title: Functional Polymorphisms in Dopaminergic Genes Modulate Neurobehavioral and Neurophysiological Consequences of Sleep Deprivation.
abstract: Sleep deprivation impairs cognitive performance and reliably alters brain activation in wakefulness and sleep. Nevertheless, the molecular regulators of prolonged wakefulness remain poorly understood. Evidence from genetic, behavioral, pharmacologic and imaging studies suggest that dopaminergic signaling contributes to the behavioral and electroencephalographic (EEG) consequences of sleep loss, although direct human evidence thereof is missing. We tested whether dopamine neurotransmission regulate sustained attention and evolution of EEG power during prolonged wakefulness. Here, we studied the effects of functional genetic variation in the dopamine transporter (DAT1) and the dopamine D2receptor (DRD2) genes, on psychomotor performance and standardized waking EEG oscillations during 40 hours of wakefulness in 64 to 82 healthy volunteers. Sleep deprivation consistently enhanced sleepiness, lapses of attention and the theta-to-alpha power ratio (TAR) in the waking EEG. Importantly, DAT1 and DRD2 genotypes distinctly modulated sleep loss-induced changes in subjective sleepiness, PVT lapses and TAR, according to inverted U-shaped relationships. Together, the data suggest that genetically determined differences in DAT1 and DRD2 expression modulate functional consequences of sleep deprivation, supporting the hypothesis that striato-thalamo-cortical dopaminergic pathways modulate the neurobehavioral and neurophysiological consequences of sleep loss in humans.
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zürich, Zürich, Switzerland.|Zurich Center of Interdisciplinary Sleep Research, University of Zürich, Zürich, Switzerland.|Zurich Center for Integrative Human Physiology, University of Zürich, Zürich, Switzerland.
authors.forename: Sebastian C
authors.initials: SC
authors.lastname: Holst
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zürich, Zürich, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Müller
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zürich, Zürich, Switzerland.|Zurich Center of Interdisciplinary Sleep Research, University of Zürich, Zürich, Switzerland.|Zurich Center for Integrative Human Physiology, University of Zürich, Zürich, Switzerland.
authors.forename: Amandine
authors.initials: A
authors.lastname: Valomon
authors.affiliation: Institute of Medical Molecular Genetics, University of Zürich, Schlieren, Switzerland.|Zurich Center of Neuroscience (ZNZ), University of Zurich and Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland.
authors.forename: Britta
authors.initials: B
authors.lastname: Seebauer
authors.affiliation: Zurich Center for Integrative Human Physiology, University of Zürich, Zürich, Switzerland.|Institute of Medical Molecular Genetics, University of Zürich, Schlieren, Switzerland.|Zurich Center of Neuroscience (ZNZ), University of Zurich and Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Berger
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zürich, Zürich, Switzerland.|Zurich Center of Interdisciplinary Sleep Research, University of Zürich, Zürich, Switzerland.|Zurich Center for Integrative Human Physiology, University of Zürich, Zürich, Switzerland.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Landolt
mesh_terms: D000328:Adult; D001519:Behavior; D003710:Demography; D004298:Dopamine / Q000235:genetics*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics*; D004569:Electroencephalography; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D011110:Polymorphism, Genetic; D011597:Psychomotor Performance; D017448:Receptors, Dopamine D2 / Q000235:genetics*; D012892:Sleep Deprivation / Q000235:genetics* / Q000503:physiopathology*; D013647:Task Performance and Analysis; D014851:Wakefulness / Q000235:genetics; D055815:Young Adult
chemical_list: C581293:DRD2 protein, human; D050483:Dopamine Plasma Membrane Transport Proteins; D017448:Receptors, Dopamine D2; C493214:SLC6A3 protein, human; D004298:Dopamine