This proposal is submitted in response to a request for applications to develop small animal models for screening antiepileptic drugs (AEDs). The project relies on a new model of recurrent limbic seizures triggered by focal electrical stimuli that has been developed and extensively characterized in our laboratory. We propose to use this model to screen AED efficacy in complex partial seizures, the most pressing need in the drug therapy of epilepsy. The duration and threshold of afterdischarges will be measured with electroencephalographic recordings at the site of stimulation. A behavioral scoring system will monitor the intensity of clinical seizure activity. The first phase of the study will establish stimulus parameters to maximize the number of data points collected in a given period of observation while maintaining a stable baseline of intense seizures against which AED action can be tested. The second phase will study the potency of established prototypic and newer AEDs against this seizure model. Means to quantitatively define dose-response and time-action relationships quickly and with a minimum number of animals will be developed. Probit analysis will be used to define effectiveness in terms of ED50's as well as estimate the inherent reliability of these values. The final phase of the study will adapt the model so that it can also be applied to drugs useful against simple partial seizures. The overall goal is to bring to full implementation a reliable, inexpensive, rapid and easy means to screen the clinical efficacy of potential AEDs while establishing the pharmacokinetic characteristics of effective drugs and simultaneously assessing their neurotoxicity. This system will be designed and developed to permit duplication in other laboratories with modest start up expenses and using standard equipment.
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