DA/GABA MODULATION OF CORTICAL ACH RELEASE

描述（改编自申请人摘要）：中脑边缘功能障碍 已经假设了主要神经精神障碍的基础通路 和药物滥用 虽然NAC输入在DA能神经元调节中的作用 DA受体的作用 调节NAC传出投射神经元的活性还不是很好 研究了 确定NAC传出神经的DA能调节， 它在认知中的作用将为行为学提供重要的见解， 异常的中脑边缘功能的后果。 拟议的研究是 旨在检验NAC DA抑制主要NAC传出神经的假设 - GABA能投射到腹侧苍白球区[具体来说， 无名质（SI）]。 由于这种DA介导的抑制， SI中的GABA释放，NAC内的DA能传递调节活性 基底前脑Achergic系统。 这个Achergic系统激活了所有 皮层区域，从而有效地控制皮层信息处理。 这项研究使用体内微透析技术， 表征皮质ACh释放的动态、跨突触调节。 DA（NAC）、GABA（SI）和 将在清醒大鼠中测定ACh（皮质）外排。 第一系列 实验将验证NAC DA受体增加的假设， 活动与局部灌注安非他明将减少GABA流出， SI，并因此增加皮质中的ACh流出。 第二系列 实验将证明，NAC内安非他明的能力， 增加皮质ACh流出可以通过药物增强和减弱， 分别增加和减少SI中GABA能传递。 的 最后一系列的实验将利用微透析在任务执行 动物，以检验NAC DA-基底前脑 GABA能调节皮层ACh选择性介导注意 功能协调发展的 这些实验将证实 认知过程基本方面的中缘-皮层回路， 从而有助于我们理解 这些回路中的异常

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.