Ethanol regulation of γ-aminobutyric acid_A receptors: Genomic and nongenomic mechanisms

γ-Aminobutyric acid_A (GABA_A) receptors are ligand-gated ion channels that, predominately, mediate inhibitory synaptic transmission in the CNS. These receptors are pentameric complexes that are comprised of subunits from several classes (α, β, γ, δ, ε), with each class consisting of several isoforms. Chronic ethanol consumption alters GABA_A receptor function producing cellular tolerance to GABA and ethanol, cross-tolerance to benzodiazepines and barbiturates, and sensitization to inverse agonists. Recent studies have clearly demonstrated that GABA_A receptors play an important role in ethanol dependence and functional properties of GABA_A receptor are altered following chronic ethanol administration. However, the exact mechanisms that account for alterations in GABA_A receptor function following chronic ethanol administration have not been resolved. The mechanisms responsible for adaptation of GABA_A receptors to chronic ethanol exposure may involve ethanol-induced changes in cell surface expression, subcellular localization, synaptic localization, receptor phosphorylation, neurosteroids, and/or changes in GABA_A receptor subunit composition. In this review, we provide an overview of recent data pertaining to mechanisms that could be responsible for altered properties and expression of GABA _A receptors following chronic ethanol administration.