Influence of D(-)CPP and (+/-)CPP upon the protective action of conventional antiepileptic drugs against electroconvulsions in mice

Competitive antagonists of N-methyl-D-aspartate (NMDA) receptors, D(-) CPP (up to 0.625 mg/kg) and (+/-)CPP (up to 0.625 mg/kg), did not influence the electroconvulsive threshold in mice. At a dose of 1.25 mg/kg, both drugs significantly elevated the threshold. D(-)CPP (0.625 mg/kg) and (+/-)CPP (0.625 mg/kg) potentiated the anticonvulsant activity of valproate, carbamazepine and phenobarbital. No potentiation was observed in the case of diphenylhydantoin. Moreover, these competitive NMDA antagonists did not influence the plasma levels of antiepileptic drugs, so a pharmacokinetic interaction, in terms of total and free plasma levels at least, is not probable. The combined treatment of both CPP agents with either carbamazepine, diphenylhydantoin or phenobarbital (providing a 50% protection against maximal electroshock) was devoid of significant side effects (in the tests evaluating motor and long-term memory impairment). Valproate co-administered with CPP compounds caused a moderate motor impairment, but did not affect cognitive functions in mice. It is noteworthy that valproate and phenobarbital given alone at doses equal to their ED50s resulted in significant long-term memory deficit. The results indicate that combinations of antiepileptic drugs with some NMDA receptor antagonists, apart from enhanced anticonvulsant potential, may not necessarily result in the occurrence of considerable adverse reactions.