BASAL GANGLIA--MOLECULAR PHARMACOLOGY AND ANATOMY

多巴胺和乙酰胆碱在神经元内具有深刻的调节作用， 灵长类新纹状体 介导这些效应的受体是重要的 作为药物治疗的靶点， 是帕金森病和其他运动的发病机制的核心 紊乱 最近，一个庞大而多样的群体， 受体亚型已被鉴定。 虽然它们的分布和 功能在很大程度上是未知的，D1和D2（多巴胺）和m1，m2和m4 （毒蕈碱乙酰胆碱）是存在于细胞中的主要受体亚型。 壳核 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 通过免疫印迹使用亚型特异性抗体， 克隆和天然受体的免疫沉淀。 初步 在大鼠、猴和人脑中的免疫细胞化学发现支持我们的观点， 假设单个运动壳核。 第一个目标是 研究是描绘区域和细胞分布D1，D2， 通过光学显微镜观察猴和人壳核中的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 用电子显微镜观察猴子壳核。 此外，D1将与 与其他受体一起定位，以确定亚型是否 在相同、重叠或分离的神经元群体中表达 在壳核中。 第二个目标是确定这些关系 应用联合方法，研究了投射到GPe和GPi的壳核神经元的受体， 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的关系， 这些感受器被鉴定为壳状传入。 初级传入 和辅助运动皮质，运动丘脑（中央中核）， 黑质，中脑被盖锥体外系区将是 通过光镜和电镜顺行追踪鉴定 程度. 这些结果将促进我们对分子生物学的理解。 药理学和灵长类基底神经节的突触组织，和 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， 基底神经节疾病和其他病症。

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.