CHOLINERGIC AND DOPAMINERGIC SYSTEMS IN THE BRAIN AND MULTIPLE INTERACTIONS

大脑中的胆碱能和多巴胺能系统以及多种相互作用

• 批准号: 6201627
• 负责人: PATRICIA S GOLDMAN-RAKIC
• 金额: $ 26.59万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6201627
• 关键词: Macaca mulatta; acetylcholine; brain mapping; cerebral cortex; cognition; dopamine; electron microscopy; immunocytochemistry; mesencephalon; neural transmission; neuroanatomy; neurotransmitter metabolism; neurotransmitter receptor; prosencephalon; synapses

Impairment of cholinergic-dopaminergic interaction are a prominent feature in drug abuse. Imbalance in either the cholinergic or dopaminergic system automatically affects the other system and inevitably leads to impaired perception, motor control and/or cognition. We propose to examine the neuronal circuits, synaptology and types of receptors involved in ACh-DA interactions in the cerebral cortex and in the mesencephalon and basal forebrain systems that innervate the cerebral cortex. Specific Aim #1 focuses on the chemical neuroanatomy of cholinergic influence on the mesencephalic dopamine system of neurons and explores, among other issues, the possibility that DA transmission is influenced by particular nicotinic receptor subunits. Specific Aim #2 addresses the converse relationship, i.e., the dopaminergic inputs to the basal forebrain cholinergic cortical projecting neurons and the localization of dopaminergic D1/D5 receptors on these neurons, as an indirect mechanism for explaining ACh release in cortex induced by D1 agonists. Finally, in Specific Aim #3, we propose to examine the direct and indirect interplay of the two systems in the cerebral cortex where each is known to influence and modulate the cognitive processes that are impaired/accentuated by drugs of abuse. As will be detailed in Background, the ascending circuitry of the brain stem DA system has recently been shown to differ from that of the rodent and some of the questions that will be addressed in this project arise from this difference. Further, the expansion and differentiation of cerebral cortex in primates is an opportunity to illuminate the substrates of drug action that may be regionally and functionally specialized. We have the necessary experience in the principal methods of light and electronmicroscopic immunohistochemistry independently and in combination with retrograde tracing and have previously successfully delineated features of cortical and subcortical synaptic architecture in the primate brain. The subtype specific antibodies against dopamine receptor fusion proteins developed at Yale and antibodies to alpha and beta nicotinic subunits needed to carry out the proposed research are also available to us. Only by knowledge of the dopamine-cholinergic synaptic interactions at several major levels of the neuroaxis will it be possible to obtain a comprehensive picture of systemic drug influence, including that of drugs of abuse, on behavior.

胆碱能-多巴胺能相互作用受损是一个显着特征 在药物滥用方面。胆碱能或多巴胺能系统失衡 自动影响其他系统并不可避免地导致受损 感知、运动控制和/或认知。我们建议审查 ACh-DA 涉及的神经元回路、突触和受体类型 大脑皮层、中脑和基底层的相互作用 支配大脑皮层的前脑系统。具体目标#1 专注于胆碱能影响的化学神经解剖学 神经元的中脑多巴胺系统，并探索除其他问题外， DA 传输受特定烟碱影响的可能性 受体亚基。具体目标 #2 解决了相反的关系， 即，基底前脑胆碱能皮质的多巴胺能输入 投射神经元和多巴胺能 D1/D5 受体的定位 这些神经元，作为解释乙酰胆碱释放的间接机制 D1激动剂诱导的皮质。最后，在具体目标#3中，我们建议 检查两个系统的直接和间接相互作用 大脑皮层中的每一个都已知影响和调节 因滥用药物而受损/加剧的认知过程。作为 将在背景中详细介绍，脑干的上升回路 最近被证明 DA 系统与啮齿动物和 该项目将解决的一些问题来自 这个区别。此外，大脑的扩张和分化 灵长类动物的皮质是阐明药物底物的机会 可能具有区域性和功能性专门化的行动。我们有 光和光的主要方法的必要经验 独立和组合的电子显微镜免疫组织化学 具有逆行追踪功能并且之前已成功描绘 灵长类动物皮质和皮质下突触结构的特征 脑。抗多巴胺受体融合的亚型特异性抗体 耶鲁大学开发的蛋白质以及α和β烟碱抗体 进行拟议研究所需的子单元也可用于 我们。仅通过了解多巴胺-胆碱能突触相互作用 神经轴的几个主要水平将有可能获得 全面了解药物的全身影响，包括药物的影响 虐待，行为。