D1 receptor agonist improves sleep–wake parameters in experimental parkinsonism
Introduction
Sleep disturbances and excessive daytime sleepiness (EDS) are among the most frequent and disabling non-motor symptoms of Parkinson's disease (PD) (Ghorayeb et al., 2007). They negatively impact the quality of life of PD patients as well as that of their caregivers and in some cases even more than the motor symptoms of the disease. Excessive daytime sleepiness is multifactorial and is known to correlate both with PD severity (Ondo et al., 2001) and high daily levodopa-equivalent dosage (Ghorayeb et al., 2007). Drug-induced EDS is a particular problem as many dopamine agonists have EDS as an adverse effect (Knie et al., 2011), while rapid eye movement (REM) sleep alteration with recurrent vivid dreams is another complication of dopaminergic treatments (Pappert et al., 1999). This suggests that dopaminergic medication may be deleterious to sleep–wake cycle regulation and may make the global management of the motor and non-motor symptoms of PD more complex. Given the similarity between motor and non-motor clinical features of PD patients and that of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) macaque monkey (Barraud et al., 2009, Bezard et al., 2001), we assessed the effects of D1- and D2-like receptor agonists (SKF38393 and quinpirole, respectively) on the sleep–wake pattern of macaques rendered parkinsonian with MPTP. Long-term and continuous monitoring of sleep–wake parameters were determined using electroencephalogram (EEG), electrooculogram (EOG) and electromyogram (EMG) telemetry recordings in unrestrained animals (Barraud et al., 2009).
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Animals
Nine adult female macaque monkeys (3 Macaca mulatta, Bioprim, France and 6 Macaca fascicularis, Xierxin, China) were fed according to standard husbandry protocols and had ad libitum access to water. All experiments were performed in accordance with French (87–848, Ministère de l'Agriculture et de la Forêt) and European Communities Council Directive (2010/63/EU) guidelines for the care of laboratory animals and were approved by the Ethical Committee of University Bordeaux Segalen (CEEA50;
Results
MPTP injections progressively impaired motor behaviour with the occurrence of bradykinesia and rigidity reminiscent of parkinsonism, as previously described (Barraud et al., 2009, Bezard et al., 1997, Bezard et al., 2001). The remarkable baseline night-to-night consistency of sleep architecture (Fig. 2A) within each MPTP-injected animal was markedly disrupted the night after the first MPTP administration (Fig. 2B) and before the occurrence of any motor symptoms of parkinsonism (Barraud et al.,
Discussion
The present study demonstrates a clear dichotomy between the pharmacological effects of selective dopamine agonists on sleep–wake parameters in MPTP-intoxicated animals. While acute quinpirole challenges had no effect either on EDS or on REM sleep percentages compared to both acute and chronic parkinsonian conditions, both parameters were improved by the D1 agonist SKF38393 in the MPTP macaque model of PD.
The MPTP-intoxicated non-human primate replicates most of the essential motor symptoms
Conclusion
This pioneering study highlights the differential role of D2/D3 and D1 dopamine receptors in worsening or improving respectively the wake–sleep parameters in parkinsonism. Given the beneficial effects of the long-term administration of D2/D3 dopamine agonists on the motor symptoms of PD, our study emphasizes the fact that sleep-related disorders in PD should be considered in therapeutic approaches for improving the management of the disease.
Acknowledgments
Dr. Imad Ghorayeb received unrestricted research donations from the French Association of Willis Ekbom disease (AFE). We thank Dr. Li Qin, Li Hao, Tho Hai Nguyen and, Hugues Orignac from the Bordeaux primate facility for the technical assistance and animal care.
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2017, Experimental NeurologyCitation Excerpt :In modelling both cognitive deficits and subtle motor dysfunction in MPTP-treated nhps, the translational value allows for tests of single or combined drug treatment strategies that produce the most desired clinical outcome among the myriad of disease symptoms (Ko et al., 2016). Sleep disturbances seen in PD patients such as rapid eye movement sleep behaviour disorder (Postuma et al., 2009) can also be evaluated in MPTP-treated monkeys using continuous electroencephalography, which has been used to assess the effects of different pharmacological treatments on sleep disturbances (Barraud et al., 2009; Hyacinthe et al., 2014). While MPTP administration causes severe loss of dopaminergic neurons in the SNc, there is also a broad neurotoxic effect with loss of extra-nigral dopaminergic, serotoninergic and adrenergic neurons (Forno et al., 1986; Mitchell et al., 1985; Perez-Otano et al., 1991).
- 1
The authors equally contributed.
- 2
Present address: Center for Neuroprosthetics and Brain Mind Institute, Swiss Federal Institute of Technology (EPFL), 1015 Lausanne, EPFL SV BMI — station 19, Switzerland.