Differentially Modulating the VTA: A Role for Delta-mediated GABA(A) Tonic Inhibition and the Stress Neuropeptide CRF during Ethanol Intake
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, ... read moreextrasynaptic 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
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.read less