Alcoholism is a public health problem that is associated with debilitating medical, social, and psychological consequences. The abuse of alcohol is controlled by multiple effects of the drug, including its subjective and reinforcing effects and its capacity to trigger relapse. Preclinical methods have been developed to assess the contribution of these controlling factors and their neurobiological underpinnings, and to provide empirically-based models for evaluating potential treatment strategies. The purpose of this proposal is to investigate the role of alpha1GABAA and alpha5GABAA receptor mechanisms in nonhuman primate models of the abuse-related effects of alcohol. Recent findings support a role for both alpha1GABAA and alpha5GABAA receptor mechanisms in alcohol's discriminative stimulus effects in monkeys and its reinforcing effects in rodents. We will build on these new findings to systematically investigate the contribution of alpha1GABAA (Specific Aim 1) and alpha5GABAA (Specific Aim 2) receptor mechanisms to the behavioral effects of alcohol by determining how receptor selective agonists and antagonists modulate: 1) the discriminative stimulus effects of alcohol in rhesus monkeys trained to discriminate intragastrically-administered alcohol from vehicle, 2) oral self- administration of alcohol in rhesus monkeys, and 3) reinstatement of alcohol seeking in rhesus monkeys whose oral self-administration has been extinguished and subsequently reinstated by alcohol priming. The degree to which the effects of alpha1GABAA and alpha5GABAA receptor ligands selectively modify alcohol-controlled behavior (Specific Aim 3) will be evaluated in rhesus monkeys that self-administer a sucrose solution instead of alcohol and in concurrent observational studies of the effects these ligands, alone or combined with alcohol, on unconditioned motor behavior. The ability of selected alpha1GABAA and alpha5GABAA ligands to blunt the discriminative stimulus effects of alcohol, reduce alcohol self-administration and attenuate priming- induced reinstatement of alcohol seeking at doses that do not produce a generalized disruption of behavior or debilitating side effects may be predictive of potential therapeutic utility. Integration of results from these three specific aims will provide needed information about specific GABAA mechanisms that may underlie the addictive effects of alcohol and will aid identification of receptor targets for the pharmacological management of alcohol abuse and relapse.
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