Elsevier

Sleep Medicine Reviews

Volume 17, Issue 5, October 2013, Pages 367-375
Sleep Medicine Reviews

Clinical review
Sleep disturbances in Parkinson's disease: The contribution of dopamine in REM sleep regulation

https://doi.org/10.1016/j.smrv.2012.10.006Get rights and content

Summary

Nearly all patients with Parkinson's disease (PD) have sleep disturbances. While it has been suggested that these disturbances involve a dopaminergic component, the specific mechanisms that contribute to this behavior are far from being fully understood. In this article, we have reviewed the current understanding of the linkage between sleep and PD, focusing on the participation of the dopaminergic system in the regulation of rapid eye movement (REM) sleep. The presence of an REM sleep behavior disorder in patients with PD might reflect the early involvement of dopaminergic neurotransmission in REM sleep-related structures. Therefore, it has been suggested that these structures are affected by an imbalance of dopamine levels. Several studies have demonstrated that neurons in the substantia nigra pars compacta (SNpc) and in the ventral tegmental area (VTA) are active during REM sleep and that sleep-related disturbances may result when these neurons are targeted by neurotoxins. We discuss current evidence suggesting the presence of a putative reciprocal connectivity between the SNpc, VTA, the pedunculopontine tegmental nucleus and reticular formation, which may exert an important influence on the REM sleep mechanism. This review provides a comprehensive overview of the literature that addresses this challenging and unrecognized component of PD.

Introduction

Parkinson's disease (PD) is the second most common neurodegenerative disease, afflicting about 1% of people over 65 y old and 4–5% of people over 85 y old.1, 2 At presentation, the major clinical features include the asymmetric onset of bradykinesia, rigidity, rest tremor and disturbances in balance. While sleep disturbances have only recently been recognized in PD and other movement disorders, such frequent afflictions were originally reported in James Parkinson's initial description of the disorder: “…the sleep becomes much disturbed. The tremulous motion of the limbs occurs during sleep, and augments until they awaken the patient, and frequently with much agitation and alarm”.3 These sleep disturbances primarily include insomnia, abnormal movements during sleep (e.g., periodic limb movements [PLM], rapid eye movement [REM] sleep behavior disorder [RBD]) and excessive daytime sleepiness.4 These disturbances have an important impact on the patient's quality of life, increasing the risk of self or bed-partner injuries (due to RBD/PLM) and/or the risk of driving or machinery accidents (due to the excessive daytime sleepiness). They may precede the cardinal motor features of the disease by many years, and therefore may serve as early biomarkers of the premotor phase of PD.5, 6

The specific mechanisms of these sleep disturbances are far from being fully understood, but they do include an apparent dopaminergic component that is still discussed in the literature. Due to the multiple variables (e.g., age, medication, depression, anxiety, cognitive decline, etc.) in PD, it is difficult to attribute the sleep disturbances exclusively to the degeneration of nigrostriatal dopaminergic neurons. Therefore, animal models may improve our knowledge of both the physiopathology of sleep alterations in PD in general and of the role of dopaminergic lesions in particular.

In recent years, most relevant published articles have narrowly focused on findings that contest the hypothesis that dopaminergic neurons of the substantia nigra pars compacta (SNpc) and of the ventral tegmental area (VTA) do not display robust alterations in firing rate across sleep-wake states.7, 8, 9 It was demonstrated that dopamine (DA)-containing neurons exhibit enhanced activity in bursts of spikes associated with REM sleep.10 Despite the supposed static firing rate of dopaminergic neurons throughout sleep-wake states, extracellular concentrations of DA in the striatum and prefrontal cortex are significantly elevated during periods of wakefulness.11 Another study has demonstrated the existence of changes in DA release in both the medial prefrontal cortex and the nucleus accumbens as a function of sleep-wake state in rats.12 The authors hypothesized that during REM sleep, the elevated levels of DA observed in the medial prefrontal cortex and in the nucleus accumbens could contribute to the specific cognitive processes that take place during this state. In light of these results, several other studies have provided useful information about the participation of DA in sleep regulation and the associated implications in PD.

In this article, we will review current evidence addressing the dopaminergic link between sleep and PD, focusing most closely on those studies that explore the mechanisms by which PD and sleep may be intertwined, whether as predictors or consequences of dopaminergic neurodegeneration. A comprehensive understanding and overview of the relationship between sleep regulation and PD is needed to guide future research in the field as well as facilitate the clinical management of the disease.

