Progesterone and its Metabolites: Anticonvulsant and Behavioral Studies

AbstractProgesterone is a well-known anticonvulsant neurosteroid. Progesterone's inhibitory effects in the brain have long been attributed to its secondary metabolite, 3-alpha,5-alpha-tetrahydroprogesterone (THP, also known as allopregnanolone), a powerful positive modulator of GABA-A receptors. Behavioral and electrophysiological studies of progesterone and its metabolites were conducted for this thesis. Behavioral ExperimentsRecent studies in our laboratory suggested that the primary progesterone metabolite 5-alpha-dihydroprogesterone (DHP) might have anticonvulsant effects in amygdala-kindled rats. Simple measures of sedation and ataxia were minimal in kindled rats treated with anticonvulsant doses DHP and THP. We therefore hypothesized that anticonvulsant doses of DHP and THP (5-10 mg/kg) would not cause psychotoxicity.Anticonvulsant doses of DHP and THP were tested in the elevated plus maze, the forced swim test, open field test, and the Morris water maze, models of anxiety, depression, locomotion, and learning and memory, respectively. No psychotoxicity was found the forced swim test, the open field test or the elevated plus maze. Minimal psychotoxicity was observed in the Morris water maze.Electrophysiology ExperimentsPilot studies in our laboratory had also indicated that progesterone might have anticonvulsant effects in mice independent of its metabolites. We hypothesized that progesterone had a non-GABAergic, non-THP-mediated mechanism of anticonvulsant action.We first conducted studies in hippocampal kindled mice using a range of doses of progesterone (10-160 mg/kg), DHP (5, 10 mg/kg), THP (1-30 mg/kg), progesterone (100 mg/kg) with finasteride (50 mg/kg), as well as finasteride alone (50 mg/kg), the anticonvulsant drugs carbamazepine (50 mg/kg) and midazolam (2 mg/kg). DHP was not anticonvulsant, whereas THP was anticonvulsant at sedative doses. Surprisingly, high doses of progesterone were anticonvulsant when metabolism to DHP and THP was inhibited with finasteride. Focal seizures were not prevented, but seizure spread and severity were attenuated. Subsequent studies were done in the entorhinal slice preparation in the presence of 4-aminopyridine and the GABA-A receptor antagonist picrotoxin. We found that progesterone, in the presence and absence of finasteride, was antiepileptiform. This result confirmed that progesterone had, at least in part, a non-GABAergic mechanism of antiepileptiform action independent of progesterone's metabolism to THP. These are novel findings.Ph.D