The proposed research project is component of a broadly based effort to elucidate abnormalities responsible for the epilepsies. More specifically, the project is designed to determine the role of central nervous system noradrenergic transmission in the regulation of seizure predisposition in the genetically epilepsy-prone rat (GEPR). These animals have been chosen for this investigation partially because extensive data derived from their use provide an intriguing neurochemical foundation for our proposed studies. Also, the existing body of data suggests a high probability for a positive experimental outcome. Another major consideration persuaded us to select GEPRs as experimental outcome. Another major consideration persuaded us to select GEPRs as experimental subjects. These animals are attractive as a model of human epilepsy. The accumulating body of neurochemical evidence strongly supports the concept that brain noradrenergic deficits in the GEPR are partially responsible for the marked degree of seizure predisposition characteristic of these animals. Importantly, we now have data which provides clues for anatomically localizing the etiologically important noradrenergic terminal fields within the brain. The current project is designed to capitalize on this information. Discrete intracerebral neurotoxic lesions or pharmacologic treatments will be used to produce specific noradrenergic deficits or increments in terminal fields which are candidates for regulation of seizure predisposition in the GEPR. Once a noradrenergic alteration has been made, we will determine whether it causes changes in selected indices of seizure predisposition. The approaches to be utilized will enable us to identify the noradrenergic terminal fields which are responsible for epileptogenesis.
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