PRENATAL AED EXPOSURE AND SEIZURE SUSCEPTIBILITY

拟议的实验旨在确定产前的影响， 抗癫痫药物（AED）对惊厥行为的影响 大鼠子代。 目前的假设是， 发育中的大脑对这些药剂的剂量，如果不是致畸的， 诱导CNS的长期变化，从而改变癫痫发作的易感性。 将对大鼠给予苯巴比妥、丙戊酸钠和氯硝西泮 在妊娠第15-21天，以产生人血清水平的剂量给药 治疗范围。 在第一系列实验中，后代将 进行戊四唑（PTZ）诱导的癫痫发作，以确定1）如果 在妊娠晚期产前暴露于AEDs可以保护 使其后代免受这种化学惊厥剂的作用或使其对这种化学惊厥剂的作用敏感; 2)这个变化区域的个体发育参数是什么; 3）如果暴露前 改变这些药物的抗惊厥功效; 4）是否或 未观察到抽搐行为的改变是性二态性的;并且 5)如果外周代谢酶的变化是导致 PTZ诱导的惊厥行为的变化。 第二系列实验将研究两种母体的作用， 癫痫活动和AED对动物惊厥发展的影响 癫痫发作的易感性由遗传决定的模型：听源性 癫痫易感性（AGSS）大鼠。 在确定行为后， 反应，AGS的成熟参数和AED的疗效 针对我们殖民地的这些缉获量，我们将调查 在怀孕前或怀孕期间， 后代的癫痫易感性。 在这两个系列的实验中， 苯巴比妥、氯硝西泮和丙戊酸盐的血浆水平以及 蛋白质将在妊娠期间的女性和 出生后的后代。 这些实验应该提供有关脆弱性的信息 发育中的大脑对AEDs的敏感性和随后的癫痫易感性 后代。 它们还可以决定遗传和 确定癫痫发作阈值的环境因素， 妊娠期癫痫的治疗指南。

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.