Chronic ethanol and pentobarbital administration in the rat: Effects on GABA_A receptor function and expression in brain

Chronic exposure of rats to ethanol significantly decreases GABA_A receptor-mediated ³⁶Cl^- uptake in cerebral cortical synaptoneurosomes. Muscimol and pentobarbital stimulation as well as ethanol enhancement of muscimol-stimulated ³⁶Cl^- flux are significantly decreased following chronic ethanol inhalation. Repeated pentobarbital administration has a similar effect on muscimol and pentobarbital-stimulated ³⁶Cl^- uptake in cerebral cortical synaptoneurosomes. We have postulated that these adaptive responses may be associated with an alteration of GABA_A receptor gene expression. Chronic ethanol exposure resulted in a significant reduction in the levels of GABA_A receptor α-subunit mRNA's. The most abundant mRNA species in the rat cerebral cortex were reduced 40-50% (4.4 Kb mRNA, 43%, 4.8 Kb mRNA, 47%) β-Actin mRNA and poly(A)+ RNA levels were not significantly reduced following chronic ethanol exposure. Repeated pentobarbital administration had no effect on the level of the 4.4 and 4.8 Kb transcripts of α-subunit mRNAs in rat cerebral cortex. These data suggest that chronic ethanol exposure alters the level of mRNA's coding for the α-subunit of the GABA_A receptor. This decrease may reflect an alteration of mRNA processing in the cell or an alteration in GABA_A receptor gene expression.