DA/GABA MODULATION OF CORTICAL ACH RELEASE

描述(摘自申请者的摘要)：中脑边缘功能障碍 通路被认为是主要神经精神障碍的基础。 和吸毒。而NAC输入在多巴胺能神经递质调节中的作用 传递受到了相当大的关注，DA受体的作用 调节NAC传出投射神经元的活动一直不是很好 学习。NAC传出神经和NAC神经递质DAR能调节的测定 它在认知中的作用将提供对行为的批判性见解 中脑边缘功能异常的后果。拟议的研究是 旨在测试NAC DA抑制主要NAC传出的假设 -GABA能投射到苍白球腹侧区[具体地说，是到 无名实质(SI)]。由于这种DA介导的抑制作用 GABA在SI中的释放，NAc内的DA能传递调节其活性 基底前脑缺血能系统。这个无能系统支配着所有 大脑皮层区域，因此，有效地开启了皮层信息处理的大门。 这项拟议的研究使用体内微透析技术来 描述皮层ACh释放的动态、跨突触调节。 多巴胺(NAC)、氨基丁酸(SI)和多巴胺(DA)的药理和行为决定因素 将在清醒的大鼠中测定ACh(皮质)外流。第一个系列 实验将验证NAC DA受体增加的假设 局部灌流苯丙胺的活性将减少GABA在脑内的外流 因此，增加大脑皮层ACh的外流。第二个系列 实验将证明NAC内的苯丙胺能够 增加皮质ACh外流可通过以下药物增强和减弱 分别增加和减少SI的GABA能传递。这个 最后一系列实验将在任务执行中使用微透析 为了验证NAC DA-基底前脑的假说 大脑皮层ACh的GABA能调制选择性地介导注意 功能。这些实验将证实 认知过程基本方面的中脑边缘-皮质环路， 从而有助于我们理解认知后果 这些回路内的像差。

DESCRIPTION (Adapted from applicant's abstract): Dysfunctions of mesolimbic pathways have been postulated to underlie major neuropsychiatric disorders and drug abuse. While the role of NAC inputs in the regulation of DAergic transmission has received considerable attention, the role of DA receptor activity in modulating NAC efferent projection neurons has not been well studied. The determination of the DAergic regulation of NAC efferents and its role in cognition will provide critical insights into the behavioral consequences of abnormal mesolimbic functioning. The proposed research is designed to test the hypothesis that NAC DA inhibits the main NAC efferents - a GABAergic projection to ventral pallidal areas [specifically, to the substantia innominate (SI)]. As a result of this DA-mediated inhibition of GABA release in SI, DAergic transmission within NAC regulates the activity of basal forebrain AChergic system. This AChergic system innervates all cortical areas and thus, potently gates cortical information processing. The proposed research uses the technique of in vivo microdialysis to characterize the dynamic, trans-synaptic regulation of cortical ACh release. The pharmacological and behavioral determinants of DA (NAC), GABA (SI) and ACh (cortex) efflux will be determined in awake rats. The first series of experiments will test the hypothesis that increases in NAC DA receptor activity with local perfusions of amphetamine will decrease GABA efflux in SI and, as a result, increase ACh efflux in cortex. The second series of experiments will demonstrate that the ability of intra-NAC amphetamine to increase cortical ACh efflux can be potentiated and attenuated by drugs that increase and decrease, respectively, GABAergic transmission in SI. The final series of experiments will utilize microdialysis in task-performing animals in order to test the hypothesis that NAC DA-basal forebrain GABAergic modulation of cortical ACh selectively mediates attentional functions. These experiments will substantiate the role of mesolimbic-cortical circuits in fundamental aspects of cognitive processes, and thus will contribute to our understanding of the cognitive consequences of aberrations within these circuits.