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

•Dopamine D2/D3 receptor but not D1 receptor antagonists prevent the rapid antidepressant-like effect of ketamine.•Dopamine D2/D3 receptor but not D1 receptor antagonists prevent the rapid antidepressant-like effect of MK-801.•Co-administration of sub-effective dose of ketamine and dopamine D2/D3 receptor agonist exert antidepressant-like effect. 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 (20mg/kg) significantly reduced the immobility time in the forced swim test. MK-801 (0.1mg/kg), the more selective NMDA antagonist, also exerted rapid antidepressant-like effects. In contrast, fluoxetine (10mg/kg) did not significantly reduced the immobility time in the forced swim test after 30min administration. Notably, pretreatment with haloperidol (0.15mg/kg, a nonselective dopamine D2/D3 antagonist), but not SCH23390 (0.04 and 0.1mg/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 (10mg/kg) in combination with pramipexole (0.3mg/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.