ALLOPREGNANOLONE (THP) MEDIATES ANESTHETIC EFFECTS OF PROGESTERONE INRAT-BRAIN

Intravenous infusion of the progesterone or that of progesterone 5 alp ha-reduced metabolite, 3 alpha-hydroxy-5 alpha-pregnan-20-one (THP), i nduces the loss of righting reflex in freely moving rats at the doses of 49 +/- 15 mg/kg or 5.6 +/- 2.2 mg/kg, respectively. The recovery ti me of righting reflex was 71 +/- 12 min and 21 +/- 5 min for progester one and THP, respectively. The time course of brain concentrations of THP, but not that of progesterone, correlated with the loss and the re covery of righting reflex. The pretreatment of animals with uncompetit ive inhibitor of 5 alpha-reductase 17 diisopropylcarbamoyl)-androst-3- diene-3-carboxylic acid (SKF 105111) significantly reduces the anesthe tic activity of progesterone, but not that of THP. Following progester one infusion brain level of THP in SKF 105111 pretreated rats was 12% that of vehicle-treated control, and the level of progesterone was 160 %. No effect of SKF 105111 on brain THP level was detected in animals infused with THP. These results demonstrate that anesthetic effect of progesterone is mediated through its conversion to THP and support the hypothesis that endogenous metabolites of progesterone may be involve d in the regulation of behavior in rats. (C) 1996 Academic Press, Inc.