Section snippets

Procedure

To identify potential studies of interest, literature searches were performed using the electronic database SCOPUS, covering all publications from January 2000 up to (and including) January 2012. The search terms, employed either isolated or in combination (with the operator AND), were as follows: “sleep”, “Parkinson's disease”, “dopamine” and “substantia nigra pars compacta.” We included studies that (i) reported original data; (ii) reported empirical data, including review articles; (iii)

Sleep disturbances in PD

Nearly all patients with PD have sleep disturbances, and studies show that this pattern usually emerges early in the disease course.13, 14, 15 The causes of sleep disturbances are multifactorial, but the pathological degeneration of classical sleep regulation centers in the brainstem and thalamocortical pathways is likely to be an important factor. Sleep disturbances are secondarily promoted by nocturnal manifestations of the disease and by the side effects of pharmacological treatment. Lastly,

The prototypical stages of degeneration

Typically, PD is the result of the degeneration of neurons in the SNpc, which leads to the subsequent reduction of dopaminergic input to the striatum. Moreover, there is a degeneration of neurons of selected brainstem nuclei (LC, raphe nuclei, dorsal motor nucleus of the vagus), cortical neurons (particularly within the cingulated gyrus and the entorhinal cortex), the nucleus basalis of Meynert and of preganglionic sympathetic and parasympathetic neurons. In the soma of these neurons, the

A proposal for dopaminergic control of REM sleep

Episodes of excessive daytime somnolence after MPTP injections in monkeys have been anecdotally reported as a prominent feature of parkinsonism.50, 59 The first report to provide evidence of sleep disruption by MPTP demonstrated a selective REM sleep suppression that lasted 6–9 d after the last dose of the neurotoxin in cats.60 Almost one decade later, additional studies have elucidated different details on this topic. Almirall and colleagues demonstrated a strong relationship between motor

Conclusions

A substantial portion of the literature now links perturbations in the dopaminergic system with the sleep disturbances observed in PD. Although many questions remain, evidence suggests that SNpc and VTA may largely account for the well-documented association between sleep disturbances and PD. More recently, several reports have employed experimental models of PD in which neurochemical and electrophysiological data are quantified. These studies reinforce the hypothesis that the PPT and LDT,

Acknowledgments

This paper was supported by the CNPq Casadinho/Procad Grant No: 552226/2011-4. MMSL is recipient of Fundação Araucária - Governo do Estado do Paraná fellowship. The author has declared that no conflict of interests exists.

References (86)

  • J.C. Moller et al.

    Restless Legs Syndrome (RLS) and Parkinson's disease (PD)-related disorders or different entities?

    J Neurol Sci

    (2010)
  • M. Angelini et al.

    A study of the prevalence of restless legs syndrome in previously untreated Parkinson's disease patients: absence of co-morbid association

    J Neurol Sci

    (2011)
  • A. Iranzo et al.

    Rapid-eye-movement sleep behaviour disorder as an early marker for a neurodegenerative disorder: a descriptive study

    Lancet Neurol

    (2006)
  • J.F. Gagnon et al.

    Rapid-eye-movement sleep behaviour disorder and neurodegenerative diseases

    Lancet Neurol

    (2006)
  • A. Iranzo

    Sleep-wake changes in the premotor stage of Parkinson disease

    J Neurol Sci

    (2011)
  • L.T. Grinberg et al.

    Brainstem pathology and non-motor symptoms in PD

    J Neurol Sci

    (2010)
  • H. Braak et al.

    Staging of brain pathology related to sporadic Parkinson's disease

    Neurobiol Aging

    (2003)
  • K. Pungor et al.

    A novel effect of MPTP: the selective suppression of paradoxical sleep in cats

    Brain Res

    (1990)
  • H. Almirall et al.

    Ultradian and circadian body temperature and activity rhythms in chronic MPTP treated monkeys

    Neurophysiol Clin

    (2001)
  • C. Laloux et al.

    The effects of serotoninergic, noradrenergic, cholinergic and dopaminergic drugs on vigilance states in MPTP-treated mice

    Brain Res

    (2007)
  • M.M.S. Lima et al.

    Blockage of dopaminergic D(2) receptors produces decrease of REM but not of slow wave sleep in rats after REM sleep deprivation

    Behav Brain Res

    (2008)
  • F. Garcia-Garcia et al.

