DA-GABA modulation of cortical ACh release

描述(申请人提供)：这是一份竞争性续签申请。这项研究的总体目标是了解整个分布式神经系统中功能递质的相互作用，该神经系统被认为是调节注意加工的。该系统包括伏核的壳区(NAC)、基底前脑(BF，皮质顶叶胆碱能神经元的所在地)和内侧前额叶皮质(MPFC)。这个系统内各种神经递质之间的功能相互作用还不是很清楚。大鼠注意加工需要完整的基底前脑-皮质胆碱能系统(BFCS)。此外，皮质乙酰胆碱(Ach)在持续注意任务的表现过程中也会增加。这项拟议的研究利用了一种强大的微透析程序，在该程序中，3个探针被同时放置到清醒的大鼠(进入NAC、BF和mPFC)，以直接比较基线条件下和在明显影响注意处理的条件下的动态递质相互作用。我们推测，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]，并且这一调节受NAC DA受体活性的调节。我们还提出，这些递质相互作用的性质受到测量时动物是否正在进行注意加工的深刻影响。我们将检验以下特定假设：1)阻断NAC中的离子型Glu受体或刺激代谢型Glu受体会减少BF中GABA的释放并刺激BF中的Glu释放，从而刺激mPFC中的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和皮质中不同于控制任务的不同的递质释放，而控制任务不会明确地对注意处理征税。4)基底内对GABA或Glu受体活性的操纵将影响持续注意任务而不是控制操作任务的动物的表现和皮质Ach释放。了解调节基底前脑皮质胆碱能系统兴奋性的机制，对于我们理解以注意加工障碍为特征的神经精神障碍的病因和潜在的治疗方法是至关重要的。

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.