NEUROTRANSMITTER MECHANISMS IN EPILEPSY

癫痫中的神经递质机制

• 批准号: 3402255
• 负责人: CARL L FAINGOLD
• 金额: $ 8.86万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-09-23 至 1991-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3402255
• 关键词: aminoacid; anticonvulsants; aspartate; auditory stimulus; brain disorder chemotherapy; brain electrical activity; brain stem; disease /disorder model; electroencephalography; electrophysiology; gamma aminobutyrate; genetic models; glutamates; histology; inferior colliculus; laboratory rat; neurochemistry; neuropharmacology; neurotransmitter metabolism; neurotransmitters; nontherapeutic iontophoresis; norepinephrine; olivary body; reflex epilepsy; reticular formation; serotonin; stimulus /response; substantia nigra; superior colliculus

The proposed project will examine neurotransmitter mechanisms involved in seizures in genetically epilepsy-prone rats (GEPRs). The GEPR is abnormally susceptible to thermal, electroshock, convulsant, hyperbaric, kindling and audiogenic seizures (AGS) and has been shown to be a valid model of certain forms of human epilepsy. The brainstem auditory nuclei, particularly the inferior colliculus (IC), as well as the substantia nigra and brainstem reticular formation play important roles in initiation and propaga- tion of seizures in this naturally-occurring model of epilepsy. Extensive evidence indicates that neurotransmitter abnormalities. Recent iontophoretic, microinjection, histochemical, and neurochemical evidence indicates that the actions of GABA and excitant amino acids are altered in the IC of the GEPR. This proposal will examine the neuronal mechanisms subserving epileptogenesis in freely moving GEPRs and examine the effects of anticonvulsants on these mechanisms. These anticonvulsants include excitant amino acid antagonists and will be administered systemically and by focal microinjection into specific brain regions. We have successfully produced susceptibility to AGS in normal rats by focal injection of an excitant amino acid into the IC, but the convulsions lack the tonic components seen in the GEPR. Norepinephrine and 5-hydroxytryptamine deficits are reported in the GEPR, and we will attempt to reproduce the maximal seizures of the GEPR by microinjection of an excitant amino acid into the IC of normal rats while simultaneously blocking noradrenergic or serotonergic function in other nuclei of the seizure pathway. This approach has resulted in AGS with tonic components in preliminary studies. The seizure severity increases in the GEPR with the appearance of epileptiform EEG changes following daily repetition of AGS. This proposal will investigate the neural mechanisms subserving this severity increase and examine the effects of anticonvulsants on its development. The GEPR is generally more susceptible to other seizure-inducing stimuli, but is not clear if the brain sites and mechanisms involved in this general susceptibility are the same as those involved in AGS. Therefore, the proposal will utilize focal microinjection into specific brain regions of substances affecting excitant and inhibitory amino acid action to assess effects on hyperbaric seizures in the GEPR. These studies should yield significant new information about neurotransmitter mechanisms in a naturally-occurring, life-long genetic model of generalized epilepsy which could be of great value in increasing our understanding of mechanisms of epileptogenesis and increase our understanding of how certain new potentially useful anticonvulsant drugs act to prevent seizures.

拟议的项目将研究神经递质机制 参与遗传性癫痫易感大鼠（GEPRs）的癫痫发作。 GEPR对热电击异常敏感 惊厥、高压、点燃和听源性癫痫发作（AGS）， 已经被证明是某些人类形式的有效模型 癫痫 脑干听觉核团，尤其是下丘脑 丘（IC），以及黑质和脑干 网状结构在植物的发生和繁殖中起重要作用， 在这种自然发生的癫痫模型中的癫痫发作。 大量证据表明神经递质异常。 最近的离子电渗，显微注射，组织化学， 神经化学证据表明，GABA和 刺激性氨基酸在GEPR的IC中改变。 这 建议将研究神经机制， 癫痫发生在自由移动的GEPRs和检查的影响， 抗惊厥药对这些机制。 这些抗惊厥药包括 兴奋性氨基酸拮抗剂， 全身性和通过局部显微注射到特定脑中 地区 我们已经成功地在小鼠中产生了对AGS的敏感性。 通过将兴奋性氨基酸局部注射到正常大鼠的 但抽搐缺乏GEPR中所见的强直成分。 去甲肾上腺素和5-羟色胺缺乏症报告在 GEPR，我们将尝试重现最大的癫痫发作的 通过将一种兴奋性氨基酸微量注射到 正常大鼠，同时阻断去甲肾上腺素能或 癫痫发作途径其他核团中的多巴胺能功能。 这 这种方法导致了AGS与滋补成分在初步 问题研究 GEPR中的癫痫发作严重程度随着 每日重复出现癫痫样脑电图改变 的AGS。 该提案将研究神经机制 降低这种严重性增加，并检查的影响， 抗惊厥药对其发展的影响。 一般来说，GEPR 易受其他诱发性刺激的影响，但不清楚是否 参与这一普遍现象的大脑部位和机制 易感性与AGS中涉及的易感性相同。 因此，我们认为， 该提案将利用局部显微注射到特定大脑中 影响兴奋性和抑制性氨基酸的物质区域 在GEPR中评估对高压癫痫发作的影响。 这些 研究应该产生重要的新信息， 神经递质机制在一个自然发生的，终身 广泛性癫痫的遗传模型，可能具有重要价值 来加深我们对癫痫发生机制的理解 并增加我们对某些新的潜在的 有用的抗惊厥药物用于预防癫痫发作。