Hypocretin, Histamine and the Restless Legs Syndrome

描述（由申请人提供）：不宁腿综合征（RLS）是一种常见的感觉运动障碍，其症状主要发生在夜间，通常导致严重的睡眠丧失和生活质量的变化。休息和睡眠与清醒之间的过渡会加重RLS症状。因此，警觉活动减少，而催眠活动加剧症状。然而，镇静药物如苯二氮卓类药物似乎不会加重这种疾病。RLS，即使是中度严重时，也会严重干扰睡眠，使睡眠时间减少到5-6小时或更少。患者报告了一些白天的警觉性和认知清晰度问题，但尽管睡眠时间减少，未经治疗的患者并没有描述维持这种限制性睡眠时间表的正常受试者发生的严重嗜睡事件。很明显，有某种警报机制部分补偿了睡眠的损失。 我们最近的研究发现，夜间脑脊液下丘脑分泌素/食欲素（Hcrt）值升高RLS患者目前没有治疗。Hcrt在发作性睡病患者中几乎不存在，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，几名患者还报告了镇静抗组胺药导致的RLS症状明显加重。我们提出，Hcrt和组胺系统激活减少某些RLS患者的RLS症状。DA治疗可能会减少该系统的激活益处，使患者容易嗜睡，但也会因抗组胺药物进一步减少该系统而使症状进一步恶化。因此，在该模型中，DA治疗的患者的夜间Hcrt水平将较低，抗组胺激发提供了一种区分具有RLS这一方面的患者的测试，在我们先前的工作中鉴定为具有家族性早发性形式的RLS的患者。因此，抗组胺激发可能提供一种新的技术来区分类型的RLS，可能有助于RLS的诊断和开辟一个新的领域的RLS的研究。该方法也可以扩展到其他DA相关的疾病，包括DA治疗的嗜睡。本项目旨在确定RLS患者在DA治疗时夜间CSF下丘脑泌素是否较低，并探索用于测试RLS患者的抗组胺激发的开发和评价。

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.