Sleepiness in Parkinson's Disease

描述(申请人提供)：据估计，高达50%的帕金森病(PD)患者患有日间过度嗜睡(EDS)。帕金森病是一种慢性进行性神经退行性疾病，通常会损害运动技能(肌肉僵硬、震颤和运动迟缓)。此外，睡眠发作(SA)的突然发作(无前驱症状的睡眠发作)出现在帕金森病患者中，这种症状更常发生在服用多巴胺D2/3激动剂的患者中。人们对帕金森病的运动障碍给予了相当大的关注，而对无法抗拒的日间嗜睡却很少关注。尽管这些睡眠症状也会显著影响患者的生活质量或威胁到他们的健康 目前的研究并不集中在这些症状上，涉及EDS/SA的病理机制尚不清楚。考虑到帕金森病患者多巴胺能传递受损，D2/3激动剂引发睡眠症状，再加上大多数促醒化合物增强多巴胺能神经传递，D2/3自身受体介导的抑制性多巴胺能神经传递可能在帕金森病EDS/SA中起关键作用。在这项建议中，我们将使用新的PD遗传小鼠模型(即Mitopark小鼠)，通过系统地评估正常和Mitopark PD小鼠服用D2/3激动剂前后的睡眠行为和监测多巴胺释放，剖析PD患者EDS和多巴胺激动剂诱导SA的机制。这项研究的结果将确定导致D2/3激动剂引起帕金森病病理性嗜睡的主要因素(S)，并证明在预防/治疗这种危及生命的致残性疾病方面具有参考价值。

DESCRIPTION (provided by applicant): It is estimated that up to 50% of patients with Parkinson's disease (PD), a chronically progressive neurodegenerative disease that often impairs motor skills (muscle rigidity, tremor and bradykinesia), have suffered from excessive daytime sleepiness (EDS). In addition, sudden onsets of sleep attacks (SA) (sleep episodes without prodroma) appear in PD, with this symptom occurring more often in those patients who intake dopamine D2/3 agonists. Considerable attention has been devoted to the movement impairments in PD, while little attention has been paid to irresistible daytime sleepiness. Although these sleep symptoms also significantly affect patients' quality of life or threaten their lives (i.e., car accidents), current research does not focus on these symptoms, and the pathological mechanism involved in EDS/SA is unknown. Considering that dopaminergic transmission is impaired and D2/3 agonists trigger sleep symptoms in PD patients, combined with the fact that most wake- promoting compounds enhance dopaminergic neurotransmission, the D2/3 autoreceptor-mediated inhibitory dopaminergic neurotransmission likely plays a key role in EDS/SA in PD. In this proposal, we will dissect mechanisms responsible for EDS and dopamine agonist-induced SA in PD patients using the new genetic mouse model of PD (i.e., Mitopark mouse) by systematic evaluations of sleep behavior and monitoring of dopamine release before and after administration of D2/3 agonists in normal and Mitopark PD mice. The results of the study will determine the major factor(s) contributing to the D2/3 agonist induced pathological sleepiness in PD, and prove informative in preventing/treating this life-threatening, disabling disease.