DOPAMINE & ENKEPHALIN/TACHYKININ IN BASAL GANGLION

研究表明，神经递质多巴胺（DA） 与脑啡肽（ENK，例如Met 5-脑啡肽）相互作用， 含肽能神经元的速激肽（TAK，例如P物质） 基底神经节 例如，DA受体阻断或损伤 黑质纹状体DA能神经元的激活导致ENK增强， 基底神经节和/或黑质中的TAK浓度。 然而，发展的确切性质和长期性 DA缺乏时这些肽能系统的可塑性 不清楚，部分原因是缺乏有关信息 它们的生物合成过程（例如转录、翻译和 肽形成）。 DA-ENK/TAK关系的阐明 这一点很重要，因为DA的缺乏与 运动障碍与帕金森综合征和Lesch- Nyhan病。 工作假设是， 和维持纹状体内肽的生物合成 ENK和纹状体黑质TAK神经元处于调节控制之下 黑质纹状体DA的活动， 神经元也会改变生物合成。 神经毒素，6- 羟多巴胺诱导大鼠早期DA缺乏 产后期将用作研究DA-ENK/TAK的模型 关系 肽能神经元的状态将是 根据前脑啡肽原的转录率进行评估 和前速激肽原基因， 通过分子杂交， 某些前体和肽的浓度， 放射免疫测定 DA、5-羟色胺及其 还将分析代谢物。 该提案将解决 以下具体问题：a）分子事件是什么 参与ENK的出生后发育和生物合成 和TAK肽？ B）是否由母体诱导的DA缺乏症 导致增强ENK和延迟TAK生物合成;如果是这样， 这发生在发展的哪个时期？ （c）意愿 补充缺乏的递质DA，或用 选择性DA受体（D1或D2）激动剂或肽（TAK），或 阿片拮抗剂在适当的发育期逆转 或改变肽能和某些行为改变 与多巴胺缺乏症有关吗 （d）如何销毁 已知的肾上腺素能终末在脑内增殖， 新生儿DA缺乏对纹状体肽能的影响 神经元？ 所获得的结果将与进一步的 了解基底神经节功能的神经生物学基础。

Studies indicate that the neurotransmitter dopamine (DA) interacts with the enkephalin (ENK, e.g. Met5-enkephalin) and tachykinin (TAK, e.g. substance P) containing peptidergic neurons of the basal ganglia. For example, DA receptor blockade or lesion of nigrostriatal DA neurons leads to enhance ENK and decreased TAK concentrations in the basal ganglia and/or substantia nigra. However, the precise nature of development and long-term plasticity in these peptidergic systems during DA deficiency is unclear, partly because of the paucity of information concerning their biosynthetic processes (e.g. transcription, translation and peptide formation). An elucidation of DA-ENK/TAK relationship is important, since a deficiency of DA is implicated to the movement disorders associated with Parkinsonism and Lesch- Nyhan disease. The working hypothesis is that the development and maintenance of peptide biosynthesis in the striatopallidal ENK and striatonigral TAK neurons is under a regulatory control of nigrostriatal DA and that events that alter the activity of DA neurons will also modify the biosynthesis. The neurotoxin, 6- hydroxydopamine induced DA deficiency in rat during an early postnatal period will be used as a model to study DA-ENK/TAK relationship. The status of the peptidergic neurons will be assessed in terms of the rate of transcription of preproenkephalin and preprotachykinin genes by transcription run-on assays, the abundance of specific mRNAs by molecular hybridization, the concentrations of certain precursor and peptides by radioimmunoassays. DA, 5-hydroxytryptamine and their metabolites will also be assayed. This proposal will address the following specific questions: a) What are the molecular events involved in the postnatal development and biosynthesis of ENK and TAK peptides? b) Does neonatally induced DA deficiency lead to enhanced ENK and retarded TAK biosynthesis; if so, at what period in development does this occur? c) Will replenishment of the deficit transmitter DA, or treatment with selective DA receptor (D1 or D2) agonists or peptide (TAK) or opioid antagonist at the appropriate development period reverse or modify the peptidergic and certain behavioral alterations associated with DA deficiency? d) How does the destruction of serotonergic terminals which are known to proliferate in the striatum following neonatal DA deficiency affect the peptidergic neurons? The results obtained will be highly relevant to further understanding of neurobiologic basis of basal ganglia function.