Phenytoin antagonism of electrically induced maximal seizures in frogs and mice and effects on central nervous system levels of adenosine 3',5'-monophosphate and guanosine 3',5'-monophosphate

Phenytoin antagonized the electroshock-induced increase in levels of cyclic adenosine 3',5'-monophosphate (cAMP) and cyclic guanosine 3',5'-monophosphate (cGMP) in cerebrum and cerebellum, respectively, from CF-1 mice. However, the effective dose range of phenytoin for significant reduction of the elevated levels of cAMP and cGMP was 2 to 5 times higher than that for prevention of tonic hindlimb extension in 95% of mice. The effective dose range of phenytoin for alteration of cyclic nucleotide levels was nearer to that for preventing tonic flexion and clonus; endpoints which are less relevant to anticonvulsant efficacy than is prevention of tonic hindlimb extension. Also, the greatest reduction in cyclic nucleotide levels occurred at a dose (100 mg/kg) which produced toxic signs in mice. Quaking mice (qk/qk), a mutant strain which exhibits spontaneous seuzures, did not have abnormal levels of cAMP or cGMP in cerebrum or cerebellum, and a dose of phenytoin (15 mg/kg) which abolished all seizure activity did not alter levels of these cyclic nucleotides. In frogs, the electroshock-associated increase in levels of cAMP and cGMP in the central nervous system was not altered by phenytoin even when the doses administered were up to twice the ED₉₅ for prevention of tonic hindlimb extension. Because these data from mice and frogs show that the anticonvulsant effect of phenytoin is dissociated, by dose, from effects on central nervous system cyclic nucleotide levels, it is doubtful that the alteration of cyclic nucleotide levels is a mechanism by which phenytoin exerts its anticonvulsant effect.