Chronic ethanol administration alters γ-aminobutyric acid(A) receptor gene expression

M. C. Mhatre, M. K. Ticku

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204 Scopus citations

Abstract

Chronic ethanol (alcohol) administration has been associated with alterations in the binding and function of the γ-aminobutyric acid (GABA(A)) receptor. To evaluate the mechanism underlying these changes, we measured the steady state levels of the mRNAs for the α1, α2, α3, α5, and α6 subunits of the GABA(A) receptor after chronic ethanol administration to rats and ethanol withdrawal for 24 hr. The results indicated that chronic ethanol administration resulted in a 61% decline in the level of the GABA(A) receptor α1 subunit mRNAs [3.8 and 4.3 kilobases (kb)] in the cerebral cortex in rats. The levels of the α2 subunit mRNAs (6 and 3 kb) and the α5 subunit mRNA (2.8 kb) were also reduced, by 61, 45, and 51%, respectively, whereas there was no change in the level of the α3 subunit mRNA (3 kb). Furthermore, the ethanol-induced decrease in receptor mRNA levels persisted for 24 hr, after withdrawal of ethanol and returned to control values at 36 hr of withdrawal. α1 mRNA levels in cerebellum also decreased by 28%. The level of the α6 subunit mRNA, which selectively encodes Ro15-4513 binding sites, was found to be increased by ~76% in the cerebellum. Also, the photoaffinity labeling studies using [3H]Ro15-4513 indicated an increase in the levels of various protein components of the GABA(A) receptor, in the cerebellum and the cerebral cortex (e.g., 50- and 55-kDa proteins in the cerebellum and 41- and 50-kDa proteins in the cortex), after chronic ethanol treatment. The increase in α6 mRNA in the cerebellum might be related to the increased labeling of the 55-kDa (~56-kDa) protein and partially responsible for the increased binding, as reported previously by us. Because the α6 subunit is not expressed in cortex, involvement of an as yet unknown subunit in this region cannot be ruled out. The effect of chronic ethanol treatment appears to be specific for GABA(A) receptor subunit mRNAs, because the same treatment did not alter the levels of glyceraldehyde-3-dehydrogenase mRNA or poly(A)+ RNA. In summary, these data indicate that chronic ethanol treatment results in an alteration in the regulation of expression of GABA(A) receptor subunit-encoding mRNAs, which could be due to alterations in transcription or mRNA stability.

Original languageEnglish (US)
Pages (from-to)415-422
Number of pages8
JournalMolecular pharmacology
Volume42
Issue number3
StatePublished - 1992

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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