Dopaminergic Role in Stimulant-Induced Wakefulness

J Neurosci. 2001 Mar 1;21(5):1787-94. doi: 10.1523/JNEUROSCI.21-05-01787.2001.

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

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 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*

Substances

  • Benzhydryl Compounds
  • Carrier Proteins
  • Central Nervous System Stimulants
  • Dopamine Plasma Membrane Transport Proteins
  • Dopamine Uptake Inhibitors
  • Membrane Glycoproteins
  • Membrane Transport Proteins
  • Nerve Tissue Proteins
  • Orexin Receptors
  • Receptors, G-Protein-Coupled
  • Receptors, Neuropeptide
  • Slc6a3 protein, mouse
  • Caffeine
  • Methamphetamine
  • Amphetamine
  • Modafinil
  • Dopamine