Abstract
The role of dopamine in sleep regulation and in mediating the effects of wake-promoting therapeutics is controversial. In this study, polygraphic recordings and caudate microdialysate dopamine measurements in narcoleptic dogs revealed that the wake-promoting antinarcoleptic compounds modafinil and amphetamine increase extracellular dopamine in a hypocretin receptor 2-independent manner. In mice, deletion of the dopamine transporter (DAT) gene reduced non-rapid eye movement sleep time and increased wakefulness consolidation independently from locomotor effects. DAT knock-out mice were also unresponsive to the normally robust wake-promoting action of modafinil, methamphetamine, and the selective DAT blocker GBR12909 but were hypersensitive to the wake-promoting effects of caffeine. Thus, dopamine transporters play an important role in sleep regulation and are necessary for the specific wake-promoting action of amphetamines and modafinil.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amphetamine / administration & dosage
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Animals
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Benzhydryl Compounds / administration & dosage
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Caffeine / administration & dosage
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Carrier Proteins / antagonists & inhibitors
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Caudate Nucleus / metabolism
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Central Nervous System Stimulants / pharmacology*
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Disease Models, Animal
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Dogs
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Dopamine / analysis
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Dopamine / metabolism*
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Dopamine Plasma Membrane Transport Proteins
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Dopamine Uptake Inhibitors / pharmacology
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Dose-Response Relationship, Drug
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Electroencephalography
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Electromyography
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Membrane Glycoproteins*
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Membrane Transport Proteins*
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Methamphetamine / administration & dosage
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Mice
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Mice, Knockout
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Microdialysis
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Modafinil
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Motor Activity / drug effects
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Narcolepsy / drug therapy
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Narcolepsy / metabolism*
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Nerve Tissue Proteins*
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Orexin Receptors
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Receptors, G-Protein-Coupled
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Receptors, Neuropeptide / metabolism
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Wakefulness / drug effects*
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Wakefulness / physiology*
Substances
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Benzhydryl Compounds
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Carrier Proteins
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Central Nervous System Stimulants
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Dopamine Plasma Membrane Transport Proteins
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Dopamine Uptake Inhibitors
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Membrane Glycoproteins
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Membrane Transport Proteins
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Nerve Tissue Proteins
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Orexin Receptors
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Receptors, G-Protein-Coupled
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Receptors, Neuropeptide
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Slc6a3 protein, mouse
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Caffeine
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Methamphetamine
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Amphetamine
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Modafinil
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Dopamine