MULTIDISCIPLINARY STUDIES OF MUSCARINIC RECEPTORS (RCDA)

拟议的工作是基于多学科方法来研究 中枢神经系统，特别强调应用 生化和组织学技术，以更好地了解 神经递质系统在调节行为功能中的作用。各种各样的 实验室正在进行技术检查，以检查 行为中的毒鼠碱胆碱能系统。放射自显影研究已经 确定具有M受体独特群体的大脑区域 子类型。毒扁豆碱受体活性测定，包括 磷脂酰肌醇周转、GTP水解与乙酰胆碱调节 释放，增加了我们对行动后果的理解 亚型选择性毒鼠强的药物。使用选择性的行为测试 毒鼠碱拮抗剂和胆碱能神经毒素对我们的 对参与记忆的M受体类型的理解 功能以及长期的生理后果 毒鼠强毒剂的管理。实验室最近的工作已经 重点开发治疗慢性支气管炎的新型毒鼠碱激动剂 阿尔兹迈尔氏病。 拟议的研究将扩大我们对以下角色的了解 毒鼠碱系统的行为，并提供必要的新信息 治疗神经性疾病的合理方法。 具体地说，利用选择性毒扁豆碱进行受体结合研究 配体将被扩展，使用所表达的克隆的毒鼠碱受体 在A9 L细胞中。此外，免疫细胞化学和免疫组织化学技术 原位杂交将用于更好地了解神经解剖学 选择性毒扁豆碱类药物的作用部位及其与药物的关系 其他神经递质系统。长期目标是一个更好的 了解神经递质和药物是如何在分子水平上发挥作用的 水平，调节特定的行为反应。拟议的研究将 增加我们对疾病过程的知识，并提供合理的 各种疾病的治疗干预方法，包括 阿尔茨海默氏症、帕金森氏症、焦虑、中风和药物滥用。

The proposed work is based on a multidisciplinary approach to the study of the central nervous system with particular emphasis on the application of biochemical and histological techniques to better understand the role of neurotransmitter systems in mediating behavioral function. A variety of techniques are ongoing in the laboratory to examine the involvement of muscarinic cholinergic systems in behavior. Autoradiographic studies have identified regions of brain with unique populations of muscarinic receptor subtypes. Assays of muscarinic receptor activity, including phosphoinositide turnover, GTP hydrolysis and regulation of acetylcholine release, have increased our understanding of the consequences of the action of subtype-selective muscarinic drugs. Behavioral testing using selective muscarinic antagonists and cholinergic neurotoxins has contributed to our understanding of the types of muscarinic receptors involved in memory function as well as the physiological consequences of long-term administrations of muscarinic agents. Recent work in the laboratory has focused on the development of novel muscarinic agonists for treatment of Alzhemier's disease. The proposed studies will extend our understanding of the role of muscarinic systems in behavior and provide new information necessary for rational approaches to the treatment of neurological disorders. Specifically, receptor binding studies utilizing selective muscarinic ligands will be extended, using cloned muscarinic receptors as expressed in A9 L cells. In addition, the techniques of immunocytochemistry and in situ hybridization will be applied to better understand the neuroanatomical sites of action of selective muscarinic drugs and their relationship with other neurotransmitter systems. The long-term objective is a better understanding of how neurotransmitters and drugs, working at the molecular level, mediate specific behavioral responses. The proposed studies will increase our knowledge of disease processes, and provide rational approaches for therapeutic intervention in a variety of disorders including Alzheimer's disease, Parkinson's disease, anxiety, strokes, and drug abuse.