SEX-DIFFERENCES IN THE ANTICONVULSANT EFFICACY OF PHENYTOIN IN AMYGDALA-KINDLED RATS

The anticonvulsant effects of phenytoin were compared in female and male amygdala-kindled rats. Phenytoin was administered at a dosage of 75 mg/kg i.p. and the threshold for induction of amygdaloid afterdischarges (ADT) was determined 1 h after drug application. This ADT determination was repeated three times in each animal at intervals of one week. For control of drug absorption, phenytoin was determined in plasma in each of the four drug trials. In a total of 104 drug trials in females and 78 trials in males, anticonvulsant responses (i.e. increases in ADT above pre-drug control) were found in 76% of trials in female rats but only 42% of trials in male rats, the difference being highly significant. Consistent responses to phenytoin (i.e. ADT increases of more than 100% in four consecutive trials) were found in 31% of the female rats but only 6% of the male rats. Twenty-four percent of the females but 58% of the males never responded to phenytoin with an ADT increase. About 50% of both female and male rats showed variable responses. Although plasma levels of phenytoin were slightly lower in male than in female rats, there was no significant difference in drug levels between phenytoin responders and nonresponders in both sexes, indicating that the sex difference in anticonvulsant efficacy of phenytoin was not due to differences in drug pharmacokinetics. This was substantiated by the finding that in experiments with anticonvulsant response, the phenytoin-induced ADT increases were similar in male and female rats. With respect to kindling, no sex-related differences were found in kindling development or severity and duration of kindled seizures, but the post-kindling decrease in ADT was much more marked in female than in male rats. The data demonstrate that phenytoin is less effective in male than in female kindled rats. Kindled rats with different responses to phenytoin can be selected from both sexes, but the frequency of phenytoin resistant rats is much higher in males. This offers the opportunity to study the mechanisms which are involved in drug resistance of kindled seizures in both genders.