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National Institute on Drug Abuse

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

February, 2000

Research Findings

Behavioral Research

Some Abused Steroids Do Not Elicit Aggression in Rats

Marilyn McGinnis and her colleagues are examining the interaction between anabolic steroids and aggressive behaviors in rats under three conditions: different social contexts, different environmental contexts (home cage, opponent's cage, neutral territory), and under physical provocation (tail-pinch). Animals were treated with one of three steroids (testosterone propionate (TP), nandrolone decanoate (ND), or stanozolol (ST)) or with oil. In general, she found that TP produced the most aggression and animals treated with TP were less discriminating in their response to the provoking stimulus (any provocation would make them aggressive). ND and ST treatment was by far less effective in provoking aggression in the rats; often their levels of aggressive behavior were less than that seen in the controls. The magnitude of the androgenic effects of the three steroids on peripheral tissues paralleled their effects on aggressive behaviors. Testes weights were decreased only in the ST rats whereas ST and ND decreased the weights of the prostates and seminal vesicles. In contrast, TP increased the weights of these tissues. Thus ND and ST are not only less androgenic than TP, but may be anti-androgenic when compared to testosterone. Breuer, M., McGinnis, M., Possidente, B., Lumia, A.R. The Effects of Environmental, Social and Physical Manipulations on Male Rats Receiving Chronic Doses of Anabolic Androgenic Steroids. Soc. Behav. Neuroendocrinol., 3, p. 56, 1999.

A New Method for Measuring Heroin Addiction

Researchers at the University of Vermont used a self-report questionnaire to ask heroin- dependent patients about their preference for cigarettes and heroin at various hypothetical prices. The results from the simulation, in which no drugs were actually given to the patients, indicated that at low prices, cigarettes were preferred to heroin, but as price increased demand for heroin stayed relatively high while the demand for cigarettes declined. This simulation generated orderly measures of demand suggesting that this method can provide valuable information for assessing drug consumption habits. In addition, this method could be practically and easily used in a clinical setting as an adjunct method for assessing the severity of a patient's drug habit. Jacobs, E.A, and Bickel, W.K., Modeling Drug Consumption in the Clinic Via Simulation Procedures: Demand for Heroin Cigarettes in Opioid Dependent Outpatients. Experimental & Clinical Psychopharmacology 7, pp. 412-426, 1999.

Impulsivity and Cigarette Smoking

One characteristic of drug addiction is that drug-dependent individuals often choose to use an immediately available drug and forego prosocial delayed activities. This aspect of drug addiction is characterized as impulsive behavior. Investigators at the University of Vermont examined impulsive behavior in cigarette smokers, ex-smokers and persons who had never smoked. A delay discounting procedure was used in which no money was actually given to participants in the experimental setting, individuals were asked about their preferences for varying amounts of money that were either immediately available or could be received following a delay of several days to several months. For all individuals, the longer one had to wait for a given amount of money, the less that money was valued relative to a more immediately available amount. Interestingly, the researchers found that smokers, discounted money significantly more than did either ex-smokers or persons who had never smoked. That is, delayed money was significantly less valuable for smokers than for the other groups studied. These data suggest that drug dependence is associated with greater impulsivity. These data further suggest that cigarette smoking, as with other forms of drug addiction, is associated with a rapid loss of subjective value for future outcomes. That impulsivity is associated with cigarette smoking suggests that impulsivity may relate to the drug effect and drug dependence directly given that cigarette smokers do not often suffer other life-disrupting consequences (e.g. homelessness, unemployment) associated with addiction to other drugs of abuse. Bickel, W.K., Odum, A.L., and Madden G.J. Impulsivity and Cigarette Smoking: Delayed Discounting in Current, Never, and Ex-smokers. Psychopharmacology, 146, pp. 447-454, 1999.

