BASAL GANGLIA--MOLECULAR PHARMACOLOGY AND ANATOMY

多巴胺和乙酰胆碱具有深刻的调节作用。 新纹状体灵长类动物。介导这些效应的受体是重要的。 药物治疗的靶点，如这些递质系统的功能障碍 是帕金森氏病和其他运动的发病机制的核心 精神错乱。最近，一大群基因截然不同的 受体亚型已经确定。尽管它们的分布和 功能在很大程度上是未知的，d1和d2(多巴胺)和m1，m2和m4 (M受体亚型)是存在于 壳核。我们最近开发了免疫学方法来治疗 多巴胺和M胆碱能受体的定位 使用抗体通过免疫印迹和亚型特异性 克隆受体和天然受体的免疫沉淀。初步 在大鼠、猴子和人脑中的免疫细胞化学结果支持我们的 假设单个运动壳核。其中的第一个目标是 研究的目的是描绘区域和细胞分布的d1，d2， 光镜观察猴和人壳核的m1、m2和m4受体 以及它们精确的亚细胞(例如突触前和突触后)分布 通过电子显微镜观察猴子体内的壳质。此外，首相府将联席 与其他受体结合以确定亚型是否为 在相同的、重叠的或分离的神经元群体中表达 在壳牌。第二个目标是确定它们之间的关系 壳核神经元向GPE和GPI投射的受体联合应用 逆行追踪技术和受体免疫细胞化学。这些 研究将提供直接的形态证据来支持或驳斥 平行纹状体输出之间受体亚型分离的模型 小路。第三个目标是确定大脑皮层的突触关系 受体识别壳核传入。从主要传入 以及辅助运动皮质、运动丘脑(中央正中核)、 黑质和中脑被盖锥体外区 光学和电子显微镜顺行示踪鉴定 级别。这些结果将促进我们对分子的理解。 灵长类基底节的药理学和突触组织，以及 将有助于合理发展，更加具体有效 针对这些分子靶点的治疗帕金森氏症的药物 基底节疾病和其他疾病。

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.