Actions at GABAA receptors in the hippocampus may mediate some antiseizure effects of progestins

Progestins can have antiseizure effects; however, the mechanisms and sites of action of these effects are not well-understood. Whether progesterone's actions at GABAA receptors in the hippocampus are important for its antiseizure effects was investigated. In Experiment 1, ovariectomized rats were administered sesame oil vehicle or a regimen of progesterone (500 μg sc, which produces physiological concentrations in plasma and the hippocampus), followed 2.5 hours later by administration of saline vehicle or a regimen of bicuculline (1 mg/kg, sc), a GABAA receptor antagonist, which does not produce any intrinsic effects on seizures. Progesterone, compared with vehicle, significantly increased the latency to, and decreased the number of, pentylenetetrazole-induced tonic seizures and increased GABA-stimulated chloride flux. Co-administration of bicuculline attenuated progesterone's antiseizure effects and decreased GABA-stimulated chloride flux in the hippocampus. Bicuculline did not alter ictal behavior compared with vehicle. In Experiment 2, ovariectomized rats were subcutaneously administered sesame oil or progesterone (500 μg), followed 2.5 hours later by bilateral infusions of bicuculline (100 ng) or vehicle (saline) into the hippocampus. Infusion of bicuculline into the hippocampus of progesterone-primed rats significantly increased ictal activity, compared with that induced by progesterone administration alone, but alone did not alter seizures compared with that produced by saline infusions into the hippocampus. These data suggest that actions of progesterone at GABAA receptors in the hippocampus are important for progesterone's antiseizure effects.