Anxiolytic effects of 3 alpha-hydroxy-5 alpha[beta]-pregnan-20-one: endogenous metabolites of progesterone that are active at the GABAA receptor.

The effects of intracerebroventricular administration of reduced metabolites of progesterone on locomotor activity and on exploration in the elevated plus-maze were assessed in adult female rats. Allopregnanolone (3 alpha-hydroxy-5 alpha-pregnan-20-one; 1.25, 5.0, and 10 micrograms) and pregnanolone (3 alpha-hydroxy-5 beta-pregnan-20-one; 2.5, 5.0, and 10 micrograms) elicited anxiolytic effects and, at the highest dose tested, allopregnanolone resulted in sedation. In contrast, the 3 beta-hydroxy-epimer of allopregnanolone was without effect in either behavioral paradigm. The anxiolytic response to pregnanolone was blocked by picrotoxin (0.75 mg/kg, i.p.), a dose that by itself did not affect behavior in the plus-maze. These data suggest that the anxiolytic effect of 3 alpha-hydroxy metabolites of progesterone is mediated by brain GABAA receptors in a stereospecific manner, and are in good agreement with the well-documented in vitro effects of these steroids as potent modulators of the GABAA receptor.