Involvement of NMDA receptors in the antidepressant-like effect of tramadol in the mouse forced swimming test

Tramadol is an analgesic agent that is mainly used to treat moderate to severe pain. There is evidence that tramadol may have antidepressant property. However, the mechanisms underlying the antidepressant effects of tramadol have not been elucidated yet. Considering that fact that N-methyl-D-aspartate (NMDA) receptor signaling may play an important role in the pathophysiology of depression, the aim of the present study was to investigate the role of NMDA receptor signaling in the possible antidepressant-like effects of tramadol in the mouse forced swimming test (mFST). We found that tramadol exerted antidepressant-like effects at high dose (40 mg/kg, intraperitoneally [i.p.]) in the mFST. Co-administration of non-effective doses of NMDA receptor antagonists (ketamine [1 mg/kg, i.p.], MK-801 [0.05 mg/kg, i.p.], or magnesium sulfate [10 mg/kg, i.p.]) with sub-effective dose of tramadol (20 mg/kg, i.p.) exerted significant antidepressant-like effects in the mFST. The antidepressant-like effects of tramadol (40 mg/kg) was also inhibited by pre-treatment with non-effective dose of the NMDA receptor agonist NMDA (75 mg/kg, i.p.). Our data suggest a role for NMDA receptor signaling in the antidepressant-like effects of tramadol in the mFST.