DOPAMINE & ENKEPHALIN/TACHYKININ IN BASAL GANGLION

研究表明，神经递质多巴胺(DA) 与脑啡肽(ENK，例如甲基5-脑啡肽)相互作用 含有肽能神经元的速激肽(TAK，如P物质) 基底节的位置。例如，DA受体被阻断或损害 黑质纹状体DA神经元导致ENK增强和降低 Tak在基底节和/或黑质的浓度。 然而，发展的精确性和长期性 这些肽能系统在DA缺乏期间的可塑性是 不清楚，部分原因是缺乏关于以下方面的信息 它们的生物合成过程(例如转录、翻译和 多肽形成)。DA-ENK/TAK关系的阐明 是很重要的，因为DA的缺乏与 与帕金森氏症和莱施相关的运动障碍- 尼汉病。工作假说是， 纹状体中多肽生物合成的维持 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的变化以及改变DA活性的事件 神经元也会改变生物合成。神经毒素，6- 羟基多巴胺致大鼠早期多巴胺缺乏 出生后时期将作为研究DA-ENK/TAK的模型 两性关系。肽能神经元的状态将是 根据前脑啡肽原转录速率进行评估 和速激肽原基因，通过转录运行分析， 通过分子杂交获得特定mRNAs的丰度， 某些前体和多肽的浓度通过 放射免疫分析。DA，5-羟色胺及其衍生物 代谢物也将被检测。这项提案将解决 以下是具体问题：a)分子事件是什么 参与ENK的出生后发育和生物合成 和TAK多肽？B)新生儿是否导致DA缺乏症 导致ENK增强和TAK生物合成受阻；如果是这样，在 在发展的哪个阶段会出现这种情况？C)将 补充赤字传递员DA，或用 选择性DA受体(d1或d2)激动剂或多肽(TAK)或 阿片类拮抗剂在适当发育期逆转 或改变多肽和某些行为改变 与DA缺乏症有关？D)如何破坏 已知的5-羟色胺能终末在 新生儿DA缺乏后纹状体对肽能的影响 神经元？所获得的结果将与进一步的 了解基底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.