Ethanol regulation of gamma-aminobutyric acid A receptors: genomic and nongenomic mechanisms

gamma-Aminobutyric acid(A) (GABA(A)) receptors are ligand-gated ion channels that, predominantly, mediate inhibitory synaptic transmission in the CNS. These receptors are pentameric complexes that are comprised of subunits from several classes (alpha, beta, gamma, delta, ), 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.