are altered every five minutes, dependent upon the rate of lever press responding for milk. Using this procedure, Dr. Balster was able to show concentration-dependent decreases in lever pressing and established a subthreshold and minimal concentrations that affect this behavior. This new approach for adjusting exposures to solvents will be useful in the rapid assessment of compounds that are potentially behaviorally disruptive and allow for determining "near threshold" levels of exposure in an animal model. Bowen, S.E., Hamilton, J., and Balster, R.E. Neurotoxicology and Teratology, 2, pp. 169-180, 1998.

Cannabinoid History Determines Cannabinoid Response

Previous studies have revealed that drug history affects the subsequent responsivity to psychotropic drugs. Dr. Harriet de Wit at the University of Chicago found this to be the case for the subjective effects of oral tetrahydrocannabinol (THC) in humans. Dr. de Wit assessed self-reported measures from several scales following oral THC administration in subjects who differed in the extent of their prior marijuana exposure. She found that the groups differed in their self-reports of "feel" drug effects, "high", and "like", but that these differences depended on the dose of oral THC administered. At the 7.5-mg dose level, infrequent users showed no increases on any of these measures, whereas habitual users showed increased scores on all three scales. At a higher dose of 15 mg, only the infrequent users reported sedation and decreases in the "like" scale. Interestingly, no differences in either heart rate or performance cannabinoid effects were noted between subject populations. These varying profiles of subjective effects for users differing in their prior marijuana exposure suggests that conditioning and expectancies may play a role in the ability to detect THC effects seen in frequent marijuana users. Furthermore, frequent users may develop tolerance to unpleasant subjective drug effects independent of the drug's cardiovascular effects. Kirk, J.M., and de Wit, H. Pharmacology, Biochemistry and Behavior, 63, pp. 137-142, 1999.

Relapse to Drug Use: It's Not Enough to Discriminate the Drug's Effects

Experimenter-induced stress has been observed to enhance the acquisition of drug self-administration and to prompt a return to drug-seeking behavior in animal models of relapse. Dr. Nick Goeders at the Louisiana State University Medical Center in Shreveport, Louisiana recently reported that footshock-induced reinstatement of responding for cocaine during extinction could be blocked by ketoconazole, an antimycotic drug that inhibits adrenocorticosteroid synthesis and antagonizes glucocorticoid receptors. This and many other previous observations implicate the activation of central corticosterone systems in relapse. It has further been suggested that the "internal state" produced by a stressor may mimic components of the subjective drug experience. In support of this hypothesis, Dr. Goeders also found that footshock generalized to the cocaine cue in drug discrimination procedures with the rat. However, unlike the effects of ketoconazole on footshock-induced reinstatement, the glucocorticoid antagonist was without effect on the ability of footshock to engender cocaine appropriate responding in the drug discrimination task. From these findings, Dr. Goeders concluded that, in these animal models, reproduction of cocaine's discriminative properties alone, may be insufficient for prompting a return to drug-seeking behavior. Mantsch, J.R., and Goeders, N.E. Psychopharmacology, 142, pp. 399-407, 1999.

Antagonism by MK-801 and Conditioned Place Preference

This study examined if conditioned place preference preparation is useful in studying the appetitive quality of novelty, whether IV cocaine would condition an increase in preference, and the role of the N-methyl-D-aspartate (NMDA) receptor in this paradigm. In 3 separate experiments with 95 male rats, repeated access to novel objects in one of 2 distinct environments conditioned an increase in preference for the novelty-paired environment. A conditioned increase in preference was found whether novel objects were paired with a randomly chosen environment or with the less preferred of 2 environments (conditioned against a preference). This enhanced preference did not depend on the control group employed. IV infusions of cocaine produced an increase in preference using the procedures employed with novel objects. Pretreatment with the NMDA receptor antagonist MK-801 blocked acquisition of the enhanced place preference conditioned by access to novel objects without decreasing time spent with objects or inducing a place aversion in controls. Bevins, R.A. and Bardo, M.T. Conditioned Increase in Place Preference by Access to Novel Objects. Behavioral Brain Research, 99, pp. 53-60, 1999.

Dopamine Receptors and Individual Differences in Amphetamine Self-Administration

This study examined the effect DA antagonists have on single-trial conditioned place preference (CPP) produced by acute intravenous amphetamine in rats. In the first of three studies, amphetamine (0.1-3.0 mg/kg) was given in one specific compartment of a CPP chamber. Relative to sham controls amphetamine produced a dose-related increase in both activity and CPP. The second study showed that pretreatment with either SCH-22309 (0.025 and 0.25 mg/kg) or eticlopride (0.2 and 2.0 mg/kg) completely blocked both activity and CPP. Finally, single-trial amphetamine CPP did not predict subsequent self-administration of IV amphetamine (10-50 ug/infusion) using either a schedule of continuous reinforcement (CRF) or partial reinforcement progressive ratio (PR), which demonstrates that single-trial CPP and self-administration are dissociable effects of IV amphetamine. Bardo, M.T., Valone, J.M. and Bevis, R.A. Locomotion and Conditioned Place Preference Produced by Acute Intravenous Amphetamine: Role of Dopamine Receptors and Individual Differences in Amphetamine Self-Administration. Psychopharmacology, 143, pp. 39-46, 1999.

Predictor of Amphetamine Conditioned Place Preference

A study was conducted to assess whether the activity observed when rats are exposed to an inescapable novel environment may reflect escape behavior due to stress. A new test, the playground maze, designed to evaluate approach to novelty in a free choice situation was used to predict individual responses to amphetamine (1.0 or 3.0 mg/kg). The playground maze was used to categorize rats as either high or low novelty seekers. Results indicate that individual differences in novelty seeking did not predict amphetamine-induced changes in locomotion activity following either single or repeated injections. However, the high novelty seekers showed greater amphetamine-conditioned place preference than low novelty seekers. Klebaur, J.E. and Bardo M. T. Individual Differences in Novelty Seeking on the Playground Maze Predict Amphetamine Conditioned Place Preference. Pharmacology, Biochemistry and Behavior, pp. 1-6, 1999.

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