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 使用大鼠大脑的海马体结构作为测试系统， 从而探讨兴奋性氨基酸介导的作用机制。 变速箱。电生理研究表明，L-脯氨酸起着 海马锥体细胞上的一种激动剂。此外，脯氨酸诱导的 兴奋性表现为兴奋性氨基酸样药理学和脯氨酸 以钙离子依赖的方式从大鼠海马片中释放。因此， 脯氨酸，虽然缺少公认的 氨基酸刺激剂不仅可以作为内源性刺激剂发挥作用，而且还可以 也可能作为海马体结构中的传递器或调节器。 为了确定可能的“脯氨酸能”途径，生化标记物 脯氨酸(依赖于钙的释放，依赖于钠的高亲和力摄取， 突触体含量、合成酶)将与特定纤维有关 使用病变技术的区域。平行研究将比较 海马片中脯氨酸诱导兴奋的药理作用 突触传递的药理学。海马区的脯氨酸受体 用L-(~3H)-脯氨酸标记突触膜，表征和 本地化放射自显影。将采用脯氨酸结合分析 受体机制研究及受体类似物筛选 活动。N-甲基-D-天冬氨酸敏感和半定量敏感 兴奋性氨基酸受体将被L-(~3H)-谷氨酸标记。这个 N-甲基-D-天冬氨酸受体激动剂对腺苷环化酶和 多聚磷肌醇磷酸二酯酶活性将被检测到 确定谷氨酸结合的抑制是否对NMDA敏感 鸟嘌呤核苷酸的位点暗示了鸟嘌呤核苷酸依赖的链接 在受体和酶之间。兴奋性氨基酸的可能改变 颞叶点燃模型中受体密度或定位的研究 癫痫将通过放射自显影进行评估。来自这些的发现 研究将与神经系统疾病的治疗相关，如 癫痫，涉及到海马体结构的过度活动，如 以及癫痫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.