Female-specific decreases in alcohol binge-like drinking resulting from GABA_A receptor delta-subunit knockdown in the...

Binge drinking is short-term drinking that achieves blood alcohol levels of 0.08 g/dl or above. It exhibits well-established sex differences in GABAergic inhibitory neurotransmission, including extrasynaptic δ subunit-containing GABA_A receptors (δ-GABA_ARs) that mediate tonic inhibition, or synaptic γ2-containing GABA_ARs which underlie fast, synaptic, phasic inhibition have been implicated in sex differences in binge drinking. Ovarian hormones regulate δ-GABA_ARs, further implicating these receptors in potential sex differences. Here, we explored the contribution of extrasynaptic δ-GABA_ARs to male and female binge-like drinking in a critical area of mesolimbic circuitry-the ventral tegmental area (VTA). Quantitative PCR revealed higher Gabrd transcript levels and larger tonic currents in the VTA of females compared to males. In contrast, male and female Gabrg2 transcript levels and measures of phasic inhibition were equivalent. Intra-VTA infusion of AAV-Cre-GFP in floxed Gabrd mice downregulated δ-GABA_ARs and decreased binge-like drinking in females. There was no significant difference in either male or female mice after GABA_AR γ2 subunit reduction in the VTA following AAV-Cre-GFP infusion in floxed Gabrg2 mice. Collectively, these findings suggest sex differences and GABA_AR subunit specificity in alcohol intake.