CHRONIC ETHANOL TREATMENT UP-REGULATES THE GABA RECEPTOR-BETA SUBUNIT EXPRESSION

The molecular mechanisms associated with ethanol-induced tolerance and physical dependence have yet to be elucidated. In previous studies we have demonstrated that chronic ethanol administration produced a decrease in the GABA(A) receptor mRNA level of alpha(1), alpha(2), alpha(5) subunits, and a decrease in the polypeptide (alpha 1, alpha(2), and alpha(3)) expression in the rat cerebral cortex. In this study we examined the effect of chronic ethanol treatment on the mRNA levels and the expressions of the P-subunits of the GABA, receptors in rat cerebral cortex. The results indicate that chronic ethanol administration produced an upregulation of the P, subunit mRNA (12 kb) by 29 +/- 10%, beta(2) mRNA (8 kb) by 55 +/- 6% and the beta(3)-subunit (6 kb) mRNA by 72 +/- 9% in cerebral cortex. The levels of the beta(2) and beta(3) subunit mRNAs remains elevated at 24 hr withdrawal. We also investigated the effect of chronic ethanol administration on the P-subunit polypeptide expression using monoclonal antibody BD17, which recognizes the beta 2 (P56) and beta 3 (P58) polypeptides. Chronic ethanol treatment increased the levels of both of these polypeptides in cerebral cortex. Taken together, chronic ethanol administration produced an upregulation of the beta-subunit mRNA and the polypeptide expression of these subunits in rat cerebral cortex. In contrast, chronic ethanol treatment decreased the expression of various cu-subunits in the cerebral cortex. Such bidirectional changes in the expression of various subunits could alter the subunit composition of the functional receptors by substitution or altered levels, without changing the density of the receptors. In summary, chronic ethanol treatment has differential effect on various GABA(A) receptor subunits, which suggests involvement of differential regulatory mechanisms in interaction of ethanol with the GABA receptors.