Although benzodiazepines (BZs) are considered to be among the safest prescription drugs in modern medicine, their utility is constrained by a number of side effects, including the liability for abuse, and recent epidemiological research suggests BZ abuse is on the rise in the U.S. The overall goal of this application is to investigate the extent to which GABAA receptor subtypes are differentially involved in the anxiolytic effects and self-administration associated with BZ ligands, using relevant nonhuman primate models. During the past project period, we found that a compound selective for a3GABAA receptors had anxiolytic-like effects and was self-administered by monkeys experienced in BZ, but not cocaine self-administration. Some BZ-type compounds, however, were self-administered by cocaine-experienced monkeys, with the common feature among these compounds being efficacy at a1GABAA receptors. Together, these findings suggest that ?3GABAA receptor selectivity and past drug experience may be key determinants of the therapeutic and addictive effects of BZ-type compounds. Our proposed studies specifically will evaluate the hypotheses that (1) intrinsic efficacy at ?3GABAA receptor subtypes is a key mediator of the anxiolytic effects of BZs; (2) ?1GABAA and ?3GABAA receptor subtypes mediate the self-administration of BZs, but the relative contribution of each subtype depends on the past drug experience of the subject; and (3) ?3GABAA-selective are reinforcers, punishers, and/or neutral stimuli based on the past drug experience of the subject. Anxiolytic activity will be evaluated in rhesus monkeys using conflict procedures in which food-maintained behavior is concurrently suppressed by response-produced presentations of an aversive stimulus. Abuse potential will be assessed in monkeys trained to self-administer one of three commonly-abused drugs: alprazolam, cocaine, or heroin. Reinforcing effects will be evaluated using progressive-ratio schedules and a novel choice procedure. Ligands with selectivity for different BZ-sensitive receptors will be used as pharmacological probes to determine the role of these receptors in the behavioral effects of BZs. Understanding the interaction of past drug experiences and receptor subtype selectivity will provide fundamental information for developing safer and more broadly effective anti-anxiety medications.

Public Health Relevance

Valium and related drugs, referred to as 'benzodiazepines' are prescribed widely for the treatment of anxiety disorders, one of the most common psychiatric disorders in the U.S. Benzodiazepines are considered to be among the safest prescription drugs in modern medicine, but they unfortunately are also drugs of abuse. The overall goal of this application is to uncover mechanisms that control the beneficial effects as well as the abuse of benzodiazepines, with the hope of developing safer drugs for treating anxiety disorders.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
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Wetherington, Cora Lee
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University of Mississippi Medical Center
Internal Medicine/Medicine
Schools of Medicine
United States
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