Effects of Dopamine Receptor Antagonists on Cocaine Smoking

In determining the effectiveness of a pharmacological therapy for drug addiction, it is not only important to consider the therapy's neuropharmacological properties in relation to the drug of abuse, but also to consider the environmental factors that may contribute to the effectiveness of the therapy. Using an animal model of crack cocaine abuse, researchers recently reported that the "price" of crack can determine how effective dopamine antagonists are in reducing crack cocaine smoking. Dopamine is one of the major neurotransmitters that mediates cocaine's action and its rewarding properties in the brain. The researchers tested two compounds that block dopamine's action at specific dopamine brain receptors. One drug is designed to specifically block cocaine at the dopamine D1 receptor (SCH 23390) and the other drug is designed to block its effects at the D2 (raclopride) receptor. The investigators found that following the administration of either antagonist, crack cocaine consumption remained high at most prices for cocaine, except at the highest prices. That the antagonists were only effective when crack was available at a relatively "high price," suggests that these dopamine antagonists, at the doses tested, have limited efficacy in treating cocaine abuse. Campbell, U.C., Rodefer, J.S., and Carroll, M.E. Effects of Dopamine Receptor Antagonists (D1 and D2) on the Demand for Smoked Cocaine Base in Rhesus Monkeys. Psychopharmacology 144, pp. 381-388, 1999.

Neuroactive Steroids are Self-Administered by Monkeys

Pregnane steroids are present in the nervous system. These neuroactive steroids, instead of binding at a genomic (steroid) receptor, have high affinity for a recognition site on the GABA-A receptor complex. Endogenous neuroactive steroids are elevated in the brain during stressful life events and at the time of menstruation in females. NIDA grantee Dr. James Rowlett (presently at Harvard Medical School) and colleagues tested the pregnane steroid, pregnanolone, for self-administration in monkeys. Their finding that all animals tested did self-administer pregnanolone suggests that progesterone-derived compounds may have central reinforcing properties. This and other studies using animal models suggests that stress can lead to drug self-administration, and may cause drug relapse following abstinence. However, the neural events underlying stress induced relapse have not yet been identified. Dr. Rowlett's findings suggest that activation of endogenous steroid systems in the brain may be a substrate for stress induced influences on drug seeking behavior, possibly by enhancing or mimicking central reinforcement. Rowlett, J.K., Winger G., Carter, R.B., Wood, P.L., Woods, J.H., and Woolverton, W.L. Reinforcing and Discriminative Stimulus Effects of the Neuroactive Steroids Pregnanolone and Co 8-7071 in Rhesus Monkeys. Psychopharmacology, 145, pp. 205-212, 1999.

A Role for Serotonin in the Neurobiological Substrate for Incentive Motivation

Environmental stimuli previously associated with drugs of abuse take on motivational properties of their own and may prompt cravings or direct continued drug seeking behaviors. The neurobiological circuitry underlying the formation of these learned associations has yet to be identified. Using animal drug self-administration paradigms, researchers have found the brain neurotransmitter serotonin (5-HT) is involved in the development of the direct reinforcing effects of drugs such as cocaine. Some reports also suggest that 5-HT activation is important in self-reported craving for drug in human cocaine abusers. Recent reports from the laboratory of Dr. Janet Neisewander at Arizona State University suggest that these central 5-HT systems serve as a critical component in drug-seeking behavior. To test this hypotheses, Dr. Neiswander trained animals to self-administer cocaine and after cocaine availability ceased, she assessed them for 'relapse' in the presence of drug-associated cues (incentive motivational stimuli). She found that animals with low levels of 5-HT in the central nervous system exhibited significantly less cocaine 'seeking' behavior during extinction from drug self-administration. By contrast, animals with reduced 5-HT levels who had been trained to respond for food rewards, and then extinguished showed normal cue-induced food seeking. Tran-Nguyen, L.T.L., Baker, D.A., Grote, K.A., Solano, J., and Neisewander, J.L. Serotonin Depletion Attenuates Cocaine-Seeking Behavior in Rats. Psychopharmacology, 146, pp. 60-66, 1999.

The Role of Endogenous Stress Systems in Priming a Relapse to Drug-Seeking Behavior

In the September 1999 Director's Report to Council some interesting new findings from the laboratory of Dr. Nick Goeders at Louisiana State University Medical Center were reported, suggesting that although pain stimuli and cocaine may have similar internal 'cue' properties, this shared discriminative effect could not account for the ability of painful stimuli to prompt cocaine-seeking behavior in animal self-administration procedures. Now Dr. Goeders has investigated the role of brain adrenocorticosteroids in the priming effect. Priming is demonstrated when previously drug-experienced animals, after receiving a single dose of a drug, are observed to relapse to previous patterns of drug seeking behavior (e.g., again make 'trained' responses to receive the drug). When the animals received a drug that blocks adrenocorticosteroid synthesis - thus blunting internal stress systems - the priming effect of cocaine was not seen. These data suggest that although cocaine-induced priming has been observed to raise plasma corticosterone, priming does not seem critically dependent upon activation in these brain stress systems. Mantsch, J.R., and Goeders, N.E. Ketoconazole Does Not Block Cocaine Discrimination or the Cocaine-Induced Reinstatement of Cocaine-Seeking Behavior. Pharmacology, Biochemistry and Behavior, 64, pp. 65-73, 1999.

