STEROIDS, ESTRUS CYCLE, AND BRAIN EXCITABILITY

孕酮（P）和某些P代谢产物具有抗惊厥作用， 各种癫痫动物模型。本提案的目标 是表征新的类固醇识别位点介导的 P代谢物的抗惊厥作用及其机制沿着 参与并决定对惊厥药引起的癫痫发作的敏感性 作用于GABA/苯二氮卓受体（GBR）-Cl-离子载体的药物 在发情周期的不同阶段复杂。这些目标将 从而更好地了解月经性癫痫的病因 与月经周期和经前应激综合征有关。 假设是：P及其代谢物作为正常的调节剂， 脑兴奋性通过GBR-Cl-离子载体复合物。调查这一 假设使用啮齿动物模型，本提案的具体目的是 1)在体外表征介导P和P 代谢产物对大脑兴奋性的影响; 2）合成和鉴定 抗惊厥类固醇;和3）确定对惊厥药的敏感性 在不同阶段对GBR-Cl-离子载体复合物具有特异性的试剂 发情周期的一部分第一个目标将通过应用经典来实现 用于表征神经递质受体的方法。的 第二个具体目标将使用新的类固醇确定为积极的， 体外标准抗惊厥药筛选试验， 临床上有用的抗惊厥药。第三个具体目标是 通过测定惊厥剂的发作阈值和 GBR-Cl-离子载体活性类固醇在特定阶段的脑水平 发情周期总的来说，这些研究代表了 一种新膜结合类固醇位点的系统表征， 用抗惊厥药鉴定该位点的特异性配体 潜力

Progesterone (P) and certain P metabolites have anticonvulsant effects in various animal models of epilepsy. The objectives of the present proposal are to characterize the novel steroid recognition site mediating the anticonvulsant actions of P metabolites along with the mechanism(s) involved and determine susceptibility to seizures produced by convulsant agents acting at the GABA/benzodiazepine receptor (GBR)-Cl- ionophore complex during different phases of the estrus cycle. These objectives will lead to a better understanding of the etiology of catamenial epilepsy associated with the menstrual cycle and the premenstrual stress syndrome. The hypothesis is: P and its metabolite(s) act as normal modulators of brain excitability via the GBR-Cl- ionophore complex. To investigate this hypothesis using a rodent model, the specific aims of this proposal are to 1) characterize in vitro the steroid site mediating the effects of P and P metabolites on brain excitability; 2) synthesize and identify anticonvulsant steroids; and 3) determine susceptibility to convulsant agents specific for the GBR-Cl- ionophore complex during different phases of the estrus cycle. The 1st aim will be fulfilled by applying the classic approach used in the characterization of neurotransmitter receptors. The 2nd specific aim will use novel steroids identified as being active in vitro in standard anticonvulsant screening tests in order to find clinically useful anticonvulsants. Finally, the 3rd specific aim will be achieved by determining the seizure threshold of convulsant agents and the brain levels of GBR-Cl- ionophore active steroids during specific phases of the estrus cycle. Collectively, these studies represent the first step in the systematic characterization of a novel membrane-bound steroid site and the identification of specific ligands for this site with anticonvulsant potential.