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.
It is estimated that up to 50% of patients with Parkinson's disease (PD) have suffered from excessive daytime sleepiness (EDS). In addition, sudden onsets of sleep attacks (SA), (which are sleep episodes without prodroma) occur in PD, and the PD patients who intake dopamine D2/3 agonists more often exhibit this disabling symptom. Systematic evaluations of sleep behavior and monitoring of dopamine release before and after administration of D2/3 agonists in a normal and a genetic mouse model of PD will be performed in order to evaluate if altered D2/D3 receptor sensitivity contributes to EDS/SA in PD.
| Sato, Masatoshi; Sagawa, Yohei; Hirai, Nobuhide et al. (2014) Noninvasive detection of sleep/wake changes and cataplexy-like behaviors in orexin/ataxin-3 transgenic narcoleptic mice across the disease onset. Exp Neurol 261:744-51 |
