Chronic ethanol exposure alters muscimol, pentobarbital, and benzodiazepine agonist and inverse agonist effects on the function of GABA(A) receptor-gated Cl(-) channels in the central nervous system (CNS). We have recently shown that prolonged ethanol inhalation reduces the expression of GABA(A) receptor alpha1 and alpha2 subunit mRNAs in the rat cerebral cortex, with no effect on the level of alpha3 subunit transcripts, glutamic acid decarboxylase mRNA levels, or poly(A)(+) RNA levels. In the present study, rats were administered alcohol by liquid diet for 2 weeks using a pair-fed design. GABA(A) receptor alpha subunit mRNA levels were quantified by Northern analysis using specific cRNA probes. GABA(A) receptor alpha1 subunit mRNA levels were reduced in the cerebral cortex to the same extent as previously reported following prolonged ethanol inhalation. In the cerebellum, chronic ethanol ingestion reduced the levels of GABA(A) receptor alpha1 subunit mRNAs (4.8 and 4.4 kb) by 20-30% and increased the levels of GABA(A) receptor a6 subunit mRNA (2.7 kb) by 45%. GABA(A) receptor alpha2 and alpha3 subunit mRNAs were not detected in the cerebellum. Glutamic acid decarboxylase mRNA levels as well as poly(A)(+) RNA levels were not significantly altered following chronic ethanol exposure by liquid diet. Acute ethanol administration had no effect on GABA(A) receptor a6 subunit mRNA levels. However, acute administration of both Ro15-4513 and its vehicle control altered GABA(A) receptor alpha6 subunit mRNA levels in the cerebellum. Since GABA(A) receptor alpha6 subunits contain recognition sites for Ro15-4513, an inverse agonist, and an ethanol antagonist, the elevation in the expression of these subunits following chronic ethanol ingestion may account for increased sensitivity to inverse agonists after chronic ethanol administration and possibly contribute to the withdrawal syndrome. These data also suggest that chronic ethanol exposure regulates GABA(A) receptor gene expression by differential effects on the synthesis of specific subunits of GABA(A) receptors in the CNS.