DA-GABA modulation of cortical ACh release

描述（由申请人提供）：这是一个竞争性的续期申请。 本研究的总体目标是了解分布式神经系统中的功能性递质相互作用，该系统被假设为介导注意处理。 该系统包括中脑核壳区（NAC）、基底前脑（BF，皮质脑胆碱能神经元的位置）和内侧前额叶皮质（mPFC）。 在这个系统中的各种神经递质之间的功能相互作用还没有很好地理解。 大鼠的注意加工需要完整的基底前脑-皮层胆碱能系统（BFCS）。 此外，皮质乙酰胆碱（Ach）增加在持续注意力任务的性能。 拟议的研究利用了一个强大的微透析程序，其中3个探针被同时放置到清醒的大鼠（NAC，BF和mPFC）直接比较动态发射机的相互作用下的基线条件下，明确税收的注意力处理的条件下。 我们假设NAC内的谷氨酸能传递调节BFCS的兴奋性[通过BF内GABA和谷氨酸（Glu）的释放]，并且这种调节受NAC DA受体活性的调节。 我们还提出，这些发射机的相互作用的性质是深刻的影响，无论是在测量时的动物从事注意力处理。 我们将测试以下特定假设：1）NAC中亲离子型Glu受体的阻断或亲代谢型Glu受体的刺激减少BF中GABA释放并刺激Glu释放，并且因此刺激mPFC中Ach释放，2）NAC D1和D2受体双向调节Glu配体影响BF中GABA/Glu释放和mPFC中Ach释放的能力，3）在持续注意任务中的表现伴随着BF和皮层中的递质释放的不同轮廓，而不是在没有明确征税注意处理的控制任务中的表现，和4）的方法基底肌内GABA或Glu受体活性的调控会影响持续注意任务动物的表现和皮层Ach的释放，但不会影响持续注意任务动物的行为和皮层Ach的释放。控制操作性任务。 了解调节基底前脑皮质胆碱能系统兴奋性的机制，是我们理解以注意力处理功能障碍为特征的神经精神疾病的病因和潜在治疗方法的核心。

DESCRIPTION (provided by applicant): This is a competitive renewal application. The overall goal of this research is to understand functional transmitter interactions throughout a distributed neural system postulated to mediate attentional processing. This system includes the shell region of the nucleus accumbens (NAC), the basal forebrain (BF, the site of the corticopetal cholinergic neurons) and the medial prefrontal cortex (mPFC). The functional interactions among the various neurotransmitters within this system are not well understood. Attentional processing in rats requires and intact basal forebrain-cortical cholinergic system (BFCS). Moreover, cortical acetylcholine (Ach) is increased during performance in a sustained attention task. The proposed research utilizes a powerful microdialysis procedure in which 3 probes are simultaneously placed into awake rats (into NAC, BF, and mPFC) to directly compare dynamic transmitter interactions under baseline conditions and under conditions that explicitly tax attentional processing. We hypothesize that glutamatergic transmission within the NAC regulates the excitability of the BFCS [via the release of GABA and glutamate (Glu) within the BF] and that this regulation is modulated by NAC DA receptor activity. We also propose that the nature of these transmitter interactions is profoundly influenced by whether or not the animal is engaged in attentional processing at the time of the measurement. We will test the following specific hypothesis: 1) that blockade of ionotropic Glu receptors or stimulation of metabotropic Glu receptors in NAC decreases GABA release and stimulates Glu release in BF, and, as a result stimulates Ach release in mPFC, 2) that NAC D1 and D2 receptors bidirectionally modulate the ability of Glu ligands to affect GABA/Glu release in BF and Ach release in mPFC, 3) that performance in a sustained attention task is accompanied by a different profile of transmitter release in BF and cortex than performance in a control task that does not explicitly tax attentional processing, and 4) that intrabasalis manipulations of GABA or Glu receptor activity will affect performance and cortical Ach release in animals engaged in a task of sustained attention but not in control operant tasks. An understanding of the mechanisms regulating the excitability of the basal forebrain cortical cholinergic system is central to our understanding of the etiology and potential therapeutics of neuropsychiatric disorders characterized by dysfunction in attentional processing.