The Orexin System as a Target for PTSD and Comorbid Psychosis

项目概要/摘要： 精神病性症状在PTSD患者中非常普遍，通常用多巴胺D2受体治疗 拮抗剂;然而，这些药物与显著的副作用相关。我们有新的初步证据 证明丘脑室旁核（PVT）调节多巴胺神经元活性的数据。 因此，我们认为PVT代表了治疗PTSD的潜在治疗靶点， 共病精神病PVT接受特别密集的神经支配，来自中枢神经系统中含有食欲素的神经元。 下丘脑因此，食欲素系统被很好地定位以调节PVT活性，并且可能是治疗PVT的新靶点。 药物干预一种这样的药物，Suvorexant，一种食欲素受体拮抗剂，目前是FDA- 被批准用于治疗失眠我们将检验苏沃雷生可以逆转以下缺陷的假设： 表现出与共病精神病相关的回路水平改变和相应行为缺陷的啮齿动物 创伤后应激障碍具体来说，我们将研究食欲素受体拮抗剂是否可以逆转应激诱导的 行为（目标1）或神经生理/神经化学（目标2）缺陷与PTSD。然后我们将 确定在共病精神病中离散的PVT投射到脑桥核的作用（目的3）。这 因此，该建议确定了一个潜在的新的治疗靶点，并告知开发更有效的 创伤后应激障碍和共病精神病的治疗方法。

Project Summary/Abstract: Psychotic symptoms are highly prevalent in PTSD patients and are typically treated with dopamine D2 receptor antagonists; however, these drugs are associated with significant adverse effects. We have novel preliminary data demonstrating that the paraventricular nucleus of the thalamus (PVT) regulates dopamine neuron activity. We posit that the PVT therefore represents a potential therapeutic target for the treatment of PTSD as well as comorbid psychosis. The PVT receives a particularly dense innervation from orexin containing neurons in the hypothalamus. Thus, the orexin system is well positioned to regulate PVT activity and may be a novel target for pharmacological intervention. One such drug, Suvorexant, an orexin receptor antagonist, is currently FDA- approved for the treatment of insomnia. We will test the hypothesis that Suvorexant can reverse deficits in rodents displaying circuit level alterations and corresponding behavioral deficits relevant to comorbid psychosis in PTSD. Specifically, we will examine whether orexin receptor antagonists can reverse stress-induced behavioral (Aim 1) or neurophysiological/neurochemical (Aim 2) deficits associated with PTSD. We will then determine the role of discrete PVT projections to the nucleus accumbens in comorbid psychosis (Aim 3). This proposal with therefore identify a potential novel therapeutic target and inform the development of more effective treatment approaches for PTSD and comorbid psychosis.