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 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.
Sleep Disorders Research Center, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California 94305, USA. jwisor@stanford.edu
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Wisor
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Nishino
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Sora
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Uhl
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Mignot
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Edgar
D000661:Amphetamine / Q000008:administration & dosage; D000818:Animals; D001559:Benzhydryl Compounds / Q000008:administration & dosage; D002110:Caffeine / Q000008:administration & dosage; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002421:Caudate Nucleus / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D004195:Disease Models, Animal; D004285:Dogs; D004298:Dopamine / Q000032:analysis / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography; D004576:Electromyography; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D008694:Methamphetamine / Q000008:administration & dosage; D051379:Mice; D018345:Mice, Knockout; D017551:Microdialysis; D000077408:Modafinil; D009043:Motor Activity / Q000187:drug effects; D009290:Narcolepsy / Q000188:drug therapy / Q000378:metabolism*; D009419:Nerve Tissue Proteins; D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide / Q000378:metabolism; D014851:Wakefulness / Q000187:drug effects* / Q000502:physiology*
D001559:Benzhydryl Compounds; D002352:Carrier Proteins; D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; C493215:Slc6a3 protein, mouse; D002110:Caffeine; D008694:Methamphetamine; D000661:Amphetamine; D000077408:Modafinil; D004298:Dopamine