Cyclic withdrawal from endogenous and exogenous progesterone increases kainic acid and perforant pathway induced seizures

Antiseizure effects of progesterone (P) and its metabolite, 5 alpha-pregnan-3 alpha-ol-20-one (3 alpha, 5 alpha-THP) were investigated following continuous vs. discontinuous P exposure. In Experiments 1, 32 cycling Long-Evans rats were administered kainic acid (32 mg/kg SC), ictal behavior was examined, and plasma 3 alpha,5 alpha-THP levels were measured by radioimmunoassay. Proestrus/estrus rats showed less ictal activity and had elevated 3 alpha,5 alpha-THP levels prior to kainic acid compared to diestrus/metestrus subjects. In Experiment 2, 49 ovariectomized (ovx) rats were SC injected with estradiol benzoate (EB; 10 mu g) and P (500 mu g), to mimic estrus, or sesame oil vehicle (0.2 cc); all subjects were administered kainic acid. Rats tested with EB+P showed a reduced mean duration of full seizures and increased 3 alpha,5 alpha-THP, whereas those tested 24 h following EB+P had more tonic clonic seizures and lower 3 alpha,5 alpha-THP concentrations, comparable to ovx control animals. In Experiment 3, 49 ovx rats were stereotaxically implanted with bipolar electrodes into the perforant pathway. Prior to perforant pathway stimulation, rats received cholesterol or EB+P capsules for 1 month, continuously or intermittently. Irrespective of continuous or intermittent EB+P, the presence of progestins at the time of perforant pathway stimulation reduced partial seizure activity. Continuous EB+P capsules resulted in increased 3 alpha,5 alpha-THP levels compared to all other conditions, and less damage in the hilus of the hippocampus, compared to intermittent EB+P. These data confirm that P and 3 alpha,5 alpha-THP have antiseizure effects, and further suggest that repeated cycles of endogenous or exogenous P and/or 3 alpha,5 alpha-THP withdrawal influences seizure threshold and/or hippocampal integrity. (C) 1999 Elsevier Science Inc.