Alcoholism is a worldwide public health problem that is associated with debilitating medical, social, and psychological consequences. Alcoholism is characterized by persistent alcohol self-administration that is refractory to conventional interventions and by high vulnerability to relapse even after successful detoxification and abstinence. No broadly effective medications have been identified to combat alcohol abuse or relapse. Thus, the development of pharmacotherapies that reduce alcohol consumption and/or eliminate craving for alcohol remains a formidable challenge for the treatment of alcohol addiction. The purpose of this R21 proposal (RFA-AA-02-004) is to explore the role of GABAA/alpha5 receptor mechanisms in the behavioral effects of alcohol in nonhuman primates and to evaluate promising GABAA/alpha5 ligands as novel pharmacotherapies to treat alcohol addiction. Recent findings support a role for GABAA/alpha5 receptor mechanisms in alcohol's discriminative stimulus effects in monkeys and its reinforcing effects in rodents. In the proposed studies, the capacity of GABAA/alpha5 ligands to reduce oral self-administration of alcohol in rhesus monkeys will be investigated. In order to gauge the pharmacological specificity of these effects, GABAA/alpha5 ligands will also be evaluated in monkeys that self-administer sucrose solution instead of alcohol. In addition, concurrent observational studies will assess the degree to which GABAA/alpha5 ligands engender sedative and/or motoric side effects. Finally, in monkeys whose drug-seeking behavior has been extinguished and subsequently reinstated by alcohol priming, GABAA/alpha5 ligands will be evaluated for their ability to inhibit relapse to alcohol-seeking behavior. The ability of selected GABAA/alpha5 ligands to reduce oral alcohol self-administration and 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. The proposed studies will provide fundamental information regarding the viability of GABAA/alpha5 receptors as pharmacological targets for novel medications to reduce alcohol abuse and relapse.
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