    Sleep disturbances in the rotenone animal model of Parkinson disease

    Brain Res

    (2005)
  • Q. Barraud et al.

    Sleep disorders in Parkinson's disease: the contribution of the MPTP non-human primate model

    Exp Neurol

    (2009)
  • O. Marin et al.

    Evolution of the basal ganglia in tetrapods: a new perspective based on recent studies in amphibians

    Trends Neurosci

    (1998)
  • P. Winn

    Frontal syndrome as a consequence of lesions in the pedunculopontine tegmental nucleus: a short theoretical review

    Brain Res Bull

    (1998)
  • M.M.S. Lima et al.

    The dopaminergic dilema: sleep or wake? implications in Parkinson's disease

    Biosci Hypothesis

    (2008)
  • J.D. Carlson et al.

    Regional metabolic changes in the pedunculopontine nucleus of unilateral 6-hydroxydopamine Parkinson's model rats

    Brain Res

    (1999)
  • G. Orieux et al.

    Metabolic activity of excitatory parafascicular and pedunculopontine inputs to the subthalamic nucleus in a rat model of Parkinson's disease

    Neuroscience

    (2000)
  • Q.J. Zhang et al.

    The firing activity of presumed cholinergic and non-cholinergic neurons of the pedunculopontine nucleus in 6-hydroxydopamine-lesioned rats: an in vivo electrophysiological study

    Brain Res

    (2008)
  • R.D. Oades et al.

    Ventral tegmental (A10) system: neurobiology. 1. Anatomy and connectivity

    Brain Res

    (1987)
  • J. Mena-Segovia et al.

    Pedunculopontine nucleus and basal ganglia: distant relatives or part of the same family?

    Trends Neurosci

    (2004)
  • A.E. Lang et al.

    Parkinson's disease. First of two parts

    N Engl J Med

    (1998)
  • A.E. Lang et al.

    Parkinson's disease. Second of two parts

    N Engl J Med

    (1998)
  • J. Parkinson
  • V.C. De Cock et al.

    Sleep disturbances in patients with parkinsonism

    Nat Clin Pract Neurol

    (2008)
  • R.D. Abbott et al.

    Excessive daytime sleepiness and subsequent development of Parkinson disease

    Neurology

    (2005)
  • K.J. Maloney et al.

    c-Fos expression in dopaminergic and GABAergic neurons of the ventral mesencephalic tegmentum after paradoxical sleep deprivation and recovery

    Eur J Neurosci

    (2002)
  • I. Lena et al.

    Variations in extracellular levels of dopamine, noradrenaline, glutamate, and aspartate across the sleep–wake cycle in the medial prefrontal cortex and nucleus accumbens of freely moving rats

    J Neurosci Res

    (2005)
  • A.J. Lees et al.

    The nighttime problems of Parkinson's disease

    Clin Neuropharmacol

    (1988)
  • P.A. Nausieda et al.

    Sleep disruption in the course of chronic levodopa therapy: an early feature of the levodopa psychosis

    Clin Neuropharmacol

    (1982)
  • E. Tandberg et al.

    A community-based study of sleep disorders in patients with Parkinson's disease

    Mov Disord

    (1998)
  • V. Dhawan et al.

    Sleep-related problems of Parkinson's disease

    Age Ageing

    (2006)
  • S.A. Factor et al.

    Sleep disorders and sleep effect in Parkinson's disease

    Mov Disord

    (1990)
  • Cited by (83)

    • Medications that disrupt sleep

      2023, Encyclopedia of Sleep and Circadian Rhythms: Volume 1-6, Second Edition
    • Baicalein alleviates depression-like behavior in rotenone- induced Parkinson's disease model in mice through activating the BDNF/TrkB/CREB pathway

      2021, Biomedicine and Pharmacotherapy
      Citation Excerpt :

      The classical hallmarks of PD include progressive degeneration of dopaminergic neurons in substantia nigra and appearance of Lewy bodies in survival neurons [1–4]. In addition to motor symptoms, PD patients clinically manifest with a variety of non-motor symptoms, such as gastrointestinal discomfort, cognitive deficits, sleep disturbances, and affective disorders [5–7]. Depression is one of the most common psychiatric comorbidities [8,9].

    View all citing articles on Scopus

    This article is dedicated to my father Prof. João de Meira Santos Lima (in memoriam) who devoted his professional life to education, literature and poetry.

    The most important references are denoted by an asterisk.

    View full text