The Orexin System as a Target for PTSD and Comorbid Psychosis

项目摘要/摘要： 精神症状在PTSD患者中非常普遍，通常使用多巴胺D2受体进行治疗 拮抗剂；然而，这些药物与严重的不良反应有关。我们有新奇的初稿 资料显示，丘脑室旁核(PVT)调节多巴胺神经元的活动。 因此，我们假设PVT是治疗创伤后应激障碍的潜在治疗靶点。 共病精神病。下丘脑室旁核接受来自下丘脑室旁核中含有食欲素的神经元的特别密集的神经支配。 下丘脑。因此，增食欲素系统很好地调节PVT的活性，并可能成为一个新的靶点 药物干预。其中一种药物Suvorexant是一种食欲素受体拮抗剂，目前正在FDA- 被批准用于治疗失眠。我们将测试Suvorexant可以逆转赤字的假设 表现出与共病精神病相关的电路水平改变和相应的行为缺陷的啮齿动物 患有创伤后应激障碍。具体地说，我们将研究增食欲素受体拮抗剂是否可以逆转应激诱导的 与创伤后应激障碍相关的行为(目标1)或神经生理/神经化学(目标2)缺陷。到时候我们会的 确定孤立性PVT投射到伏隔核在并发精神病中的作用(目标3)。这 因此，建议确定潜在的新治疗靶点，并为更有效的开发提供信息 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.