CHRONIC ETHANOL-CONSUMPTION DIFFERENTIALLY ALTERS THE EXPRESSION OF GAMMA-AMINOBUTYRIC ACID(A) RECEPTOR SUBUNIT MESSENGER-RNAS IN RAT CEREBRAL-CORTEX - COMPETITIVE, QUANTITATIVE REVERSE TRANSCRIPTASE-POLYMERASE CHAIN-REACTION ANALYSIS

The molecular mechanisms that underlie ethanol dependence appear to in volve alterations in GABA(A), receptor function and gene expression. I n rat cerebral cortex, chronic exposure to ethanol alters many functio nal properties of GABA(A), receptors, including reduction of GABA(A), receptor-mediated chloride uptake. These functional alterations occur without a concomitant alteration in total receptor density or affinity . Previous investigations have shown that chronic ethanol exposure eli cits alterations in mRNA and polypeptide levels for several abundant G ABA(A), receptor subunits. For example, alpha 1 and alpha 2 subunit mR NA and polypeptide levels have been shown to decrease with chronic eth anol exposure. The present study was undertaken to further investigate the effects of chronic ethanol consumption on GABA(A), receptor subun it mRNA levels in rat cerebral cortex by using a competitive, quantita tive reverse transcriptase-polymerase chain reaction assay that incorp orates subunit-specific internal standards and allows for the absolute quantification of mRNA levels. We find that chronic ethanol consumpti on elicits a significant increase in alpha 4 subunit mRNA levels that is equal, in absolute amount, to a decrease in alpha 1 subunit mRNA le vels. There is a small (30%) increase in gamma 2S but not gamma 2L sub unit mRNA levels after chronic ethanol consumption. In addition, gamma 1 subunit mRNA levels are increased by 70%, whereas alpha 5, beta 1, beta 2, beta 3, gamma 3, and delta subunit mRNA levels do not change. We also reproduced results obtained previously by Northern blot analys is showing a 40% reduction in alpha 1 mRNA levels with no change in be ta 2 subunit mRNA levels after chronic ethanol consumption. These resu lts are consistent with the hypothesis that chronic ethanol consumptio n alters the function of GABA(A) receptors by eliciting changes in rec eptor subunit assembly. These changes may underlie tile development of ethanol dependence.