Evaluation of the therapeutic efficacy of the dextromethorphan–bupropion combination and its mediating pathways in a mouse model of major depressive disorder
İlay Buran Kavuran, Ebru Önalan, Zeliha İrem Türk, Hatice Eröksüz
Frontiers in Pharmacology August 19, 2026 DOI: 10.3389/fphar.2026.1910199 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized controlled trial Peer reviewed |
|---|---|
| Sample size | 36 |
| Population | BALB/c mice |
| Interventions | Dextromethorphan Bupropion |
| Duration | 6-week CUMS protocol |
| Measures | sucrose preference test, open field test, forced swim test, ELISA, qRT-PCR, immunohistochemistry |
| Topics | Depression |
| Key findings | The dextromethorphan–bupropion combination reversed CUMS-induced behavioral deficits and molecular alterations, including reduced neurotrophic gene expression and elevated inflammatory and apoptotic markers, suggesting its potential as a multimodal antidepressant. |
Abstract
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.