Dopaminergic Role in Stimulant-Induced Wakefulness

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 a...

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Bibliographic Details
Published in:	The Journal of neuroscience Vol. 21; no. 5; pp. 1787 - 1794
Main Authors:	Wisor, Jonathan P, Nishino, Seiji, Sora, Ichiro, Uhl, George H, Mignot, Emmanuel, Edgar, Dale M
Format:	Journal Article
Language:	English
Published:	United States Soc Neuroscience 01-03-2001 Society for Neuroscience
Subjects:	Amphetamine - administration & dosage Animals Benzhydryl Compounds - administration & dosage Caffeine - administration & dosage Carrier Proteins - antagonists & inhibitors Carrier Proteins - genetics Carrier Proteins - metabolism Caudate Nucleus - metabolism Central Nervous System Stimulants - pharmacology Disease Models, Animal Dogs Dopamine - analysis Dopamine - metabolism Dopamine Plasma Membrane Transport Proteins Dopamine Uptake Inhibitors - pharmacology Dose-Response Relationship, Drug Electroencephalography Electromyography Membrane Glycoproteins Membrane Transport Proteins Methamphetamine - administration & dosage Mice Mice, Knockout Microdialysis modafinil Motor Activity - drug effects Narcolepsy - drug therapy Narcolepsy - metabolism Nerve Tissue Proteins Orexin Receptors Receptors, G-Protein-Coupled Receptors, Neuropeptide - metabolism Wakefulness - drug effects Wakefulness - physiology
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Summary:	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.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0270-6474 1529-2401
DOI:	10.1523/JNEUROSCI.21-05-01787.2001