Several mechanisms for GABAA receptor adaptation following chronic ethanol exposure have been proposed that include alterations in gene expression, post-translational modification, synaptic localization, intracellular signaling, and neuroactive steroid responses to ethanol. The expression of GABAA receptors involves a highly regulated process of synthesis, assembly, endocytosis, and recycling or degradation (see Fig. 1). Golgi-derived vesicles provide newly synthesized receptors to the cell surface, whereas clathrin-coated vesicles mediate endocytosis of surface receptors that are ultimately degraded or recycled back to the cell surface (Lodish et al. 1996). Alterations in the expression and composition of various GABAA receptors could result from selective endocytosis, recycling, and/or trafficking of newly synthesized receptors to the cell surface. Recent studies have shown the importance of GABAA receptor trafficking on the surface expression of receptors following ethanol exposure (Kumar et al. 2004). Altered GABAA receptor subunit composition and expression on the cell surface following ethanol exposure is thought to contribute to the development of ethanol dependence. Therefore, investigation of the mechanisms for altered GABAA receptor trafficking following ethanol exposure may provide novel targets for drug development.
