The Alpha-1 GABAA Receptor Regulates Alcohol-Drinking Behaviors

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DESCRIPTION (provided by applicant): It is well established that the rewarding properties of ethanol [EtOH] are mediated in part by GABAA-receptor mechanisms; however, only recently has research demonstrated that the a1 receptor subunit, particularly those within the ventral pallidum [VP], may be the critical GABAergic receptor regulating EtOH reinforcement. The primary objective of this proposal will be to further evaluate the role of the GABAA a1-containing receptor subunit in regulating EtOH-seeking behaviors by employing a combination of neuropsychopharmacological and molecular biology techniques. To accomplish this goal, the selectively-bred high alcohol-drinking [HAD-1] rats will be used. The primary hypothesis to be tested is that a selective inhibition of the GABAA a1 receptor containing subunit within the VP of HAD-1 rats will lead to selective reductions in EtOH-motivated behavior, with little or no effect on sucrose-motivated behaviors. The inhibition of the GABAA a1 subunit will be accomplished by constructing a herpes simplex virus [HSV] vector, which will utilize the siRNA sequence specific, posttranscriptional gene silencing mechanism. This vector will then be infused directly into the VP of HAD-1 rats via bilateral guide cannulae. It is hypothesized that a selective reduction in EtOH-maintained responding will be observed following infusion of the vector-mediated siRNA amplicon into the VP. Specifically, reinforcer and neuroanatomical specificity will be expected, as neither suppression on sucrose maintained responding following infusion of the active virus in the VP, nor suppression on alcohol responding infusion of the active virus into the neuroanatomical control locus [e.g., caudate putamen] will be expected. In subsequent studies, a combination of in situ reverse transcriptase-PCR, immunohistochemistry, and Western analyses [immunoblotting] will be used to determine the success of the HSV-siRNA viral vector manipulations. These studies should extend our understanding of the role of the GABAA a1 receptor subtype in the regulation of alcohol-drinking behaviors.