%0 PDF %T Differentially Modulating the VTA: A Role for Delta-mediated GABA(A) Tonic Inhibition and the Stress Neuropeptide CRF during Ethanol Intake %A Darnieder, Laura. %D 2018-09-11T11:06:04.913-04:00 %8 2018-09-11 %R http://localhost/files/2227n1791 %X Abstract: Binge drinking is a prevalent form of short-term alcohol consumption resulting in blood alcohol levels of 0.08 g/dl. Although more frequent in men, binge drinking has become increasingly common in women. To this end, sex-specific changes are evident in underlying mesocorticolimbic circuitry, including the modulation of GABAergic inhibitory neurotransmission. Broadly speaking, extrasynaptic GABAA receptors (GABAARs) incorporating the δ subunit mediate tonic inhibition, while synaptic 2-containing GABAARs underlie fast, phasic inhibition. GABAARs incorporating the δ-subunit-containing are sensitive to the low-to-moderate alcohol doses typically found in binge drinking. Critically, they can also be modulated by ovarian-derived hormones, indicating possible sex-specific differences in δ-mediated inhibition. Given this, it was hypothesized that -subunit-containing GABAARs would play a sex-specific role in male and female binge-like drinking in a region critical to mesocorticolimbic circuitry—the ventral tegmental area (VTA). Initial qPCR results revealed a nearly two-fold increase in Gabrd transcript levels in female VTA relative to males, but no sex-specific Gabrg2 differences. These baseline differences were also functionally evident, with increased levels of tonic inhibition in female VTA. To determine if Gabrd removal would sex-specifically alter binge-like drinking, both male and female floxed Gabrd and floxed Gabrg2 mice were given bilateral injections into the VTA of either AAV-Cre-GFP or AAV-GFP for Cre-mediated Gabrd or Gabrg2 excision. Mice were subjected to one cycle of a binge-like drinking protocol, with results indicating that female subjects with VTA-specific -excision had decreased binge-like alcohol intake. -excision had no significant effect on male binge-like drinking and there were no differences in binge-like intake in either male or female 2-excised subjects. While the posterior VTA had the highest viral reporter expression and is also known to contain a population of GABAergic interneurons, later cell-type-specific analysis revealed no sex-specific difference in parvalbumin-positive interneurons/δ subunit colocalization. Although these results demonstrate increased baseline δ-mediated tonic inhibition in the VTA of females is asymmetrically important in low-to-moderate binge-like drinking, a better understanding of underlying cell type will be the focus of future work.; Thesis (Ph.D.)--Tufts University, 2018.; Submitted to the Dept. of Neuroscience.; Advisors: Jamie Maguire, and Klaus Miczek.; Committee: Maribel Rios, Joe DeBold, and Uwe Rudolph.; Keywords: Neurosciences, Psychobiology, and Psychology. %[ 2022-10-11 %9 Text %~ Tufts Digital Library %W Institution