Moderate doses of ethanol fail to increase plasma levels of neurosteroid 3α-hydroxy-5α-pregnan-20-one-like immunoreactivity in healthy men and women

Rationale: The endogenous GABAergic neuroactive steroid 3 alpha -hydroxy-5 alpha -pregnan-20-one (3 alpha ,5 alpha -THP, allopregnanolone) has been proposed to contribute to ethanol actions. Humans synthesize 3 alpha ,5 alpha -THP, but its role in response to systemic administration of ethanol is unclear. Objective: The present study aims to determine the effect of a moderate dose of ethanol on progesterone and 3 alpha ,5 alpha -THP concentrations in plasma samples of healthy male and female subjects and to determine if these levels are related to the subjective effects of ethanol. Females were tested in both the follicular and luteal phases of the menstrual cycle. Methods: Healthy men (N=9) and women (N=12) aged 21-35 participated in the study. Men participated in two sessions on which they received ethanol (0.8 g/kg) or placebo. Women participated in four sessions on which they received ethanol (0.7 g/kg) or placebo during the follicular and luteal phases of their cycle. Subjective states and mood were measured by standardized self-report questionnaires and a measure of psychomotor performance. Steroid levels (progesterone, 3 alpha ,5 alpha -THP, estradiol, and cortisol) were measured in plasma samples by radioimmunoassay. Results: Ethanol significantly increased plasma levels of progesterone, but not 3 alpha ,5 alpha -THP-like immunoreactivity, in women in the luteal phase. Ethanol had no effect on progesterone or 3 alpha ,5 alpha -THP-like immunoreactivity levels in women in the follicular phase or in men, and it did not increase cortisol in men or women. Ethanol also did not affect estradiol in men or women. Conclusions: 3 alpha ,5 alpha -THP-like immunoreactivity levels in human plasma are not increased following moderate ethanol consumption, suggesting that circulating levels of progesterone or its tetrahydro-reduced metabolites do not play a major role in ethanol action. However, the possibility remains that ethanol increases endogenous brain production of GABAergic neurosteroids without affecting plasma levels. Moreover, humans synthesize 5 beta -reduced GABAergic steroids, and levels of these steroids may be altered in plasma or brain.