In the first experiment, the relationship between the phase of the estrous cycle and the number of spontaneously occurring spike-wave discharges was investigated in WAG/Rij rats, a model for generalized absence epilepsy. The electroencephalogram (EEG) was continuously recorded for 96 h in eight rats chronically equipped with cortical EEG electrodes. A circadian pattern emerged for the number of spike-wave discharges: a nadir during the first hours of the light period, and an acrophase during the first hours of the dark period. This daily maximum was increased at proestrus day compared with the other days of the cycle, when the plasma level of progesterone is enhanced specifically at these hours of this day. This suggests that progesterone enhances spike-wave discharges. There was no difference in the first few hours of the light period in the number of spike-wave discharges between proestrus and the three other days, suggesting that estradiol has no effect on spike-wave discharges. In the second study, the effects of the systemic administration of progesterone and 17 beta-estradiol on spike-wave discharges and spontaneous behavior were investigated. It was shown that progesterone (20 and 30 mg/kg) but not estradiol (0.17-1.5 mg/kg) increased the number and total duration of spike-wave discharges. On the other hand, injection of RU 38486 (10 and 30 mg/kg), an antagonist of intracellular progesterone receptors, had no effect on spike-wave discharges and did not block the stimulatory effect of progesterone. The antagonist of 17 beta-estradiol tamoxifen (1 and 3 mg/kg) did not evoke alterations in the number or duration of spike-wave discharges. Our results indicate that progesterone aggravates spike-wave discharges, but is not mediated through intracellular receptors. Since progesterone is rapidly metabolized in the brain to the positive modulator of GABA(A) receptor allopregnanolone, which increases spike-wave discharges in WAG/Rij rats, it is possible that the epileptiformic effects of progesterone are mediated through this metabolite.