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: 6238048
• 负责人: PATRICIA S GOLDMAN-RAKIC
• 金额: $ 26.07万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-05 至 1998-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6238048
• 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突出的特征 滥用药物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。我们建议研究 ACh-DA参与的神经元回路、突触学和受体类型 在大脑皮层和中脑和基底 支配大脑皮层的前脑系统。具体目标#1 重点是胆碱能对神经系统的化学神经解剖学影响， 中脑多巴胺系统的神经元，并探讨，除其他问题外， 多巴胺传递受特定烟碱影响的可能性 受体亚单位具体目标#2解决了匡威的关系， 也就是说，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，作为一个间接的机制，解释乙酰胆碱释放， D1激动剂诱导的皮质。最后，在具体目标#3中，我们建议 研究这两个系统的直接和间接相互作用， 大脑皮层中的每一个都是已知的影响和调节 滥用药物损害/加重的认知过程。作为 将在背景中详细介绍，脑干的上行回路 DA系统最近被证明不同于啮齿动物的DA系统， 本项目中要解决的一些问题来自于 这种差异。此外，大脑的扩张和分化 灵长类动物的皮层是阐明药物作用的底物的一个机会 可能在区域和功能上专门化的行动。我们有 光的主要方法的必要经验， 电子显微镜免疫组织化学单独和联合 逆行追踪，并已成功描绘 灵长类皮质和皮质下突触构筑的特征 个脑袋多巴胺受体融合亚型特异性抗体的研究 耶鲁大学开发的蛋白质和α和β烟碱的抗体 开展拟议研究所需的子单位也可用于 我们只有了解多巴胺-胆碱能突触的相互作用， 神经轴的几个主要水平将有可能获得 全面了解药物对全身的影响，包括药物的影响 虐待行为