EXCITATORY AMINO ACID TRANSMITTERS IN CNS

兴奋性氨基酸，如谷氨酸和天冬氨酸，是突出的 哺乳动物中枢神经系统中的神经递质。 这个项目 采用大鼠大脑的海马结构作为测试系统， 探讨兴奋性氨基酸介导的 传输 电生理学研究表明，L-脯氨酸作为 对海马锥体细胞有刺激作用。 此外，脯氨酸诱导的 兴奋表现出兴奋性氨基酸样药理学和脯氨酸 以Ca 2+依赖的方式从大鼠海马脑片释放。 因此 脯氨酸，虽然缺乏公认的第二个酸性基团， 氨基酸兴奋剂，可能不仅作为内源性兴奋剂， 也可能作为海马结构中的递质或调节剂。 为了确定可能的“脯氨酸能”途径， 脯氨酸（Ca 2+依赖性释放，Na+依赖性高亲和力摄取， 突触体内容物、合成酶）将与特定纤维相关 使用损伤技术的管道。 平行研究将比较 海马脑片脯氨酸诱导兴奋的药理学 突触传递的药理学 海马脯氨酸受体 突触膜将用L-（3 H）脯氨酸标记，表征并 放射自显影定位。 将采用脯氨酸结合试验 研究受体机制和筛选受体类似物 活动 N-甲基-D-天冬氨酸敏感和使君子酸敏感 兴奋性氨基酸受体用L-（3 H）-谷氨酸标记。 的 NMDA受体激动剂对腺苷酸环化酶和 将测试聚磷酸肌醇磷酸二酯酶活性， 确定是否抑制谷氨酸结合NMDA敏感 由鸟嘌呤核苷酸组成的位点意味着鸟嘌呤核苷酸依赖性连接 受体和酶之间的联系 兴奋性氨基酸的可能改变 颞叶点燃模型的受体密度或定位 癫痫将通过放射自显影进行评估。 这些调查结果 研究将与神经系统疾病的治疗有关， 如癫痫，涉及海马结构的过度活跃， 以及癫痫发作和精神发育迟滞的病因， 与高脯氨酸血症有关。

Excitatory amino acids, such as glutamate and aspartate, are prominent neurotransmitters in the mammalian central nervous system. This project employs the hippocampal formation of the rat brain as a test system with which to investigate the mechanisms of excitatory amino acid-mediated transmission. Electrophysiological studies indicate that L-proline acts as an excitant on hippocampal pyramidal cells. In addition, proline-induced excitations exhibit an excitatory amino acid-like pharmacology and proline is released from rat hippocampal slices in a Ca2+-dependent manner. Thus proline, although lacking the second acidic group possessed by recognized amino acid excitants, may function not only as an endogenous excitant but possibly also as a transmitter or modulator in the hippocampal formation. To identify possible "prolinergic" pathways, biochemical markers for proline (Ca2+-dependent release, Na+-dependent high affinity uptake, synaptosomal content, synthetic enzymes) will be related to specific fiber tracts with use of lesion techniques. Parallel studies will compare the pharmacology of proline-induced excitation in the hippocampal slice to the pharmacology of synaptic transmission. Proline receptors on hippocampal synaptic membranes will be labeled with L-(3H)proline, characterized and localized autoradiographically. The proline binding assay will be employed to study receptor mechanisms and to screen analogues for receptor activity. N-Methyl-D-aspartate-sensitive and quisqualate-sensitive excitatory amino acid receptors will be labeled with L-(3H)-glutamate. The effect of NMDA receptor agonists on adenylate cyclase and polyphosphoinositide phosphodiesterase activities will be tested to determine whether the inhibition of glutamate binding to NMDA-sensitive sites by guanine nucleotides implies a guanine nucleotide-dependent link between receptor and enzyme. Possible alterations in excitatory amino acid receptor density or localization in the kindling model of temporal lobe epilepsy will be assessed autoradiographically. Findings from these studies will be relevant to the treatment of neurological conditions, such as epilepsy, which involve hyperactivity of the hippocampal formation, as well as to the etiology of seizures and mental retardation frequently associated with hyperprolinemia.