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

描述(申请人提供)：失眠是正常人群中最普遍的睡眠障碍，也是几种精神障碍的基本特征。失眠与白天嗜睡、疲劳、表现和记忆受损、认知和精神运动障碍以及焦虑和易怒增加有关。尽管对健康和生产力有有害的影响，但人们对这种睡眠障碍背后的基本神经机制知之甚少。目前治疗失眠的方法针对的是症状，而不是这些症状背后的病理生理变化，这些治疗方法与不良副作用以及滥用和依赖的高风险有关。此外，目前的治疗方法大幅减少了REM睡眠，无法恢复正常睡眠。因此，开发更有针对性的治疗失眠的药物疗法是当务之急。失眠是由易感个体的应激性生活事件引发的，一般来说，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)是一种信号分子，在外周和中枢都有发现。外周血管紧张素转换酶因其在心血管调节中的作用而广为人知，阻断血管紧张素转换酶信号的药物经常用于治疗心血管疾病。最近的研究表明，大脑血管紧张素Ⅱ参与了应激反应的调节。中枢血管紧张素Ⅱ和血管紧张素ⅡAT1受体的表达在应激过程中增加，进而激活交感肾上腺和神经内分泌系统。这些作用可被血管紧张素转换酶拮抗剂阻断，或被血管紧张素转换酶中央管理系统模拟。已经在参与应激反应的脑区发现了血管紧张素Ⅱ受体，这表明血管紧张素Ⅱ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，在心理情绪应激期间，脑血管紧张素主要参与心血管唤醒的调节。我们建立了一种应激性失眠的大鼠模型，并表征了失眠期间激活的神经解剖回路。我们发现，由昼夜节律和体内平衡驱动的促进睡眠的区域，以及由于情绪压力而产生的边缘和唤醒(觉醒)系统同时激活。因此，在失眠期间，边缘系统(参与情绪处理)被激活，进而激活部分唤醒系统，随后激活大脑皮层，导致在这种疾病中观察到的睡眠障碍。失眠时激活的相关边缘结构表达高水平的血管紧张素ⅡAT1受体。我们的假设是，给予血管紧张素转换酶1拮抗剂将抑制这些边缘群，随后抑制下游回路(唤醒系统和皮质)，减弱应激对睡眠的影响，帮助恢复正常睡眠。这项建议的目的是通过在我们的应激诱导失眠模型中测试血管紧张素转换酶拮抗剂坎地沙坦来评估这一假说，这对于首次筛选具有潜在抗失眠特性的化合物是有用的。我们的目标是找到一种治疗失眠的药物疗法，通过作用于更特定的大脑靶点，恢复自然睡眠并将副作用降至最低。 与公共健康相关：失眠是最普遍的睡眠障碍，由压力引起。目前的药物治疗都是非特异性的，并且会引起不良的副作用。这项建议的目的是测试一种血管紧张素II拮抗剂，它已知具有强大的抗应激作用，可以改善在失眠大鼠模型中观察到的睡眠障碍。

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. PUBLIC HEALTH RELEVANCE: Insomnia, the most prevalent sleep disorder, is induced by stress. Current pharmacologic treatments are unspecific and cause undesirable side-effects. The aim of this proposal is to test an angiotensin II antagonist, known to exert a potent anti-stress effect, in ameliorating the sleep disturbances observed in a rat model of insomnia.