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.
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