CHOLINERGIC AND DOPAMINERGIC SYSTEMS IN THE BRAIN AND MULTIPLE INTERACTIONS

胆碱能-多巴胺能相互作用受损是一个显著的特征 滥用药物。胆碱能或多巴胺能系统的失衡 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的神经元回路、突触和受体类型 大脑皮层、中脑和基底区的相互作用 支配大脑皮层的前脑系统。具体目标#1 重点阐述了化学神经解剖学对胆碱能神经功能的影响 中脑神经元的多巴胺系统，并探索了其他问题， 多巴胺传递受特定烟碱影响的可能性 受体亚基。具体目标#2解决了反向关系， 即多巴胺能传入基底前脑胆碱能皮层 投射神经元与多巴胺能D_1/D_5受体在脑内的定位 作为解释ACh释放的间接机制，这些神经元 由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已知影响和调节 因滥用药物而受损/加重的认知过程。AS 将在背景中详细介绍，脑干的上升回路 最近发现DA系统与啮齿动物的系统不同，并且 本项目中将解决的一些问题来自 这种不同。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 行动可能在区域和职能上是专门的。我们有 对光和光的主要方法有必要的经验 单独和联合应用的电子显微镜免疫组织化学 具有逆行追踪，并在之前成功地描绘了 灵长类皮质和皮质下突触结构的特点 大脑。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和对α和β尼古丁的抗体 进行拟议研究所需的亚基也可用于 我们。仅通过对多巴胺-胆碱能突触相互作用的了解 神经轴的几个主要水平是否有可能获得 全身性药物影响的全貌，包括药物的影响 虐待，对行为的影响。

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.