Evaluation of the therapeutic efficacy of the dextromethorphan–bupropion combination and its mediating pathways in a mouse model of major depressive disorder

Background: Major depressive disorder (MDD) is associated with multiple pathophysiological mechanisms, including dysregulation of monoaminergic systems, excessive glutamatergic activity, reduced neurotrophic support, inflammation, and oxidative stress. The combination of dextromethorphan, an N-methyl-D-aspartate (NMDA) receptor antagonist and sigma-1 receptor agonist, with bupropion, a dopamine/norepinephrine reuptake inhibitor, has been reported to exert rapid antidepressant effects. In the present study, we evaluated the therapeutic effects of the dextromethorphan–bupropion combination on behavioral outcomes and neurotransmitter, inflammatory, and apoptotic pathways in a mouse model of MDD.

Methods: A total of 36 BALB/c mice were randomly assigned to four groups: Control, CUMS, DXM + BUP, and CUMS + DXM + BUP. The chronic unpredictable mild stress (CUMS) protocol was applied for 6 weeks. Depressive-like behaviors were assessed using the sucrose preference test, open field test, and forced swim test. At the end of the experiment, hippocampal and prefrontal cortex tissues were collected. Serum serotonin, dopamine, GABA, glutamate, and norepinephrine levels were quantified by ELISA. Gene expression levels of Slc6a15 , Bdnf , Ntrk2 , Gdnf , Gfra1 , Ngf , Ntf3 , Ntf4 , Creb1 , Trpm2 , Parp1 , Parg , Casp3 , Mapk14 , Mapk1 , Nfkb1 , Tnf , and Il6 were analyzed by qRT-PCR. GluN2B, TRPM2, and Caspase-3 immunoreactivity was evaluated by immunohistochemistry.

Results: The CUMS group exhibited significant weight loss, anhedonia, increased immobility, elevated glutamate and norepinephrine levels, and reduced serotonin and dopamine levels. In addition, decreased expression of neurotrophic genes and increased expression of Trpm2 , Mapk14 , Tnf , and Il6 , together with elevated Caspase-3 immunoreactivity, was observed. Administration of the dextromethorphan–bupropion combination significantly reversed these behavioral and molecular alterations. Immunohistochemical analyses further demonstrated reduced TRPM2, GluN2B, and Caspase-3 immunoreactivity in the treatment groups compared with the CUMS group.

Conclusion: The dextromethorphan–bupropion combination ameliorated CUMS-induced depressive phenotypes at behavioral, neurotrophic, inflammatory, and apoptotic levels. These findings suggest that this combination represents a potent multimodal therapeutic candidate for stress-related depression.