BASAL GANGLIA--MOLECULAR PHARMACOLOGY AND ANATOMY

基底神经节--分子药理学和解剖学

• 批准号: 6112470
• 负责人: ALLAN I LEVEY
• 金额: --
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 1999-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6112470
• 关键词: Macaca nemestrina; afferent nerve; antireceptor antibody; basal ganglia; brain mapping; central neural pathway /tract; dopamine receptor; human tissue; immunocytochemistry; immunoelectron microscopy; light microscopy; muscarinic receptor; neocortex; neuropharmacology; occipital lobe /cortex; postmortem; putamen; receptor expression

Dopamine and acetylcholine have profound modulatory effects in the primate neostriatum. The receptors mediating these effects are important targets for drug therapies, as dysfunction of these transmitter systems is central to the pathogenesis of Parkinson's disease and other movement disorders. Recently, a large and diverse group of genetically distinct receptor subtypes have been identified. Although their distributions and functions are largely unknown, D1 and D2 (dopamine) and m1, m2 and m4 (muscarinic acetylcholine) are the major receptor subtypes present in the putamen. We have recently developed immunological methods for localization of these dopamine and muscarinic acetylcholine receptors using antibodies to be subtype-specific by immunoblotting and immunoprecipitation of the cloned and native receptors. Preliminary immunocytochemical findings in rat, monkey, and human brain support our hypothesis that individual motor putamen. The first goal of these studies is to delineate the regional and cellular distributions D1, D2, m1, m2, and m4 receptors in monkey and human putamen by light microscopy, and their precise subcellular (e.g., pre- and postsynaptic) distributions in monkeys putamen by electron microscopy. In addition, D1 will be co- localized with the other receptors to determine if the subtypes are expressed in the same, overlapping, or segregated populations of neurons in putamen. The second goal is to determine the relationships of these receptors to putamenal neurons projecting to GPe and GPi, using combined retrograde tracing techniques and receptor immunocytochemistry. These studies will provide direct morphological evidence to support or refute models of receptor subtype segregation between parallel striatal output pathways. The third goal is to determine the synaptic relationships of the receptors wit identified putamental afferent. Afferent from primary and supplementary motor cortices, motor thalamus (centromedian nucleus), substantia nigra, and the midbrain tegmental extrapyramidal area will be identified by anterograde tracing at light and electron microscopic levels. The results will advance our understanding of the molecular pharmacology and synaptic organization of the primate basal ganglia, and will aid in the rational development of more specific and effective drugs, aimed at these molecular targets, for the treatment of Parkinson's disease and other disorders of the basal ganglia.

多巴胺和乙酰胆碱具有深远的调节作用 灵长类新纹状体。 介导这些效应的受体很重要 药物治疗的目标，因为这些递质系统的功能障碍 是帕金森病和其他运动发病机制的核心 失调。 最近，一大群具有不同基因的多样化群体 受体亚型已被鉴定。 尽管他们的分布和 功能很大程度上未知，D1 和 D2（多巴胺）以及 m1、m2 和 m4 （毒蕈碱乙酰胆碱）是存在于体内的主要受体亚型 壳门。 我们最近开发了免疫学方法 这些多巴胺和毒蕈碱乙酰胆碱受体的定位 通过免疫印迹使用抗体进行亚型特异性 克隆和天然受体的免疫沉淀。 初步的 大鼠、猴子和人脑的免疫细胞化学研究结果支持了我们的观点 假设个体运动壳核。 这些的第一个目标 研究的目的是描绘区域和细胞分布 D1、D2、 通过光学显微镜观察猴子和人类壳核中的 m1、m2 和 m4 受体， 及其精确的亚细胞（例如突触前和突触后）分布 通过电子显微镜观察猴子壳核。 此外，D1将共同 与其他受体一起定位以确定亚型是否是 在相同、重叠或分离的神经元群体中表达 在壳门。 第二个目标是确定这些之间的关系 壳核神经元的受体投射到 GPe 和 GPi，使用组合 逆行示踪技术和受体免疫细胞化学。 这些 研究将提供直接的形态学证据来支持或反驳 平行纹状体输出之间的受体亚型分离模型 途径。 第三个目标是确定突触关系 受体机智地识别壳膜传入。 从初级传入 和辅助运动皮质、运动丘脑（中心正中核）、 黑质和中脑被盖锥体外区 通过光学和电子显微镜顺行追踪识别 水平。 研究结果将增进我们对分子的理解 灵长类基底神经节的药理学和突触组织，以及 将有助于合理制定更具体、更有效的 针对这些分子靶点的药物，用于治疗帕金森病 基底神经节疾病和其他疾病。