FEMALE RATS RELEASE MORE CORTICOSTERONE THAN MALES IN RESPONSE TO ALCOHOL - INFLUENCE OF CIRCULATING SEX STEROIDS AND POSSIBLE CONSEQUENCES FOR BLOOD-ALCOHOL LEVELS

The hypothalamic-pituitary-adrenal (HPA) axis of female rats is more responsive to a variety of stimuli than that of males. Proestrous females are also reported to release more ACTH and corticosterone in response to restraint stress than females at other stages of the estrous cycle. Finally, blood alcohol levels (BALs) reached in response to a standard dose of alcohol also indicate the presence of a gender specificity, with females exhibiting higher BALs than males. The aim of this study was therefore 2-fold: first, we investigated the influence of gender on the ability of alcohol to increase plasma ACTH and corticosterone secretion in the rat. Second, we tested the hypothesis that corticosterone alters alcohol metabolism and asked whether this might represent a mechanism underlying the sex difference in BALs. We observed that compared with intact males, intact females taken at random stages of the estrous cycle secreted significantly (p < 0.01) more ACTH and corticosterone in response to alcohol (0.2-1.8 g/kg). Within females, the intraperitoneal administration of alcohol was followed by higher plasma ACTH and corticosteroids levels during proestrus and estrus, compared with diestrus. Removal of circulating sex steroids abolished the gender difference in terms of ACTH secretion, but ovariectomized females still released more corticosterone than castrated males in response to 0.6 and 1.8 g alcohol/kg. This difference could not be explained by a sex-related component of pituitary responsiveness to corticotropin-releasing factor. These results demonstrate the existence of a sex-specific activation of the HPA axis in response to alcohol, and suggest that sex steroids exert an activational influence on ACTH and corticosterone release in response to ethanol. The possible influence of corticosteroids on the pharmacokinetics of alcohol was investigated in intact males, intact females, and adrenalectomized (ADX) males bearing 15 mg (low dose) or 150 mg (high dose) corticosterone pellets. Following the intraperitoneal injection of a standard dose of ethanol (1.5 g/kg), ADX animals with low corticosterone therapy had higher BALs than either intact rats, or ADX animals with high corticosterone replacement. Intact females exhibited the highest corticosterone levels of all groups of animals, but showed BALs that were intermediate between those of intact males and ADX rats with the low dose corticosterone pellets. Thus, although we cannot exclude an influence of body water content in ADX rats replaced with various regimens of corticosteroids, our results indicate that corticosteroids may modulate alcohol metabolism in the rat. In summary, we have shown that, in the rat, alcohol induces a gender-specific pattern of ACTH and corticosterone secretion that appears to be at least in part dependent on circulating sex steroids. Our results also suggest that although corticosteroids may play a role in regulating the rate of alcohol metabolism, this effect cannot account for the higher BALs measured in female rats.