COMPETITIVE NMDA RECEPTOR ANTAGONISTS ENHANCE THE ANTIELECTROSHOCK ACTIVITY OF VARIOUS ANTIEPILEPTICS

CGP 37849 (1 mg/kg i.p.) enhanced the protective action of carbamazepi ne. diphenylhydantoin and phenobarbital against maximal electroshock-i nduced convulsions in mice. At 0.25 mg/kg CGP 37849 was inactive and a t 0.5 mg/kg it potentiated the anticonvulsive activity of phenobarbita l. CGP 39551 (5 mg/kg i.p.) reduced the ED50 values of diphenylhydanto in and phenobarbital, being without influence on carbamazepine. In the dose of 1.25 mg/kg, CGP 39551 potentiated the antielectroshock action of diphenylhydantoin and at 2.5 mg/kg that of phenobarbital. Neither NMDA receptor antagonist elevated the total plasma levels of antiepile ptic drugs. Consequently, a pharmacokinetic interaction (in terms of t otal plasma levels at least) seems unlikely to be responsible for the observed potentiation of the antiepileptic drugs' activity. Combinatio ns of CGP 37849 with either carbamazepine or phenobarbital resulted in a motor and memory impairment quantified by the chimney test and pass ive avoidance task, respectively. Moreover, combined treatment with ph enobarbital and CGP 39551 caused a memory deficit. In contrast, diphen ylhydantoin combined with either CGP 37849 or 39551 was devoid of adve rse effects. It may be concluded that NMDA receptor blockade results i n enhanced anticonvulsive action of common antiepileptics against maxi mal electroshock-induced seizures.