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The Journal of Neuroscience, March 1, 2001, 21(5):1787-1794

Dopaminergic Role in Stimulant-Induced Wakefulness

Jonathan P. Wisor¹, Seiji Nishino¹, Ichiro Sora², George H. Uhl², Emmanuel Mignot¹, and Dale M. Edgar¹

¹ Sleep Disorders Research Center, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California 94305, and ² Molecular Neurobiology Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224

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.

Key words: sleep-wake cycle; modafinil; amphetamine; caffeine; hypocretin; dopamine; narcolepsy

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Copyright © 2001 Society for Neuroscience  0270-6474/01/2151787-08$05.00/0

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