STEROIDS, ESTRUS CYCLE, AND BRAIN EXCITABILITY

孕酮(P)和某些P代谢物具有抗惊厥作用 各种癫痫动物模型。本提案的目标 是为了表征新的类固醇识别位点，它介导了 磷代谢产物的抗惊厥作用及其机制(S) 参与并确定惊厥剂引起的癫痫的易感性 作用于GABA/苯二氮卓类受体(GBR)-氯离子载体的药物 在发情周期的不同阶段是复杂的。这些目标将 加深对月经性癫痫病因的了解 与月经周期和经前应激综合征有关。 假说是：P及其代谢物(S)起正常的调节作用。 通过GBR-Cl-离子载体复合体的脑兴奋性。来调查这件事 假设使用啮齿动物模型，这项建议的具体目的是 1)体外鉴定P和P作用的类固醇部位 代谢物对大脑兴奋性的影响；2)合成和鉴定 抗惊厥剂类固醇；以及3)确定惊厥剂的敏感性 GBR-Cl-离子载体复合体在不同阶段的专有试剂 在发情周期中。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。这个 第二个特定目标将使用被确认为有效的新型类固醇 在体外进行标准的抗惊厥药物筛选试验，以找到 临床上有用的抗惊厥药。最后，第三个具体目标将是 通过确定惊厥剂的发作阈值和 脑内GBR-Cl-离子载体活性类固醇激素水平的变化 发情周期。总体而言，这些研究代表着 一种新的膜结合类固醇位点的系统表征和 抗惊厥药物对该部位特异性配基的鉴定 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.