Sex differences in steroid modulation of ethanol withdrawal in male and female rats

We investigated the actions of the neuroactive steroid, pregnanolone [corrected] and the ovarian steroid, 17beta-estradiol, on seizure expression during two time points of ethanol withdrawal (EW). Both steroids can exert rapid, nongenomic actions on the brain that include modulation of seizure activity. Because their basal levels differ in adult males and females and a major symptom of EW is increased seizure risk, we wanted to determine whether these steroids were anticonvulsant during EW. Rats were made ethanol-dependent by administration of 6% ethanol in a nutritionally complete liquid diet for 14 days. After removal of the ethanol-containing diet, EW and paired control rats were tested at 1 or 3 days for seizure responses to pentylenetetrazol. Consistent with previous reports, females seemed to have recovered from EW more quickly than males. We observed significant sex differences in responses to the steroids, primarily at 3 days EW. Pregnanolone afforded protection against seizures with larger effects during EW than in control conditions and greater effects in female than male rats. In contrast, effects of estradiol were mixed. Some responses of ovariectomized female rats were similar to intact females, whereas other responses were more similar to males. Our behavioral findings are consistent with observed EW-induced changes in plasma corticosterone levels, showing persistent elevations in male but not female rats. These results support and extend earlier findings suggesting that although the hormonal milieu influences EW, innate differences in brain structure between the sexes also contribute to sex differences in EW.