The discriminative stimulus effects of drugs in animals serve as an excellent model of the subject effects of drugs in humans. Since subjective effects play a major role in drug abuse, pharmacological analysis of the DS effect in animals can provide basic information about mechanisms that mediate subjective effects and may suggest ways to pharmacologically modify subjective effects that may be useful in the treatment of drug abuse. Moreover, drug discrimination (DD) can be used to predict the subjective effects of novel compounds. The present proposal is designed to address each of these issues in rhesus monkeys trained in a two-lever, DD paradigm to discriminate a stimulant (d- amphetamine: AMPH), a depressant (pentobarbital: PB) or a hallucinogen [1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane DOM] from saline. In AMPH-trained monkeys, we will examine two hypotheses. The first is that serotoninlA (5-HT1A) receptors can modulate the DS effects of stimulants. Based on preliminary findings, we propose to examine the effects of combining drugs that vary in their efficacies at 5-HT1A receptors with AMPH. The second is that changes in the basic phenylalkylamine (PAA) nucleus will modify the DS effect of AMPH in a systematic way. We propose to establish structure-activity relationships (SARs) among PAAs for AMPH- like DS effects. In PB-trained monkeys, we will also test two hypotheses. The first is that dopamine (DA) D1 receptors can modulate the DS effect of depressants. Based on preliminary findings, we propose to examine the interaction of PB with drugs that vary in their efficacies at D1 receptors. The second is that efficacy at benzodiazepine (BZ) receptors determines the extent to which BZs engender PB-like DS effects. We propose to examine a series of BZ agonists alone and in combination with flumazenil in PB-trained monkeys. In DOM-trained monkeys, we will use selective agonists and antagonists to test the hypothesis that the DS effect of hallucinogens in monkeys involves agonist action at 5-HT2 receptors. In addition, we will conduct a SAR analysis of a series of PAAs to establish structural requirements for DOM-like activity in monkeys. Finally, we will continue to evaluate the DS effects of novel compounds as part of the Drug Evaluation Committee (DEC) of the College on Problems of Drug Dependence (CPDD). We will test compounds for AMPH-, PB- or DOM-like DS effects. Compounds with DS effects comparable to those of AMPH, PB or DOM would be predicted to have subjective effects similar to that compound in humans. The proposed research will enhance our understanding of the neuropharmacological mechanisms underlying the DS and subjective effects of drugs of abuse. In addition to providing basic information, our results may aid in the development of novel pharmacological approaches to the treatment of drug abuse. Evaluation of the DS effects of novel compounds will provide information used to predict their abuse liability and in scheduling decisions. Together with research from the other laboratories of this IRPG, we will help provide a comprehensive analysis of the behavioral effects of these three important classes of abused drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA009139-05
Application #
2749093
Study Section
Special Emphasis Panel (SRCD)
Project Start
1994-08-15
Project End
2001-07-31
Budget Start
1998-08-01
Budget End
2001-07-31
Support Year
5
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Mississippi Medical Center
Department
Psychiatry
Type
Schools of Medicine
DUNS #
928824473
City
Jackson
State
MS
Country
United States
Zip Code
39216
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Rowlett, J K; Woolverton, W L (2001) Discriminative stimulus effects of panadiplon (U-78875), a partial agonist at the benzodiazepine site, in pentobarbital-trained rhesus monkeys. Drug Alcohol Depend 61:229-36
Woolverton, W L; Rowlett, J K; Winger, G et al. (1999) Evaluation of the reinforcing and discriminative stimulus effects of gamma-hydroxybutyrate in rhesus monkeys. Drug Alcohol Depend 54:137-43
Rowlett, J K; Winger, G; Carter, R B et al. (1999) Reinforcing and discriminative stimulus effects of the neuroactive steroids pregnanolone and Co 8-7071 in rhesus monkeys. Psychopharmacology (Berl) 145:205-12
Rowlett, J K; Wilcox, K M; Woolverton, W L (1999) Discriminative stimulus effects of ethyl-beta-carboline-3-carboxylate at two training doses in rats. Psychopharmacology (Berl) 145:324-32
Rowlett, J K; Woolverton, W L (1998) Discriminative stimulus effects of benzodiazepine agonists and partial agonists in pentobarbital-trained rhesus monkeys. Behav Pharmacol 9:81-92
Rowlett, J K; Woolverton, W L (1997) Discriminative stimulus effects of zolpidem in pentobarbital-trained subjects: I. Comparison with triazolam in rhesus monkeys and rats. J Pharmacol Exp Ther 280:162-73
Woolverton, W L; English, J A (1997) Effects of some phenylethylamines in rhesus monkeys trained to discriminate (+)-amphetamine from saline. Drug Alcohol Depend 44:79-85

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