Progestin receptors mediate progesterone suppression of epileptiform activity in tetanized hippocampal slices in vitro

Clinical and laboratory studies suggest that progesterone reduces epileptic seizure activity. The mechanisms underlying this effect are not known. The present study determined the effects of progesterone on extracellular evok ed responses recorded in the CA1 field of hippocampal slices, as well as ep ileptiform responses recorded from tetanized slices. Slices were prepared f rom ovariectomized rats, with or without estrogen replacement. Hippocampal slices were superfused in vitro with one of the following treatments: proge sterone with or without RU486 (a progesterone receptor antagonist); allopre gnanolone (a progesterone metabolite that potentiates GABA action at GABAA receptors); RU5020 (a high-affinity progesterone receptor agonist); or chol esterol (control). In non-tetanized slices, a twofold increase in the excit atory postsynaptic field potential and population spike amplitude occurred during both cholesterol and progesterone superfusion. In contrast, under th e same conditions, exposure to allopreganolone caused a 25% reduction in bo th field potential and population spike amplitude of evoked responses withi n 30 min of treatment. In tetanized slices, progesterone and RU5020, but no t allopregnanolone or cholesterol, caused significant reductions in the fie ld potential and population spike amplitude of evoked responses. Progestero ne and RU5020 also significantly reduced the duration of tetanic stimulus-i nduced afterdischarges and the frequency of spontaneous interictal discharg es. The effects of allopregnanolone were restricted to a reduction in the p rimary afterdischarge duration. Estrogen replacement slightly attenuated pr ogesterone's suppression of spontaneous discharges and depression of evoked responses. All responses to progesterone were blocked by prior or concurre nt exposure to RU486. These data indicate that allopregnanolone suppresses evoked potentials in n on-tetanized hippocampal slices, consistent with previous reports that this neurosteroid has marked anxiolytic and anticonvulsant effects. After tetan ization, however, progesterone receptor-mediated responses become quantitat ively more important as a mechanism for suppressing hippocampal electrical activity. (C) 2000 IBRO. Published by Elsevier Science Ltd. All rights rese rved.