GABA-A receptor subtype mechanisms and the abuse-related effects of alcohol

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The abuse of alcohol is controlled by multiple effects of the drug, including its subjective, reinforcing, and re- lapse-inducing effects. Preclinical methods have been developed to assess the contribution of these control- ling factors and their neurobiological underpinnings, and to provide empirically based models for evaluating potential treatment strategies. Alcohol's ability to potentiate the activity of γ-aminobutyric acid (GABA) at GABAA receptors has been implicated as a key mechanism underlying the abuse-related effects of alcohol in both humans and laboratory animals, making this system an attractive candidate for the development of thera- peutics. The complex molecular biology of GABAA receptors raises the possibility that subtype-selective agents might be developed with therapeutic specificity against alcohol. In this application, we will investigate the role of γ- and δ-containing α4GABAA and α6GABAA receptor mechanisms in nonhuman primate and rodent models of the abuse-related effects of alcohol. We will use first-in-kind compounds that are selective for α4δ, α6δ, α4γ, and/or α6γGABAA receptors to investigate the contribution of these subtypes to: 1) the discriminative stimulus effects of alcohol in monkeys trained to discriminate intra-gastrically-administered alcohol from vehi- cle, 2) the reinforcing effects of alcohol in monkeys orally self-administering alcohol, and 3) the relapse- inducing effects of alcohol in rats trained in either cue-induced reinstatement or alcohol deprivation effect pro- cedures (Specific Aim 1). Understanding the neuropharmacological mechanisms underlying the addictive ef- fects of alcohol is an important initial step in the development of candidate pharmacotherapies for the treat- ment of alcohol abuse and dependence. The degree to which the effects of γ- and δ-selective α4GABAA and α6GABAA ligands selectively modify alcohol-controlled behavior will be evaluated in monkeys that self- administer a sucrose solution instead of alcohol and in rats trained in a cue-induced sucrose seeking proce- dure. In monkeys, concurrent observational studies will characterize the effects of the ligands, alone or com- bined with alcohol, on unconditioned motor behavior (Specific Aim 2). The ability of these ligands to mimic or modulate the discriminative stimulus effects of alcohol, alcohol self-administration, and cue-induced alcohol seeking and relapse-like drinking at doses that do not produce a generalized disruption of behavior or debilitat- ing side effects may be predictive of potential therapeutic utility. Finally, we will investigate the utility of selec- tive GABAergic ligands with favorable side effect profiles to serve as co-therapies in a model of medication- assisted treatment (Specific Aim 3). These studies will make use of a novel resurgence model of contingency management developed recently in our laboratory and, initially, ligands that either mimic or attenuate the be- havioral effects of alcohol. Integration of results from the aims will continue to yield needed information about neuropharmacological mechanisms underlying the addictive effects of alcohol and begin to identify clinical scenarios in which pharmacological approaches might be expected to produce improved patient outcomes.