In addition to the molecular changes observed in the GluN system following long-term alcohol exposures, the GABAaRs are subject to dynamic regulation by the drug (see Figure 1B for a summary). The subunits of the GABAaR are differentially expressed subsequent to chronic alcohol in a region- and subunit-specific manner [for detailed review see Ref. (138)]. Evidence suggests an exchange of subunits expressed on the cell surface with a reported reduction in A1 subunits in the hippocampus (139) and an increase of A4 (140–142) and A5 (139) following CIE. However, subunit expression is not the only element of GABAaR modulation that is altered by chronic alcohol exposure. Following withdrawal from CIE, neurons displayed heightened excitability, which was pharmacologically attributable to increases in the number of A4 containing GABAaRs (142) as well as reductions in tonic current modulators (143), increase in A4 synaptic localization (144), and subunit-specific changes in trafficking (145), leading to a preferential increase in A4 expression over other subunits. Therefore, following chronic alcohol exposure, there is a generalized reduction of GABAaR functionality, leading to heightened neuronal activity in the absence of alcohol’s modulating effects.
