title: Sleep disorders in Parkinsonian macaques: effects of L-dopa treatment and pedunculopontine nucleus lesion.
abstract: Patients with Parkinson's disease (PD) display significant sleep disturbances and daytime sleepiness. Dopaminergic treatment dramatically improves PD motor symptoms, but its action on sleep remains controversial, suggesting a causal role of nondopaminergic lesions in these symptoms. Because the pedunculopontine nucleus (PPN) regulates sleep and arousal, and in view of the loss of its cholinergic neurons in PD, the PPN could be involved in these sleep disorders. The aims of this study were as follows: (1) to characterize sleep disorders in a monkey model of PD; (2) to investigate whether l-dopa treatment alleviates sleep disorders; and (3) to determine whether a cholinergic PPN lesion would add specific sleep alterations. To this end, long-term continuous electroencephalographic monitoring of vigilance states was performed in macaques, using an implanted miniaturized telemetry device. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment induced sleep disorders that comprised sleep episodes during daytime and sleep fragmentation and a reduction of sleep efficiency at nighttime. It also induced a reduction in time spent in rapid eye movement (REM) sleep and slow-wave sleep and an increase in muscle tone during REM and non-REM sleep episodes and in the number of awakenings and movements. l-Dopa treatment resulted in a partial but significant improvement of almost all sleep parameters. PPN lesion induced a transient decrease in REM sleep and in slow-wave sleep followed by a slight improvement of sleep quality. Our data demonstrate the efficacy of l-dopa treatment in improving sleep disorders in parkinsonian monkeys, and that adding a cholinergic PPN lesion improves sleep quality after transient sleep impairment.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche-S975, Université Pierre et Marie Curie Paris 06, Unité Mixte de Recherche-S975, CNRS Unité Mixte de Recherche 7225, and Centre de Recherche-Institut du Cerveau et de la Moelle, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France.
authors.forename: Hayat
authors.initials: H
authors.lastname: Belaid
authors.affiliation: Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche-S975, Université Pierre et Marie Curie Paris 06, Unité Mixte de Recherche-S975, CNRS Unité Mixte de Recherche 7225, and Centre de Recherche-Institut du Cerveau et de la Moelle, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France.
authors.forename: Joëlle
authors.initials: J
authors.lastname: Adrien
authors.affiliation: Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche-S975, Université Pierre et Marie Curie Paris 06, Unité Mixte de Recherche-S975, CNRS Unité Mixte de Recherche 7225, and Centre de Recherche-Institut du Cerveau et de la Moelle, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Laffrat
authors.affiliation: Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche-S975, Université Pierre et Marie Curie Paris 06, Unité Mixte de Recherche-S975, CNRS Unité Mixte de Recherche 7225, and Centre de Recherche-Institut du Cerveau et de la Moelle, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Tandé
authors.affiliation: Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche-S975, Université Pierre et Marie Curie Paris 06, Unité Mixte de Recherche-S975, CNRS Unité Mixte de Recherche 7225, and Centre de Recherche-Institut du Cerveau et de la Moelle, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France.
authors.forename: Carine
authors.initials: C
authors.lastname: Karachi
authors.affiliation: Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche-S975, Université Pierre et Marie Curie Paris 06, Unité Mixte de Recherche-S975, CNRS Unité Mixte de Recherche 7225, and Centre de Recherche-Institut du Cerveau et de la Moelle, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France.
authors.forename: David
authors.initials: D
authors.lastname: Grabli
authors.affiliation: Service des pathologies du sommeil, Assistance Publique-Hôpitaux de Paris, Groupe Pitié-Salpêtrière, 75013 Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Arnulf
authors.affiliation: Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, New York 14214, and.
authors.forename: Stewart D
authors.initials: SD
authors.lastname: Clark
authors.affiliation: Physiology Department, CHU de Poitiers, 8600 Poitiers, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Drouot
authors.affiliation: Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche-S975, Université Pierre et Marie Curie Paris 06, Unité Mixte de Recherche-S975, CNRS Unité Mixte de Recherche 7225, and Centre de Recherche-Institut du Cerveau et de la Moelle, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France.
authors.forename: Etienne C
authors.initials: EC
authors.lastname: Hirsch
authors.affiliation: Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche-S975, Université Pierre et Marie Curie Paris 06, Unité Mixte de Recherche-S975, CNRS Unité Mixte de Recherche 7225, and Centre de Recherche-Institut du Cerveau et de la Moelle, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France, chantal.francois@upmc.fr.
authors.forename: Chantal
authors.initials: C
authors.lastname: François
mesh_terms: D000818:Animals; D001545:Benserazide / Q000494:pharmacology / Q000627:therapeutic use; D059329:Cholinergic Neurons / Q000187:drug effects; D004167:Diphtheria Toxin / Q000235:genetics / Q000633:toxicity; D004338:Drug Combinations; D007980:Levodopa / Q000494:pharmacology / Q000627:therapeutic use*; D020267:MPTP Poisoning / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*; D008252:Macaca fascicularis; D008297:Male; D009129:Muscle Tonus / Q000187:drug effects / Q000502:physiology; D020734:Parkinsonian Disorders / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*; D045042:Pedunculopontine Tegmental Nucleus / Q000293:injuries / Q000503:physiopathology*; D017286:Polysomnography; D011993:Recombinant Fusion Proteins / Q000633:toxicity; D012892:Sleep Deprivation / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D020919:Sleep Disorders, Intrinsic / Q000188:drug therapy / Q000209:etiology* / Q000503:physiopathology; D012895:Sleep, REM / Q000187:drug effects / Q000502:physiology; D014579:Urotensins / Q000235:genetics; D014851:Wakefulness / Q000502:physiology
chemical_list: D004167:Diphtheria Toxin; D004338:Drug Combinations; D011993:Recombinant Fusion Proteins; D014579:Urotensins; C005177:benserazide, levodopa drug combination; D007980:Levodopa; D001545:Benserazide; C029677:urotensin II
keywords: Parkinson's disease; cholinergic neurons; l-dopa; macaques; pedunculopontine nucleus; sleep disorders