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.
Rhodes
Madeline E
ME
Department of Psychology, The University at Albany-SUNY, 1400 Washington Avenue, Albany, NY 12222, USA.
Frye
Cheryl A
CA
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003900:Desoxycorticosterone / Q000031:analogs & derivatives* / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D018120:Finasteride / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D010052:Ovariectomy / Q000379:methods; D010433:Pentylenetetrazole; D011374:Progesterone / Q000008:administration & dosage / Q000097:blood; D011863:Radioimmunoassay / Q000379:methods; D051381:Rats; D020318:Rats, Long-Evans; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*
D004791:Enzyme Inhibitors; D003900:Desoxycorticosterone; C009413:tetrahydrodeoxycorticosterone; D011374:Progesterone; D018120:Finasteride; D010433:Pentylenetetrazole