Central Dopamine D3 Receptor Substrates in Cocaine-Induced Conditioned Place Preference

Dr. Janet Neisewander from the University of Arizona has been studying a potential role for central dopamine D3 receptor substrates in the reinforcing properties of cocaine. She has employed conditioned place preference (CPP) techniques to examine an animal's preference for environments previously paired with the administration of cocaine. In her studies, the mixed D2/D3 agonist 7-OH-DPAT attenuated the development of cocaine-induced CPP. This observation is different from results reported from Dr. George Koob's laboratory in 1998, wherein 7-OH-DPAT was found to potentate the reinforcing properties of cocaine with self-administration procedures. Collectively, these results might indicate that D3 substrates play a different role in direct reinforcing properties of the drug than the role they play in the acquisition of incentive motivational properties by stimuli associated with drug rewards. Alternatively, this substrate may be differentially involved in the acquisition versus the maintenance of ongoing drug-seeking behaviors. Khroyan T.V., Fuchs, R.A., Beck, A.M., Groff, R.S., and Neisewander, J.L. Behavioral Interactions Produced by Co-administration of 7-OH-DPAT with Cocaine or Apomorphine in the Rat. Psychopharmacology, 142, pp. 383-392, 1999.

Conditioned Increase in Place Preference by Access to Novel Objects: Antagonism by MK-801

A series of studies examined if the conditioned place preference preparation would prove useful in studying the appetitive quality of novelty, assessed whether iv cocaine would also condition an increase in preference, and assessed the role of the N-methyl-D-aspartate (NMDA) receptor in this place conditioning paradigm. In 3 separate place conditioning 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 also 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: Antagonism by MK-801. Behav. Brain Res, 99, pp. 53-60, 1999.

The Effects of Anxiolytic Drugs on Place Preference

This study assessed whether novelty-induced place preference resulted from an avoidance of the stress-related familiar compartment or approach to a novel compartment in rats. Seven to eight subjects per group were injected with 0.1, 0.3, 1.0, 3.0 mg/kg of diazepam in Experiment 1a, and 0 or 3.0 mg/kg of diazepam in Experiment 1b prior to a preference test. In Experiment 2, 8 subjects per group were injected with gepirone (0.1, 0.3, 1.0 mg/kg) prior to a preference test. Control subjects showed a novelty-induced place preference. Novelty-induced place preference was disrupted by diazepam, but only at a dose (3 mg/kg) that also decreased locomotor activity. Gepirone failed to alter the preference behavior, even at a dose (1 mg/kg) that decreased locomotor behavior. In Experiment 3, 14 rats, equally exposed to the compartments, were given a choice between the compartments, one had had a novel object placed in it. Subjects spent more time in a familiar compartment that contained the novel object than in a familiar compartment with no new object. Results indicate that preference for the novel compartment may reflect the rewarding effect of novelty rather than aversion to the familiar. Klebaur, J.E., and Bardo, M.T. The Effects of Anxiolytic Drugs on Novelty-Induced Place Preference. Behavioural Brain Research, 101, pp. 51-57, 1999.

Heroin Reward in Economic Terms

Recent theories of substance abuse have used value discounting of delayed rewards to partly explain the decision to take drugs. Normative-economic theory holds that an exponential function describes the effects of delay on discounting, whereas the matching law posits a hyperbolic discounting function. The ability of these functions to describe 18 human heroin-dependent individuals' monetary- and heroin-reward delay-discounting functions was assessed. In the 1st condition, participants chose to bet monetary rewards. Delayed rewards were $1,000, and the immediate reward amount was adjusted until choices reflected indifference. In the 2nd condition, participants chose between immediate and delayed heroin (the delayed amount was that which each participant reported he or she could purchase with $1,000). The hyperbolic function produced significantly higher R2 values and significantly lower sums of squared error values. Consistent with previous findings, delayed heroin rewards were discounted at a significantly higher rate than were delayed monetary rewards. Madden, G.J., Bickel, W.K., and Jacobs, E.A. Discounting of Delayed Rewards in Opioid-Dependent Outpatients: Exponential or Hyperbolic Discounting Functions? Exp Clin Psychopharm, 7(3), pp. 284-293, 1999.

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