Phenytoin potently increases the threshold for focal seizures in amygdala-kindled rats

Previous studies on the effects of phenytoin in the kindling model have yielded equivocal results, in that some groups reported anticonvulsant effects, while others found the drug to be only weakly active, inactive or even proconvulsant. Although part of these discrepancies might relate to factors such as the time of testing, route of administration, doses and administration vehicles, variable results were also obtained by studies in which these factors were comparable. For further investigation of the reasons of the reported discrepancies in the effectiveness of phenytoin in kindled rats, the influence of current intensity on the effects of phenytoin were examined in this model. In fully amygdala-kindled rats, phenytoin was only weakly active against seizures evoked by a fixed suprathreshold current of 500 microA. However, when the current was decreased to 250 microA, phenytoin exerted potent anticonvulsant effects. Determination of the threshold for focal afterdischarges showed that phenytoin, 12.5-75 mg/kg dose-dependently increased the threshold up to about 600% over controls at 75 mg/kg. Average levels in plasma, determined at this dose were about 30 micrograms/ml. In contrast to the potent effect on the seizure threshold, the severity or duration of seizures, evoked in phenytoin-pretreated rats by increasing the current, was not reduced. These data indicate that the primary effect of phenytoin in kindled rats in an increase in focal seizure threshold, while the ability of phenytoin to reduce the spread of seizures appears to be small. The present data might explain the discrepancy in reports on phenytoin in kindled rats, because most studies which found the drug to be ineffective used current intensities far exceeding the seizure threshold.