title: Catechol-O-methyltransferase, dopamine, and sleep-wake regulation.
abstract: Sleep and sleep disorders are complex and highly variable phenotypes regulated by many genes and environment. The catechol-O-methyltransferase (COMT) gene is an interesting candidate, being one of the major mammalian enzymes involved in the catabolism of catecholamines. The activity of COMT enzyme is genetically polymorphic due to a guanine-to-adenine transition at codon 158, resulting in a valine (Val) to methionine (Met) substitution. Individuals homozygous for the Val allele show higher COMT activity, and lower dopaminergic signaling in prefrontal cortex (PFC) than subjects homozygous for the Met allele. Since COMT has a crucial role in metabolising dopamine, it was suggested that the common functional polymorphism in the COMT gene impacts on cognitive function related to PFC, sleep-wake regulation, and potentially on sleep pathologies. The COMT Val158Met polymorphism may predict inter-individual differences in brain electroencephalography (EEG) alpha oscillations and recovery processes resulting from partial sleep loss in healthy individuals. The Val158Met polymorphism also exerts a sexual dimorphism and has a strong effect on objective daytime sleepiness in patients with narcolepsy-cataplexy. Since the COMT enzyme inactivates catecholamines, it was hypothesized that the response to stimulant drugs differs between COMT genotypes. Modafinil maintained executive functioning performance and vigilant attention throughout sleep deprivation in subjects with Val/Val genotype, but less in those with Met/Met genotype. Also, homozygous Met/Met patients with narcolepsy responded to lower doses of modafinil compared to Val/Val carriers. We review here the critical role of the common functional COMT gene polymorphism, COMT enzyme activity, and the prefrontal dopamine levels in the regulation of sleep and wakefulness in normal subjects, in narcolepsy and other sleep-related disorders, and its impact on the response to psychostimulants.
authors.affiliation: Centre de Référence Nationale Maladies Rares, Narcolepsie et Hypersomnie Idiopathique, Service Neurologie, Hôpital Gui-de-Chauliac, INSERM U1061, Montpellier, France. Electronic address: ydauvilliers@yahoo.fr.
authors.forename: Yves
authors.initials: Y
authors.lastname: Dauvilliers
authors.affiliation: Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland; Center for Investigation and Research in Sleep, Vaud University Hospital (CHUV), Lausanne, Switzerland.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Tafti
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zürich, Zürich, Switzerland; Zürich Center for Interdisciplinary Sleep Research, University of Zürich, Zürich, Switzerland.
authors.forename: Hans Peter
authors.initials: HP
authors.lastname: Landolt
mesh_terms: D001143:Arousal / Q000502:physiology*; D002394:Catechol O-Methyltransferase / Q000235:genetics / Q000502:physiology*; D004298:Dopamine / Q000502:physiology*; D005625:Frontal Lobe / Q000201:enzymology / Q000502:physiology; D006801:Humans; D009290:Narcolepsy / Q000201:enzymology / Q000209:etiology; D012890:Sleep / Q000502:physiology*; D012893:Sleep Wake Disorders / Q000201:enzymology / Q000209:etiology
chemical_list: C588010:COMT protein, human; D002394:Catechol O-Methyltransferase; D004298:Dopamine
keywords: Catechol-O-methyltransferase; Catecholamines; Dopamine; Genetics; Narcolepsy; Performance; Pharmacogenetic; Prefrontal; Vigilance