"Extrasynaptic" GABA-A receptors (GABARs) containing a4b3d and a6b3d subunits are increased in their activity by alcohol (EtOH) at low concentrations (3 mM, corresponding to a blood EtOH concentration after consumption of a half glass of wine) (Wallner*, Hanchar*, Olsen, PNAS 2003). GABARs containing b2 instead of b3 subunits in a4bd and a6bd receptor combinations are almost 10 times less sensitive to EtOH and GABARs containing g2s instead of d subunits in a4b and a6b receptor combinations are 3 times less sensitive to EtOH. b3 and d subunits are needed to confer this EtOH action and there are particular molecular differences between b2 and b3, d and g subunits that could explain a4b3d and a6b3d EtOH sensitivity. This proposal seeks to identify the molecular determinants that make these extrasynaptic GABARs uniquely EtOH sensitive by using chimeric constructs and point mutations. Preliminary data show mutations at potential EtOH binding sites, further increase the already very high EtOH sensitivity of these receptors. Furthermore, this EtOH binding site, involving specific amino acids of abd subunits, maybe modulated by benzodiazepines to either inhibit or enhance EtOH action on the brain.