NEUROCHEMISTRY OF STRIATUM--ALTERATION BY DA DEPLETING LESIONS

纹状体的神经化学——DA消耗性病变引起的改变

• 批准号: 6610368
• 负责人: MICHAEL J ZIGMOND
• 金额: $ 20.73万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6610368
• 关键词: 6 hydroxydopamine; Parkinson's disease; acetylcholine; cellular pathology; corpus striatum; cyclic AMP; dihydroxyphenylalanine; dopamine; dopamine antagonists; dopamine receptor; enzyme linked immunosorbent assay; experimental brain lesion; gamma aminobutyrate; glutamates; immunoprecipitation; laboratory rat; nervous system disorder diagnosis; neural plasticity; neural transmission; neurochemistry; neurons; neurotransmitter biosynthesis; receptor sensitivity; synapses; tyrosine 3 monooxygenase

This project will focus on the adaptive properties of catecholamine neurons as they relate to neuronal injury. Our principal hypothesis is that dopamine (DA) exerts both a synaptic and a non-synaptic influence on target cells in the dorsal striatum and that after DA-depleting lesions non-synaptic communication and gross motor behavior is spared until DA loss is extensive, whereas synaptic communication and more subtle motoric capabilities are disrupted in rough proportion to the injury. In the proposed experiments we will continue our examination of an animal model in which partial injury of the DA-containing projections of the nigrostriatal pathway is produced in rats by the intracerebral injection of 6-hydroxydopamine (6-OHDA). Four sets of experiments are proposed: First, we will determine the extent to which a dopaminergic influence is preserved after the partial loss of the DA input to dorsal striatum as a function of lesion size, post-operative time, and the availability of L-DOPA. Neurobiological measures of the impact of DA on its targets in intact and lesioned animals will include: acetylcholine (Ach) release (a D2-mediated response), cAMP production (primarily and D1-response), and GABA release (a complex interaction involving both D1 and D2 sites). Second, we will carry out parallel studies using behavioral endpoints, including food and water intake, motor activity, operant reaction time, and a neurological test battery. In the third experimental series we will explore the basis for the discrepancies between terminal loss and functional deficits, focussing on lesion-induced changes in DA synthesis, DA autoreceptor sensitivity, and changes glutamatergic input. Finally, we will examine the changes related to tyrosine hydroxylase (TH) gene expression after partial injury of DA neurons, comparing our results from those obtained in response to damage to noradrenergic neurons. Alterations in the amount of TH supplied to the nerve terminal will be examined, as will changes in the stability of TH within the terminal. The rate of TH synthesis also will be measured, focusing on rate of TH gene transcription and translation. We believe that the findings that will emerge from this research will have implications for understanding the cause and treatment of Parkinsonism, and will also provide important information regarding the neurobiology of dopaminergic neurons and their interactions with neurons in the basal ganglia.

该项目将重点关注儿茶酚胺的自适应特性 与神经元损伤有关的神经元。 我们的校长 假设是多巴胺（DA）同时发挥着突触 非突触对背纹状体和靶细胞的影响 在耗尽病变之后，非突触通信和 总体运动行为一直持续到DA损失广泛为止，而 突触交流和更微妙的机车能力是 与伤害的比例约为破裂。 在提议中 实验我们将继续检查动物模型 在哪个受DA的预测的部分伤害 脑纹状体途径是由脑内大鼠产生的 注射6-羟基多巴胺（6-OHDA）。 四组 提出了实验：首先，我们将确定 部分损失后保留了多巴胺能影响 向背纹状体的DA输入与病变大小的关系 术后时间和L-DOPA的可用性。 DA对其目标的影响的神经生物学测量 完整和病变的动物将包括：乙酰胆碱（ACH） 释放（D2介导的响应），营地生产（主要是 和D1反应）和GABA释放（复杂的相互作用 涉及D1和D2站点）。 其次，我们将执行 使用行为终点（包括食物和食物）的平行研究 进气，运动活动，操作反应时间和A 神经测试电池。 在第三个实验系列中，我们将 探索终端损失与 功能性缺陷，重点放在病变诱导的DA变化上 合成，DA自感受器敏感性并改变谷氨酸能 输入。 最后，我们将检查与酪氨酸有关的变化 DA部分损伤后羟化酶（Th）基因表达 神经元，比较了我们从响应于 对去甲肾上腺素能神经元的损害。 数量的改变 将检查提供给神经终端的Th 终端内TH的稳定性变化。 速率 还将测量合成，重点关注TH基因的速率 转录和翻译。 我们相信这一发现 这项研究将会产生对 了解帕金森主义的原因和待遇，并将 还提供有关神经生物学的重要信息 多巴胺能神经元及其与神经元的相互作用 基底神经节。