FUNCTIONAL ANALYSIS OF GABAERGIC SEDATIVE/ANXIOLYTICS

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DESCRIPTION: (Applicant's Abstract) Anxiolytics and sedative-hypnotics, particularly benzodiazepines (Bz), are among the most widely prescribed of all psychoactive medications. Misuse, abuse, and physiological dependence associated with these drugs are of continuing concern. The majority of these compounds act by enhancing transmission of the major inhibitory neurotransmitter gaba-aminobutyric acid (GABA). Recent advances in understanding the structure of the GABAAreceptor complex have led to development of novel compounds that are more selective in binding to subtypes of that receptor. Concurrently, compounds that are partial agonists at the GABAA Bz modulatory site also are strong candidates as new treatments for anxiety and sleep disorders. The hope is that these newer compounds will have good clinical efficacy and patient acceptability, and also show less tolerance with chronic use, have less abuse liability and less dependence potential. However, little systematic work on the functional relevance of greater receptor selectivity or partial agonism has been done in whole animal models of subjective effects or drug-taking. One major objective of the project is to provide such a systematic characterization of these novel agents in animal drug discrimination procedures, which provide a highly selective analog to a human drug categorization procedure, and thus serve as a model of subjective effects. The evaluation of novel anxiolytics and sedatives under these procedures will proceed in a context of also evaluating the extent to which the procedure itself can be made more selective and to determine how training variables (e.g., dose, context) may influence results and interpretation. Comparisons will be made among barbiturates, Bz, and related compounds. A second major objective of the project is to continue investigation of the possible interrelationships between the discriminative stimulus and reinforcing effects of drugs by studying how experience under one procedure may modulate behavior under the another. Such data are important for understanding the extent to which certain drug learning histories can increase sensitization to drug stimulus effects. Experiments also will explore the reinstatement, or priming, phenomenon with respect to sedatives and anxiolytics. This classic procedure has promise as an animal model of relapse and of drug craving. Studies will test the extent to which results from drug discrimination studies predict behavior under this procedure. This research should inform current thinking over the ways in which stimulus control processes operate in determining chronic drug-taking.