EFFECTS OF NONTOXIC AND TOXIC CONCENTRATIONS OF PHENYTOIN ON MONOAMINES LEVELS IN RAT-BRAIN

To clarify the mechanisms of the antiepileptic activity of phenytoin ( PHI), the effects of PHT on extracellular and total levels of monoamin es (dopamine and serotonin), in rat striatum and hippocampus were stud ied. The plasma concentrations of PHT associated with therapeutic acti vity did not affect striatal and hippocampal extracellular levels of m onoamines, whereas supratherapeutic concentrations of PHT decreased st riatal and hippocampal extracellular levels of monoamines, in a concen tration dependent manner. Toxic concentrations of PHT produced general ized seizures 'paradoxical intoxication' and an initial drastic decrea se in striatal and hippocampal extracellular levels of monoamines befo re seizure onset, whereas the extracellular monoamines levels increase d after seizures. In addition, the therapeutic concentrations of PHT d id not affect monoamine turnover, whereas supratherapeutic concentrati ons of PHT inhibited monoamine turnover. These results suggest that mo noaminergic transmission may not be involved in the antiepileptic mech anism of action of PHT, and that dysfunction of monoaminergic transmis sion can produce generalized tonic-clonic convulsions. Thus, the prese nt study suggests that 'Paradoxical Intoxication' induced by toxic con centrations of PHT, at least partially, can be mediated by hypo-monoam inergic function in the brain. (C) 1997 Elsevier Science B.V.