Bidirectional Alterations of GABA_A Receptor Subunit Peptide Levels in Rat Cortex During Chronic Ethanol Consumption and Withdrawal

Abstract

The pharmacological properties of y-aminobutyric acidA (GABAA) receptors are altered by prolonged exposure to ethanol both in viva and in vitro. We have shown previously that prolonged ethanol exposure elicits selective alterations in various GABAA receptor subunit mRNA levels in rat cerebral cortex. Some of these effects are rapidly reversed during ethanol withdrawal. The present study was conducted to determine the effects of prolonged ethanol exposure (dependence) and ethanol withdrawal on cerebral cortical peptide expression for several subunits. GABAA receptor cnl subunit peptide levels were decreased by nearly 40%, whereas cr4 subunit peptide levels were increased by 27% in both ethanol-dependent and withdrawn rats. These changes correlate well with observed alterations in mRNA levels following prolonged ethanol exposure in dependent rats, but do not match the effects on mRNA levels during ethanol withdrawal. /32/3 subunit peptide levels increased by -32% in both ethanol-dependent rats and rats undergoing ethanol withdrawal. We observed a 30-60% increase in yl subunit peptide levels in both dependent rats and those undergoing withdrawal, also correlating with the previous report on ethanol-induced alterations in mRNA levels.Peptide levels for y 2 subunits did not differ from control values in either condition. These findings show that specific alterations in GABAA receptor subunit peptide levels are associated with ethanol dependence in rats. GABAA receptor subunit peptide expression is more stable than mRNA expression, and mRNA levels are not representative of peptide expression during ethanol withdrawal. These findings are consistent with the suggestion that alterations in GABAA receptor gene expression underlie the functional properties of GABAA receptors in ethanoldependent rats and those undergoing ethanol withdrawal. Key Words: GABAA receptor-GABAA receptor subunit peptide expression-Ethanol.

The role of GABAA receptors in the development of alcoholism

“…Cortical peptide levels for β 2/3 and γ 1 and mRNA for γ 2S increase in ethanol-dependent rats (Devaud et al, 1997).…”

“…In contrast, a consistent finding in rodents is that chronic ethanol consumption decreases cortical mRNA and peptide levels of α 1 subunits but increases α 4 levels (Devaud et al, 1996(Devaud et al, , 1997Grobin et al, 1998;Matthews et al, 1998). Cortical peptide levels for β 2/3 and γ 1 and mRNA for γ 2S increase in ethanol-dependent rats (Devaud et al, 1997).…”

Differential Regulation of GABAA Receptor Gene Expression by Ethanol in the Rat Hippocampus Versus Cerebral Cortex

“…Northern blot analysis and RT-PCR have both shown that chronic ethanol consumption increases a 4, a6, y', and Y2s mRNA levels (Morrow et al, 1992;Devaud et al, 1995) while decreasing a1 mRNA levels (Montpied et al, 1991;Morrow et al, 1992;Devaud et al, 1995) in the cerebral cortex and cerebellum. Furthermore, alterations in GABAA receptor peptide expression mirror the changes found in mRNA expression following chronic ethanol consumption (Devaud et al, 1997). These results suggest that chronic ethanol exposure may lead to alterations in subunit assembly of GABAA receptors that could mediate the neurochemical and behavioral tolerance to ethanol and the cross-tolerance to benzodiazepines and barbiturates found following chronic ethanol consumption (Devaud et al, 1995(Devaud et al, , 1996(Devaud et al, , 1997Morrow, 1995).…”

Effects of a low dose of ethanol in an animal model of premenstrual anxiety

“…Suppression of α 4 expression prevented the response to 1-3 mM ethanol after progesterone withdrawal, further supporting the suggestion that α 4 βδ sub-unit isoforms of the GABA A receptor possess a unique sensitivity to ethanol. It is interesting that ethanol withdrawal also increases expression of the α 4 subunit of the GABA A receptor (Devaud et al, 1997;Mahmoudi et al, 1997), but it decreases expression of the δ subunit of the GABA A receptor (Cagetti et al, 2003), an effect correlated with a decrease in response to ethanol.…”