Dopamine D2/D3 but not dopamine D1 receptors are involved in the rapid antidepressant-like effects of ketamine in the forced swim test

Behav Brain Res. 2015 Feb 15;279:100-5. doi: 10.1016/j.bbr.2014.11.016. Epub 2014 Nov 15.


Major depressive disorder is one of the most prevalent and life-threatening forms of mental illnesses. The traditional antidepressants often take several weeks, even months, to obtain clinical effects. However, recent clinical studies have shown that ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, exerts rapid antidepressant effects within 2h and are long-lasting. The aim of the present study was to investigate whether dopaminergic system was involved in the rapid antidepressant effects of ketamine. The acute administration of ketamine (20 mg/kg) significantly reduced the immobility time in the forced swim test. MK-801 (0.1 mg/kg), the more selective NMDA antagonist, also exerted rapid antidepressant-like effects. In contrast, fluoxetine (10 mg/kg) did not significantly reduced the immobility time in the forced swim test after 30 min administration. Notably, pretreatment with haloperidol (0.15 mg/kg, a nonselective dopamine D2/D3 antagonist), but not SCH23390 (0.04 and 0.1 mg/kg, a selective dopamine D1 receptor antagonist), significantly prevented the effects of ketamine or MK-801. Moreover, the administration of sub-effective dose of ketamine (10 mg/kg) in combination with pramipexole (0.3 mg/kg, a dopamine D2/D3 receptor agonist) exerted antidepressant-like effects compared with each drug alone. In conclusion, our results indicated that the dopamine D2/D3 receptors, but not D1 receptors, are involved in the rapid antidepressant-like effects of ketamine.

Keywords: Antidepressant; Depression; Dopamine receptor; Forced swim test; Ketamine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology*
  • Benzazepines / pharmacology
  • Benzothiazoles / pharmacology
  • Dizocilpine Maleate / pharmacology
  • Fluoxetine / pharmacology
  • Haloperidol / pharmacology
  • Ketamine / pharmacology*
  • Male
  • Mice
  • Motor Activity / drug effects*
  • Pramipexole
  • Receptors, Dopamine D1 / agonists
  • Receptors, Dopamine D1 / physiology*
  • Receptors, Dopamine D2 / agonists
  • Receptors, Dopamine D2 / physiology*
  • Receptors, Dopamine D3 / agonists
  • Receptors, Dopamine D3 / physiology*
  • Receptors, N-Methyl-D-Aspartate / agonists
  • Swimming


  • Antidepressive Agents
  • Benzazepines
  • Benzothiazoles
  • Receptors, Dopamine D1
  • Receptors, Dopamine D2
  • Receptors, Dopamine D3
  • Receptors, N-Methyl-D-Aspartate
  • SCH 23390
  • Fluoxetine
  • Ketamine
  • Dizocilpine Maleate
  • Pramipexole
  • Haloperidol