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

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 delta subunit-containing GABA(A) receptors (delta-GABA(A)Rs) that mediate tonic inhibition, or synaptic gamma 2-containing GABA(A)Rs which underlie fast, synaptic, phasic inhibition have been implicated in sex differences in binge drinking. Ovarian hormones regulate delta-GABA(A)Rs, further implicating these receptors in potential sex differences. Here, we explored the contribution of extrasynaptic delta-GABA(A)Rs 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 delta-GABA(A)Rs and decreased binge-like drinking in females. There was no significant difference in either male or female mice after GABA(A)R gamma 2- subunit reduction in the VTA following AAVCre-GFP infusion in floxed Gabrg2 mice. Collectively, these findings suggest sex differences and GABA(A)R subunit specificity in alcohol intake.