Steroid hormones affect limbic afterdischarge thresholds and kindling rates in adult female rats

Catamenial epileptics show particular vulnerability to seizures during menstruation and at the time of ovulation, when circulating estradiol (E(2))/progesterone (P(4)) ratios are high. The present study tested the hypothesis that alterations in neuronal excitability induced by E(2) and P(4) affect thresholds and the development of secondary generalization in kindled rats.

Methods: The effects of endogenous hormones secreted during the estrous cycle, and of exogenous exposure to E(2) and P(4) after ovariectomy (OVX), with and without adrenalectomy (ADX), were tested. Kindling electrodes were implanted in the basolateral amygdala or dorsal hippocampus in adult female rats. The anticonvulsive effects of P(4) on amygdala kindled seizures were also determined in intact subjects.

Results: In intact females, afterdischarge thresholds (ADTs) in the amygdala were significantly lower (306+/-48 microA; peak to peak) at mid-day proestrus, just prior to ovulation, when serum E(2) is elevated. ADTs were more than twofold higher (808+/-95 microA) during metestrus, coincident with peak ovarian P(4) secretion. In OVX females, amygdala thresholds were lowest with E(2) replacement and highest with P(4) replacement. Hippocampal ADT was unaffected by hormone replacement after OVX. The rates of both amygdala and hippocampal kindling were significantly accelerated by E(2) and slowed by P(4). E(2) replacement significantly increased serum corticosterone (CORT) levels. In ADX rats, CORT replacement increased kindling rates, synergizing with the effects of E(2). In fully kindled animals, P(4) administration suppressed motor seizures in approximately 60% of cases.

Conclusions: E(2) lowers amygdala ADTs and facilitates kindling. This effect may involve both direct E(2) effects and indirect effects mediated via increased levels of circulating corticosterone. P(4) raises amygdala ADTs, slows kindling development and suppresses fully kindled seizures. Hence, P(4) may have potential therapeutic value for women with catamenial epilepsy.