There is increasing concern regarding the reliability of anticonvulsant drug screens currently in use and the possibility that these screens may have impeded progress towards identifying new and better classes of anticonvulsant agents. This concern has led to efforts to develop more reliable anticonvulsant drug screens. The objectives of this research proposal are to 1) characterize a relatively new and little studied animal model of sponstaneously occurring limbic and motor seizures and 2) initiate an assessment of the utility of this model as an anticonvulsant drug screen by evaluating the effects of conventional anticonvulsants on the incidence of spontaneously occurring seizures. This effort represents a significant departure from more traditional methods of assessing anticonvulsant potential which usually rely on an elicited stimulus, such as electrical current or convulsant drug, to study drug effects on seizures. Using a computer automated kindling and EEG monitoring system, male Sprague-Dawley rats will receive kindling stimulations until they display spontaneous limbic and motor seizures. (This stage is quite different from the so called """"""""kindled"""""""" state described by most investigators; where the animal has a permanent enhanced susceptibility to stimulus-induced motor seizures, but rarely displays spontaneous seizure activity). First, the spontaneous seizure model will be characterized in some detail to establish a standardized protocol for producing spontaneously seizing rats. Once the protocol is established, the effect of six drugs on the incidence of spontaneous seizures will be examined. Using osmotic minipumps to ensure constant plasma drug levels, the frequency and intensity of spontaneous seizures will be determied in drug and vehicle controls for a period of two weeks after minipump implantation. The effect of drug on spontaneous seizures will be correlated with plasma drug levels taken at several intervals during the two week drug trial. Should the spontaneous seizure model respond to conventional anticonvulsants in a pattern similar to human epileptic responses, future proposals will extend this work to drugs currently in clinical trial and experimental drugs having a rational or theoretical basis for anticonvulsant potential.
