NEUROTRANSMITTER MECHANISMS IN EPILEPSY

拟议中的项目将检查神经递质机制。 参与遗传性癫痫易感大鼠(GEPR)的癫痫发作。 GEPR异常地容易受到热、电击、 惊厥性、高压性、点燃和听源性癫痫(AGS)和 已经被证明是某些形式的人类的有效模型 癫痫。脑干听觉核团，尤指下位核团 丘脑(IC)以及黑质和脑干 网状结构在植物的萌发和传播中起着重要的作用。 在这个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。 最新离子导入、微量注射、组织化学和 神经化学证据表明，GABA和 兴奋性氨基酸在GEPR的IC中发生改变。这 提案将研究神经机制服从于 大鼠自由活动癫痫的发生机制及其对癫痫的影响 这些机制上的抗惊厥药物。这些抗惊厥药物包括 兴奋性氨基酸拮抗剂，将给予 全身注射和局部注射特定脑组织 地区。我们已经成功地产生了对AGS的敏感性 正常大鼠脑内局部注射兴奋性氨基酸 IC，但抽搐缺乏GEPR中所见的补药成分。 去甲肾上腺素和5-羟色胺缺乏症 GEPR，我们将尝试再现最大癫痫发作 脑内核内微量注射兴奋性氨基酸的GEPR 正常大鼠同时阻断去甲肾上腺素能或 癫痫路径其他核团的5-羟色胺能功能。这 方法导致了具有补剂成分的AGS在初步 学习。在GEPR中，癫痫的严重程度随着 日常重复发作后癫痫样脑电改变的表现 AGS的。这项提议将研究神经机制 顺应这种严重程度的增加，并检查 抗惊厥药物对其发展的影响。一般情况下，GEPR 对其他诱发癫痫的刺激敏感，但尚不清楚 脑部的部位和机制涉及到这一普遍 易感性与AGS的易感性相同。因此， 该提案将利用特定脑部的局部显微注射。 影响兴奋性氨基酸和抑制性氨基酸的物质区域 在GEPR中评估对高压性癫痫发作的影响的行动。这些 研究应该产生关于以下方面的重要新信息 自然发生的、终生的神经递质机制 全面性癫痫的遗传模型可能具有重要价值 增加我们对癫痫发生机制的认识 并增加我们对某些新的潜在可能性的理解 有效的抗惊厥药物可预防癫痫发作。

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.