Assessment of the rapid and sustained antidepressant-like effects of dextromethorphan in mice

The glutamatergic system has emerged as a novel pathway for treating major depressive disorder (MDD) with the focus on producing both rapid and sustained antidepressant effects. Dextromethorphan is a noncompetitive N -methyl- d -aspartate (NMDA) receptor antagonist that has produced antidepressant-like effects in forced swim and tail suspension tests (TST); however, the rapid and sustained antidepressant-like effects of dextromethorphan have not been evaluated. This study evaluated the rapid and sustained (24 h) antidepressant-like effects of dextromethorphan (0–32 mg/kg) in C56BL/6 mice using the novelty-induced hypophagia (NIH) test and TST, respectively. Additionally, we evaluated anxiety-related behavior and locomotor effects of dextromethorphan (0–56.0 mg/kg) using the light-dark and open field tests. Dextromethorphan (32 mg/kg) produced acute (30 min) antidepressant-like effects in TST, but failed to produce antidepressant-like effects 24 h after drug administration. Treatment of dextromethorphan (32 mg/kg) alone or in combination with CYP2D6 enzyme inhibitor Quinidine (32 mg/kg) failed to produce rapid antidepressant-like effects by increasing the latency to drink in the NIH test rather than decreasing the latency to drink. Dextromethorphan (56 mg/kg) produced an anxiogenic-like effect by decreasing the time spent in the light side, number of entries, and latency to enter the light side in the light-dark test. Administration of dextromethorphan (0–56 mg/kg) did not significantly alter locomotor activity. Although dextromethorphan is considered a noncompetitive NMDA receptor antagonist, dextromethorphan binds to several monoaminergic receptors (SERT and NET) and likely produces the antidepressant-like effects through these receptors similar to traditional antidepressant drugs. Additionally, these results suggest that the therapeutic window for dextromethorphan in the clinical population is small as similar doses produce antidepressant-like and anxiogenic-like behaviors.