Effects of an angiotensin ll antagonist in a rat model of insomnia

描述（由申请人提供）：失眠是正常人群中最普遍的睡眠障碍，也是几种精神疾病的主要特征。失眠与白天嗜睡、疲劳、表现和记忆受损、认知和精神运动缺陷以及焦虑和易怒增加有关。尽管对健康和工作效率有有害影响，但人们对这种睡眠障碍背后的基本神经机制知之甚少。目前的失眠治疗针对的是症状，而不是导致这些症状的病理生理改变，这些治疗与不良副作用以及滥用和依赖的高风险有关。此外，目前的治疗方法大大减少了快速眼动睡眠，并不能恢复正常的睡眠。因此，开发更具体的药物治疗失眠是当务之急。失眠是由易感个体的压力生活事件引发的，通常，失眠症患者表现出神经内分泌和交感肾上腺活动增加。血管紧张素II （AngII）是一种外周和中枢均存在的信号分子。外周AngII以其在心血管调节中的作用而闻名，阻断AngII信号的药物经常用于治疗心血管疾病。最近的研究表明，大脑AngII参与了应激反应的调节。应激时中枢AngII和AngII AT1受体表达增加，进而激活交感肾上腺和神经内分泌系统。这些作用可被AngII拮抗剂阻断或通过中枢AngII给药模拟。AngII受体已经在参与应激反应的大脑区域被发现，这表明AngII效应是通过直接激活这些神经元群而发生的。新出现的证据表明，大脑AngII主要参与心理情绪压力时心血管觉醒的调节。我们建立了应激性失眠大鼠模型，并对失眠期间激活的神经解剖回路进行了表征。我们发现，在昼夜节律和体内平衡驱动下，促进睡眠的区域同时被激活，而在情绪压力下，边缘和唤醒（觉醒）系统也同时被激活。因此，在失眠期间，边缘系统（涉及情绪处理）被激活，反过来，激活唤醒系统的一部分，随后激活大脑皮层，导致在这种疾病中观察到的睡眠障碍。失眠激活的相关边缘结构表达高水平的AngII AT1受体。我们的假设是，使用AngII AT1拮抗剂会抑制这些边缘群，随后抑制下游回路（唤醒系统和皮层），减轻压力对睡眠的影响，帮助恢复正常睡眠。这项提议的目的是通过测试坎地沙坦，一种AngII拮抗剂，在我们的应激性失眠模型中评估这一假设，这对于具有潜在抗失眠特性的化合物的首次筛选是有用的。我们的目标是找到一种药物治疗失眠症，恢复自然睡眠，并通过作用于更具体的大脑目标，最大限度地减少副作用。

DESCRIPTION (provided by applicant): Insomnia is the most prevalent sleep disorder in the normal population and it is also a cardinal feature of several psychiatric disorders. Insomnia is associated with daytime sleepiness, fatigue, impaired performance and memory, cognitive and psychomotor deficits, and increased anxiety and irritability. Despite the deleterious effects on health and productivity, little is known about the basic neural mechanisms underlying this sleep disorder. Current treatments for insomnia target the symptoms instead of the pathophysiologic alterations that underlie those symptoms, and these treatments are associated with undesirable side effects as well as high risk for abuse and dependence. In addition, current treatments decrease REM sleep substantially and do not restore normal sleep. Therefore, the development of more specific pharmacotherapy for the treatment of insomnia is a top priority. Insomnia is triggered by stressful life events in predisposed individuals and, in general, insomniacs show increased neuroendocrine and sympathoadrenal activity. Angiotensin II (AngII) is a signaling molecule found both peripherally and centrally. Peripheral AngII is well known for its role in cardiovascular regulation, and drugs that block AngII signaling are frequently used to treat cardiovascular disease. Recent work suggests that brain AngII is involved in the regulation of stress responses. Central AngII and AngII AT1 receptor expression increase during stress and, in turn, activate both the sympathoadrenal and neuroendocrine systems. These effects can be blocked by administration of AngII antagonists or mimicked by central AngII administration. AngII receptors have been identified in brain regions involved in stress responses, suggesting that AngII effect occurs via direct activation of these neuronal groups. Emerging evidence suggest that brain AngII is primarily involved in the regulation of cardiovascular arousal during psychoemotional stress. We developed a rat model of stress-induced insomnia in rats and characterized the neuroanatomical circuitry activated during insomnia. We found that there is simultaneous activation of the sleep-promoting areas, driven by the circadian and homeostatic drives, and the limbic and arousal (wake) systems due to the emotional stress. Thus, during insomnia, the limbic system (involved in emotional processing) becomes activated and, in turn, activates part of the arousal system, which subsequently activates the cerebral cortex, causing the sleep disturbances observed in this disorder. The relevant limbic structures activated in insomnia express high levels of AngII AT1 receptors. Our hypothesis is that administration of an AngII AT1 antagonist will inhibit these limbic groups and subsequently the downstream circuitry (arousal system and cortex), attenuating the effects of stress on sleep and helping to recover normal sleep. The aim of this proposal is to assess this hypothesis by testing candesartan, an AngII antagonist, in our stress-induced insomnia model, which is useful for first-pass screening of compounds with potential anti-insomnia properties. Our goal is to find a pharmacologic treatment for insomnia that restores natural sleep and minimizes side-effects by acting on more specific brain targets.