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: 6302741
• 负责人: MICHAEL J ZIGMOND
• 金额: $ 12.18万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-01 至 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6302741
• 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.

该项目将重点研究儿茶酚胺的适应性特性 神经元，因为它们与神经元损伤有关。 我们的校长 假设多巴胺 (DA) 发挥突触和突触作用 对背侧纹状体靶细胞的非突触影响 DA耗尽损伤后非突触通讯和 粗大运动行为不会受到影响，直到 DA 大量丧失为止，而 突触通讯和更微妙的运动能力 与伤害大致成比例地中断。 在提议的 实验我们将继续检查动物模型 其中含有 DA 的投影的部分损伤 黑质纹状体通路是在大鼠中由大脑内的 注射6-羟基多巴胺（6-OHDA）。 四套 建议进行实验：首先，我们将确定 部分丧失后多巴胺能影响得以保留 背侧纹状体的 DA 输入作为病变大小的函数， 术后时间和左旋多巴的可用性。 DA 对其靶标影响的神经生物学测量 完整和受损的动物将包括： 乙酰胆碱 (Ach) 释放（D2 介导的反应）、cAMP 产生（主要是 和 D1 反应），以及 GABA 释放（一种复杂的相互作用 涉及 D1 和 D2 站点）。 二、我们将开展 使用行为终点的平行研究，包括食物和 饮水量、运动活动、操作反应时间和 神经学测试电池。 在第三个实验系列中，我们将 探讨终端损耗与终端损耗之间差异的基础 功能缺陷，重点关注病变引起的 DA 变化 合成、DA 自身受体敏感性和谷氨酸能变化 输入。 最后，我们将检查与酪氨酸相关的变化 DA部分损伤后羟化酶（TH）基因表达 神经元，将我们的结果与响应获得的结果进行比较 去甲肾上腺素能神经元受损。 金额的变更 将检查供应至神经末梢的 TH，以及 终端内 TH 稳定性的变化。 的比率 TH 合成也将被测量，重点是 TH 基因的比率 转录和翻译。 我们相信研究结果表明 这项研究将会产生影响 了解帕金森病的病因和治疗方法，并会 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。