DA-GABA modulation of cortical ACh release

描述（由申请人提供）：这是一个竞争性续期申请。本研究的总体目标是了解整个分布式神经系统的功能性递质相互作用，以调解注意处理。该系统包括伏隔核（NAC）的壳区、基底前脑（BF，皮质胆碱能神经元的所在地）和内侧前额皮质（mPFC）。该系统中各种神经递质之间的功能相互作用尚不清楚。大鼠注意加工需要完整的基底前脑-皮质胆碱能系统。此外，在持续注意力任务中，皮质乙酰胆碱（Ach）增加。本研究采用一种强大的微透析方法，将3个探针同时放入清醒的大鼠体内（NAC、BF和mPFC），直接比较基线条件下和明显增加注意力处理的条件下动态递质相互作用。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]，这种调节是由NAC DA受体活性调节的。我们还提出，这些递质相互作用的性质受到动物在测量时是否参与注意加工的深刻影响。我们将检验以下具体假设：1)阻断NAC中嗜离子性Glu受体或刺激代谢性Glu受体可减少GABA释放并刺激BF中Glu释放，从而刺激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与在没有明确注意加工的控制任务中的表现相比，在BF和皮层中有不同的递质释放特征；4)基底内GABA或Glu受体活性的操纵将影响从事持续注意任务而非控制操作任务的动物的表现和皮质乙酰胆碱释放。了解基底前脑皮质胆碱能系统兴奋性的调节机制，对于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至关重要。

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.