M. Okada et al., EFFECTS OF NONTOXIC AND TOXIC CONCENTRATIONS OF PHENYTOIN ON MONOAMINES LEVELS IN RAT-BRAIN, Epilepsy research, 28(2), 1997, pp. 155-163
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.