Activation of ventral tegmental area dopamine neurons produces wakefulness through dopamine D2-like receptors in mice

Brain Struct Funct. 2017 Aug;222(6):2907-2915. doi: 10.1007/s00429-017-1365-7. Epub 2017 Jan 25.


A growing body of evidence suggests that dopamine plays a role in sleep-wake regulation, but the dopamine-producing brain areas that control sleep-wake states are unclear. In this study, we chemogenetically activated dopamine neurons in the ventral midbrain of mice to examine the role of these neurons in sleep-wake regulation. We found that activation of dopamine neurons in the ventral tegmental area (VTA), but not in the substantia nigra, strongly induced wakefulness, although both cell populations expressed the neuronal activity marker c-Fos after chemogenetic stimulation. Analysis of the pattern of behavioral states revealed that VTA activation increased the duration of wakefulness and decreased the number of wakefulness episodes, indicating that wakefulness was consolidated by VTA activation. The increased wakefulness evoked by VTA activation was completely abolished by pretreatment with the dopamine D2/D3 receptor antagonist raclopride, but not by the D1 receptor antagonist SCH23390. These findings indicate that the activation of VTA dopamine neurons promotes wakefulness via D2/D3 receptors.

Keywords: Chemogenetics; D1 receptors; DAT-Cre mice; Midbrain; Sleep; Substantia nigra.

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Dopamine D2 Receptor Antagonists / pharmacology
  • Dopamine Plasma Membrane Transport Proteins / deficiency
  • Dopamine Plasma Membrane Transport Proteins / genetics
  • Dopaminergic Neurons / drug effects
  • Dopaminergic Neurons / metabolism*
  • Electroencephalography
  • Electromyography
  • Genotype
  • Mice, Knockout
  • Phenotype
  • Proto-Oncogene Proteins c-fos / metabolism
  • Receptors, Dopamine D2 / metabolism*
  • Receptors, Dopamine D3 / metabolism
  • Substantia Nigra / drug effects
  • Substantia Nigra / metabolism
  • Time Factors
  • Ventral Tegmental Area / drug effects
  • Ventral Tegmental Area / metabolism*
  • Wakefulness* / drug effects


  • DRD2 protein, mouse
  • Dopamine D2 Receptor Antagonists
  • Dopamine Plasma Membrane Transport Proteins
  • Drd3 protein, mouse
  • Proto-Oncogene Proteins c-fos
  • Receptors, Dopamine D2
  • Receptors, Dopamine D3