Characterization of phenytoin-resistant kindled rats, a new model of drug-resistant partial epilepsy: influence of genetic factors.

Abstract

It has been recently shown that a subpopulation of amygdala-kindled Wistar rats can be selected which do not respond to phenytoin with an increase in afterdischarge threshold (ADT). Such non-responders could be a perfect model for studying the mechanisms of pharmacoresistance of complex partial seizures. Further studies on these rats suggested that the lack of anticonvulsant response was not due to the influence of experimental factors, but is an inherent property of each rat. In this study the influence of genetic factors on the pharmacoresistance to phenytoin by breeding Wistar rats which have been selected for their ability to consistently respond or not respond to phenytoin is examined. Male and female Wistar rats were implanted with bipolar electrodes in the basolateral amygdala and kindled. The fully kindled rats were repeatedly tested for their ability to respond to phenytoin (75 mg/kg i.p.) with an ADT increase. Responders and non-responders were mated and the offspring underwent the same kindling and repeated phenytoin testing procedure. Altogether, four generations of kindled rats were studied. The incidence of responses to phenytoin, i.e. ADT increased by more than 20% of control, was significantly higher in the F2 generation of the responder line compared to the non-responder line, but the number of responders and non-responders in the offspring generations F1-F3 did not significantly increase. The data suggest that the ability to respond or not to respond to phenytoin is genetically determined, although it does not follow a simple scheme of inheritance. The low reproductive success of the kindled and phenytoin-treated rats made it impossible to achieve a strain of phenytoin non-responders.