Influence of gender on chronic ethanol-induced alterations in GABAA receptors in rats

Ethanol dependence, arising from chronic ethanol exposure, is associated with neuroadaptations of GABA_A receptors, evidenced by alterations in various behaviors, receptor responsiveness and subunit gene expression. The present studies explored the effects of ethanol dependence in female rats for comparison with previous studies in our laboratory using male rats. We found that ethanol dependence resulted in differential effects on GABA_A receptor gene expression in female rat cerebral cortex compared to ethanol dependent male rats. Notably, chronic ethanol consumption did not change GABA_A receptor α1 subunit peptide levels in ethanol dependent female rat cortex, in contrast to previously observed decreases in α1 subunit expression in ethanol dependent male rat cortex. The effects of ethanol dependence on additional GABA_A receptor subunit peptide levels (α4, β2/3 and γ2) were similar, but not identical, between female and male rat cortex. When directly compared within the experiment, male and female rats had similar baseline bicuculline seizure thresholds and displayed a similar increase in seizure susceptibility during ethanol withdrawal. Ethanol withdrawn female rats were cross tolerant to the anticonvulsant effects of diazepam, similar to the findings in ethanol withdrawn male rats. Ethanol withdrawn female rats showed a dose-dependent enhancement of the anticonvulsant effect of the neuroactive steroid, THDOC (3α,21-dihydroxy-5α-pregnan-20-one) compared to control animals. This finding is similar to previous observations of increased sensitivity to the anticonvulsant effect of 3α,5α-THP (3α-hydroxy-5α-pregnan-20-one) in ethanol withdrawn male and female rats. In addition, low dose administration of THDOC elevated seizure thresholds in ethanol withdrawn female but not male rats, suggesting that ethanol withdrawn female rats were more responsive to the anticonvulsant effects of this neurosteroid than were ethanol withdrawn male rats. These findings show that gender impacts on adaptations in GABA_A receptors elicited by ethanol dependence. However, the physiological outcomes of the differential alterations are not clear. Taken together, these studies suggest that additional mechanisms, beyond effects on GABA_A receptor gene expression are involved in the mediation of ethanol dependence and withdrawal.