Hypocretin, Histamine and the Restless Legs Syndrome

描述(申请人提供)：不宁腿综合症(RLS)是一种常见的感觉-运动障碍，其症状主要在夜间，经常导致严重的睡眠不足和生活质量的改变。睡眠和清醒之间的休息和转换会加剧RLS症状。因此，警觉活动减少，而昏昏欲睡的活动会加剧症状。然而，苯二氮卓类等镇静药物似乎并不会加剧这种疾病。即使是中度严重的RLS也会严重干扰睡眠，将睡眠时间减少到5-6个小时或更少。患者报告了一些白天在警觉性和认知清晰度方面的问题，但尽管睡眠时间减少了，但未经治疗的患者并没有描述在如此有限的睡眠时间表上维持的正常受试者发生的深度嗜睡。显然，有某种警报机制可以部分补偿睡眠不足。 我们最近的工作发现，在目前未接受治疗的RLS患者中，夜间脑脊液中下丘脑-食欲素(Hcrt)的值升高。HCRT在发作性睡病患者中几乎不存在，它至少部分通过组胺系统的刺激作用来维持清醒。几名接受多巴胺药物治疗的RLS患者报告了一些他们以前没有经历过的嗜睡问题，还有几名患者还报告说，通过镇静抗组胺药物，RLS症状明显恶化。我们已经提出，HCRT和组胺系统的激活可以减轻一些RLS患者的RLS症状。DA治疗可能会减少这一系统的激活益处，使患者容易困倦，但也可能通过抗组胺药物进一步减少这一系统而进一步加剧症状。因此，在这个模型中，接受DA治疗的患者夜间Hcrt水平将较低，抗组胺挑战提供了一种测试，以区分患有这一方面的RLS的患者，在我们之前的工作中确定为家族性早发性RLS的患者。因此，抗组胺挑战可能为鉴别RLS的类型提供一种新的技术，可能有助于RLS的诊断，并开辟RLS研究的新领域。这种方法也可以推广到其他与DA相关的情况，包括DA治疗中的嗜睡。本项目旨在确定RLS患者在接受DA治疗时夜间脑脊液下丘脑分泌素是否较低，并探索用于检测RLS患者的抗组胺挑战的发展和评估。

DESCRIPTION (provided by applicant): Restless Legs Syndrome (RLS) is a common sensory-motor disorders whose symptoms predominant at night and often lead to significant sleep loss and changes in one's quality of life. Rest and transiting between sleep and wake exacerbates RLS symptoms. Accordingly, alerting activities reduce while soporific ones exacerbate the symptoms. Sedating medications such as benzodiazepines, however, do not appear to exacerbate the disorder. RLS when even moderately severe profoundly disturbs sleep, reducing sleep times to 5-6 hours or less. Patients report some daytime problems with alertness and cognitive clarity but despite this reduction in sleep times untreated patients do not describe profound episodes of sleepiness that occur for normal subjects maintained on such restricted sleep schedules. There is apparently some alerting mechanism partially compensating for the sleep loss. Our recent work has found that nocturnal CSF values of hypocretin/orexin (Hcrt) are elevated in RLS patients not currently on treatment. Hcrt is almost absent in narcoleptics and serves to maintain wakefulness operating at least in part through the stimulating aspects of the histamine system. Several RLS patients on treatment with dopamine agents report some problems with sleepiness they had not previously experienced and several also report marked exacerbation of RLS symptoms by sedating anti-histamines. We have proposed that the Hcrt and histamine system activation reduces RLS symptoms for some RLS patients. DA treatment may reduce the activating benefit from this system leaving the patient vulnerable to sleepiness but also to further exacerbation of the symptoms by further reduction in this system by an anti-histamine medication. Thus, in this model, nocturnal Hcrt levels will be less for DA treated patients and anti-histamine challenge provides a test discriminating those patients who have this aspect of RLS, identified in our prior work as those with the familial early-onset form of RLS. The anti-histamine challenge may therefore provide a new technique for discriminating types of RLS, possibly aiding in the diagnosis of RLS and opening up a new area of RLS research. The approach may also be extended to other DA related conditions involving sleepiness with DA treatment. This project seeks to determine if the nocturnal CSF hypocretin of RLS patients is lower when on DA treatment and to explore the development and evaluation of anti-histamine challenge for testing RLS patients.