Anxiogenic effects of neurosteroid exposure: sex differences and altered GABAA receptor pharmacology in adult rats

The Journal of Pharmacology and Experimental Therapeutics
Maria Gulinello, S S Smith


Acute exposure to progesterone or its neurosteroid derivative allopregnanolone (3alpha,5alpha-THP) is anxiolytic, consistent with the GABA modulatory effects of 3alpha,5alpha-THP at the GABA(A) receptor. However, continuous exposure to progesterone increases anxiety in association with increased expression of the benzodiazepine-insensitive GABA(A) receptor alpha4 subunit. Furthermore, negative mood symptoms and altered GABA(A) receptor pharmacology in patients with premenstrual dysphoric disorder occur in the early luteal phase in association with peak circulating levels of progesterone and 3alpha,5alpha-THP. Because sex differences have been reported in steroid-regulated anxiety responses, the present study investigated the role of sex and development in the regulation of anxiety after short-term exposure to 3alpha,5alpha-THP. To this end, we compared the effects of hormone administration in adult male, adult female, and juvenile female rats. Increased anxiety in the elevated plus maze was evident in all groups after 48-h exposure to either 3alpha,5alpha-THP or progesterone. At this time point, alterations in the anxiolytic profile of benzodiazepine agonists and antagonists were also observed in both adult males and females in...Continue Reading


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