NEUROTRANSMITTER SEIZURE MECHANISMS IN EPILEPTIC

本提案将利用神经药理学技术， 评估参与癫痫发作的神经递质机制， 遗传性癫痫易感（GEP）大鼠。 GEP大鼠非常容易受到 热，电休克，惊厥和声音诱导的癫痫发作，并可能服务 作为人类癫痫症的遗传模型。 先前 研究表明，下丘（IC）和脑干网状 形成发挥关键作用，在生产的缉获量在这方面， 癫痫的自然发生模型。 神经化学证据和 药理学研究表明， 在这些癫痫动物的大脑中。 我们的初步研究和 其他实验室的最新数据表明， GABA作用可能发生在该癫痫模型中。 这可能导致 对听觉刺激的起始-抵消反应的发生率增加， 我们在初步研究中观察到的GEP大鼠。 正常 去甲肾上腺素与GABA的相互作用也可能在这种情况下改变， 癫痫动物 拟议的研究将调查 这些假定的神经递质在GEP大鼠的IC神经元中是异常的。 局部（套管）植入对癫痫易感性的影响 IC、网状结构和影响因子的上级丘 这些神经递质也将被检查，以确定 这些结构在癫痫发作途径中的重要性。 兴奋性 氨基酸，谷氨酸和天冬氨酸，被认为可能是兴奋性的， 神经递质的含量 我们的初步研究表明， 这些药物的拮抗剂将显著降低癫痫发作的严重程度， GEP老鼠 因此，我们将研究对IC神经元的影响， 这些兴奋剂及其拮抗剂的反应。 以来 在GEP大鼠的耳蜗中已经报道了异常， 耳蜗核和上级橄榄核内听觉神经元的分布 将对复合物进行研究，以确定是否发生反应异常 在这些投射到IC的细胞核中。 这些研究应该会产生 关于神经递质机制的重要新信息， 自然发生的全身性癫痫的终身遗传模型， 可能对我们了解 癫痫发生

This proposal will utilize neuropharmacological techniques in order to evaluate neurotransmitter mechanisms involved in seizures in the genetically epilepsy prone (GEP) rat. The GEP rat is highly susceptible to thermal, electroshock, convulsant and sound-induced seizures and may serve as a useful genetic model of certain forms of human epilepsy. Previous studies indicate that the inferior colliculus (IC) and brain-stem reticular formation play critical roles in the production of seizures in this naturally-occurring model of epilepsy. Neurochemical evidence and pharmacological studies indicate that neurotransmitter abnormalities occur in the brains of these epileptic animals. Our preliminary studies and recent data from other laboratories suggest that a reduced effectiveness of the action of GABA may occur in this epilepsy model. This may result in the increased incidence of onset-offset responses to auditory stimuli in the GEP rat that we have observed in preliminary studies. The normal interaction of norepinephrine with GABA may also be altered in this epileptic animal. The proposed study will investigate if the action of these putative neurotransmitters is abnormal in IC neurons in the GEP rat. The effects on seizure susceptibility of local (cannula) implantation into IC, reticular formation and superior colliculus of agents which affect these neurotransmitters will also be examined in order to determine the importance of these structures in the seizure pathway. The excitatory amino acids, glutamate and aspartate, are implicated as possible excitatory neurotransmitters in the IC. Our preliminary studies suggest that an antagonist of these agents will significantly reduce seizure severity in the GEP rat. Therefore, we will examine the effects on IC neuronal responses of these excitatory agents and their antagonists. Since abnormalities have been reported in the cochlea of GEP rats, the response patterns of auditory neurons in the cochlear nucleus and superior olivary complex will be investigated to determine if response abnormalities occur in these nuclei which project to IC. 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 increasng our understanding of mechanisms of epileptogenesis.