Clinical and experimental evidence indicates that the immature CNS is more susceptible to the development of generalized seizures and the risk of status epilepticus than the adult. Recent data utilizing electrical or GABA-ergic stimulation of the substantia nigra (SN) suggest that the SN may be a crucial site in a circuitry involved in the suppression of seizures in adult animals. Therefore, the role of the SN in seizures of rat pups was investigated. Deoxyglucose (DG) autoradiographic data demonstrate a striking age related difference in the pattern of metabolism of the SN during generalized seizures induced either by kindling or by systemic administration of kainic acid. In the rat pups neither type of induced seizures produces any changes in the DG uptake in the SN; in contrast in adult rats marked increases in the DG uptake occur within the SN. In addition GABA-ergic stimulation of the SN facilitates flurothyl induced seizures in rat pups and protects against flurothyl seizures in adults. It is proposed that the increased susceptibility to generalized seizures of the developing brain may be due to an immaturity or alteration of the functional activity of the SN and its GABA-sensitive efferent system. The proposed experiments have been designed to determine 1) the regions which contain the GABA-sensitive neurons that exist in the vicinity of the SN and are involved in seizures, 2) the role of the SN-region in the modification of seizures following infusions of GABA-ergic agents in adults and rat pups, and 3) the efferent pathways that mediate the GABA-ergic effects in adults and rat pups. Kindled and flurothyl seizures, cerebral electrographic recordings, intracranial infusions of GABA-ergic agents including 3H-muscimol, as well as tritium and DG autoradiographic techniques will be used. The identification of the SN-regional circuit is important in our understanding of the inherent processes involved in seizure suppression and can potentially lead to the development of therapeutic approaches that may compensate for the maturational state of the CNS.
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