Attenuating 5alpha-pregnane-3alpha-ol-20-one formation in the hippocampus of female rats increases pentylenetetrazole-induced seizures.

Progesterone has antiseizure effects, which may be due to the actions of its 5alpha-reduced metabolite, 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP). Whether metabolism of progesterone to 3alpha,5alpha-THP in the hippocampus is essential for its antiseizure effects was investigated. In Experiment 1, ovariectomized rats were administered subcutaneous progesterone (500 microg) or vehicle (sesame oil), followed 1 hour later by subcutaneous administration of an inhibitor of the 5alpha-reductase enzyme, finasteride (50 mg/kg), or vehicle (90% sesame oil, 10% ethanol). Administration of progesterone increased the latency to, and decreased the number of, tonic seizures and increased hippocampal 3alpha,5alpha-THP levels, compared with vehicle. Administration of finasteride with progesterone attenuated progesterone's antiseizure effects and decreased levels of 3alpha,5alpha-THP in the hippocampus. Finasteride administration alone did not alter ictal behavior or 3alpha,5alpha-THP levels compared with vehicle. In Experiment 2, ovariectomized rats were administered subcutaneous progesterone (500 microg) or vehicle (sesame oil), followed 1 hour later by bilateral infusions of finasteride (10 microg) or vehicle (beta-cyclodextran) into the hippocampus. Administration of finasteride to the hippocampus of progesterone-primed rats significantly increased ictal activity and decreased hippocampal 3alpha,5alpha-THP levels, compared with progesterone administration alone. These data suggest that formation of 3alpha,5alpha-THP in the hippocampus is important for progesterone's antiseizure effects.