PRENATAL AED EXPOSURE AND SEIZURE SUSCEPTIBILITY

提出的实验旨在确定产前的影响

The proposed experiments are designed to determine the effects of prenatal exposure to antiepiletic drugs (AED) on the convulsive behavior of the offspring in rat. The working hypothesis is that exposure of the developing brain to these agents, in doses that are not teratogenic, can induce long-term changes in the CNS which alter seizure susceptibility. Phenobarbital, sodium valproate and clonazepam will be administered to rats on gestation days 15-21 in doses that produce serum levels in the human therapeutic range. In the first series of experiments offspring will be subjected to pentylene-tetrazole (PTZ)-induced seizures to determine 1) if prenatal exposure to AEDs during the third trimester can protect the offspring from or sensitize them to the action of this chemical convulsant; 2) what the ontogenetic parameters of this change area; 3) if pre-exposure in utero alters the anticovulsant efficacy of these drugs; 4) whether or not observed alterations in convulsive behavior are sexually dimorphic; and 5) if changes in peripheral metabolizing enzymes are responsible for changes in PTZ-induced convulsive behavior. A second series of experiments will investigate the role of both maternal seizure activity and AEDs on the development of convulsions in an animal model whose seizure susceptibility is genetically determine: the audiogenic seizure susceptibility (AGSS) rats. After determining the behavioral response, the maturational parameters of AGS, and the efficacy of AED against these seizures in our colony, we will investigate the effects of treated and untreated convulsions prior to or during pregnancy on the seizure susceptibility in the offspring. In both series of experiments plasma levels of phenobarbital, clonazepam, and valproate as well as plasma proteins will be determined in females during pregnancy and in the offspring after birth. These experiments should provide information concerning the vulnerability of the developing brain to AEDs and subsequent seizure susceptibility in the offspring. They may also determine the contribution of genetic and environmental factors in determining seizure thresholds and provide guidelines for the management of epilepsy in pregnancy.