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 conti nuous vs. discontinuous P exposure. In Experiments 1, 32 cycling Long-Evans rats were administered kainic acid (32 mg/kg SC), ictal behavior was exami ned, and plasma 3 alpha,5 alpha-THP levels were measured by radioimmunoassa y. Proestrus/estrus rats showed less ictal activity and had elevated 3 alph a,5 alpha-THP levels prior to kainic acid compared to diestrus/metestrus su bjects. 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 ses ame 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 increa sed 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, compara ble to ovx control animals. In Experiment 3, 49 ovx rats were stereotaxical ly implanted with bipolar electrodes into the perforant pathway. Prior to p erforant pathway stimulation, rats received cholesterol or EB+P capsules fo r 1 month, continuously or intermittently. Irrespective of continuous or in termittent EB+P, the presence of progestins at the time of perforant pathwa y stimulation reduced partial seizure activity. Continuous EB+P capsules re sulted in increased 3 alpha,5 alpha-THP levels compared to all other condit ions, and less damage in the hilus of the hippocampus, compared to intermit tent EB+P. These data confirm that P and 3 alpha,5 alpha-THP have antiseizu re effects, and further suggest that repeated cycles of endogenous or exoge nous P and/or 3 alpha,5 alpha-THP withdrawal influences seizure threshold a nd/or hippocampal integrity. (C) 1999 Elsevier Science Inc.