Influence of sex hormone antagonists on the anticonvulsant action of conventional antiepileptic drugs against amygdala-kindled seizures in male and female rats.

The effects of three gonadal steroid antihormones, tamoxifen (TXF, an estrogen antagonist), cyproterone acetate (CYP, an antiandrogen) and mifepristone (MIF, a progesterone antagonist) alone or combined with conventional antiepileptics were evaluated in amygdala-kindled seizures in male and female rats. None of the three antihormones used in this study affected any seizure parameter. TXF (50 mg/kg) and CYP (50 mg/kg), when combined with carbamazepine, or phenobarbital applied at their subprotective doses of 15 mg/kg, resulted in significant reductions of the seizure and afterdischarge durations, both in male and female rats. Additionally, the combination of carbamazepine and CYP markedly increased the afterdischarge threshold in fully-kindled rats of both genders. The interaction between antihormones and carbamazepine, or phenobarbital, was not reversed by respective sex steroid hormones (estradiol, testosterone). However, the TXF- and CYP-induced anticonvulsant effects in combinations with carbamazepine were attenuated by bicuculline, N-methyl-D-aspartate (NMDA) and aminophylline. Kainic acid and strychnine remained ineffective in this respect. The effect of a combination of TXF with phenobarbital was reversed by bicuculline and NMDA and that of CYP with phenobarbital-by bicuculline and aminophylline. Neither TXF nor CYP altered the free plasma concentrations of carbamazepine or phenobarbital, so a pharmacokinetic interaction is not probable. The combined treatment of the two antihormones with antiepileptic drugs did not affect motor performance, and did not result in significant long-term memory deficits. Our data confirm the hypothesis that sex hormone antagonist-mediated events may play some role in seizure processes in the central nervous system and can modulate the protective activity of some conventional antiepileptic drugs against kindled seizures.