Kindling alters the anticonvulsant efficacy of phenytoin in Wistar rats

We have previously shown that subgroups can be selected from large groups o f amygdala kindled Wistar rats which either respond consistently or do not respond to the anticonvulsant effect of phenytoin. Phenytoin nonresponders were proposed as a model for pharmaco-resistant temporal lobe epilepsy. In the present study we examined whether the differences of individual rats in response to phenytoin are already present before kindling or are a consequ ence of kindling. For this purpose, 52 rats were once tested with phenytoin , then kindled, and then repeatedly tested with phenytoin for selection of subgroups. For subgroup selection after kindling, the phenytoin prodrug fos phenytoin was used because of its water solubility and its improved tolerab ility and absorption after i.p. administration in rats. Before kindling, ph enytoin significantly increased the afterdischarge threshold (ADT), i.e. a sensitive measure of focal seizure activity, but there was large individual variation with only 32 of the 52 rats reacting with an ADT increase, while the remaining rats showed either no effect or ADT decreases. After kindlin g, the selection resulted in 16 rats with consistent ADT increases in respo nse to phenytoin and ten nonresponders (the remaining 26 rats showed variab le responses). Unexpectedly, in rats which were responders after kindling, phenytoin exerted no significant anticonvulsant effect before kindling, whi le kindled nonresponders were very sensitive to phenytoin before kindling, indicating that the kindling process was responsible for the loss of antico nvulsant efficacy in kindled nonresponders and the development of phenytoin 's efficacy in kindled responders. The present results substantiate that ki ndled subgroups of Wistar rats with different response to phenytoin are a v aluable source for studying the mechanisms underlying the development of ph armaco-resistant limbic seizures. (C) 2000 Elsevier Science B.V. All rights reserved.