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.
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.
