Attenuating 5α-pregnane-3α-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 5α-reduced metabolite, 5α-pregnan-3α-ol-20-one (3α,5α-THP). Whether metabolism of progesterone to 3α,5α-THP in the hippocampus is essential for its antiseizure effects was investigated. In Experiment 1, ovariectomized rats were administered subcutaneous progesterone (500 μg) or vehicle (sesame oil), followed 1 hour later by subcutaneous administration of an inhibitor of the 5α-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 3α,5α-THP levels, compared with vehicle. Administration of finasteride with progesterone attenuated progesterone's antiseizure effects and decreased levels of 3α,5α-THP in the hippocampus. Finasteride administration alone did not alter ictal behavior or 3α,5α-THP levels compared with vehicle. In Experiment 2, ovariectomized rats were administered subcutaneous progesterone (500 μg) or vehicle (sesame oil), followed 1 hour later by bilateral infusions of finasteride (10 μg) or vehicle (β-cyclodextran) into the hippocampus. Administration of finasteride to the hippocampus of progesterone-primed rats significantly increased ictal activity and decreased hippocampal 3α,5α-THP levels, compared with progesterone administration alone. These data suggest that formation of 3α,5α-THP in the hippocampus is important for progesterone's antiseizure effects.