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LL Devaud, FD Smith, DR Grayson and AL Morrow
Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill 27599-7178, USA.
The molecular mechanisms that underlie ethanol dependence appear to involve alterations in GABAA receptor function and gene expression. In rat cerebral cortex, chronic exposure to ethanol alters many functional properties of GABAA receptors, including reduction of GABAA 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 elicits alterations in mRNA and polypeptide levels for several abundant GABAA receptor subunits. For example, alpha 1 and alpha 2 subunit mRNA and polypeptide levels have been shown to decrease with chronic ethanol exposure. The present study was undertaken to further investigate the effects of chronic ethanol consumption on GABAA receptor subunit mRNA levels in rat cerebral cortex by using a competitive, quantitative reverse transcriptase-polymerase chain reaction assay that incorporates subunit-specific internal standards and allows for the absolute quantification of mRNA levels. We find that chronic ethanol consumption elicits a significant increase in alpha 4 subunit mRNA levels that is equal, in absolute amount, to a decrease in alpha 1 subunit mRNA levels. There is a small (30%) increase in gamma 2S but not gamma 2L subunit 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 analysis showing a 40% reduction in alpha 1 mRNA levels with no change in beta 2 subunit mRNA levels after chronic ethanol consumption. These results are consistent with the hypothesis that chronic ethanol consumption alters the function of GABAA receptors by eliciting changes in receptor subunit assembly. These changes may underlie the development of ethanol dependence.
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