Behavioral and biochemical analyses of the fast acting antidepressant‐like potential of dextromethorphan

Abstract

Ketamine at sub‐anesthetic doses exerts robust, rapid antidepressant effects in depressed patients, but widespread use is limited by abuse liability and adverse events. In this preclinical study, the over‐the‐counter antitussive dextromethorphan (DM) was investigated as a potential alternative to ketamine due to overlapping pharmacology. Male, Swiss Webster mice were acutely injected with DM, and behavioral (antidepressant‐like effects in the forced swim test, FST, and tail suspension test, TST) and biochemical (pro‐ and mature brain‐derived neurotrophic factor, or BDNF, expression using western blot) tests were performed. Also, the role of AMPA and σ1 receptors in the antidepressant‐like effects of DM was examined because mounting evidence suggests these mechanisms contribute to a fast onset of antidepressant efficacy and are relevant to ketamine's effects. Our results revealed that DM produces antidepressant‐like actions in both the FST and TST, similar to ketamine. In the FST, pretreatment with NBQX (AMPA antagonist) or BD1063 (σ1 antagonist) blocked the antidepressant‐like effects of DM, indicating that AMPA and σ1 receptors play pivotal roles in mediating its antidepressant‐like behaviors. DM however did not alter hippocampal pro‐BDNF or BDNF levels, while ketamine increased pro‐BDNF. Together, the data demonstrate that DM shares some, but not all, antidepressant‐like effects with ketamine. In light of a recent clinical report of DM's efficacy for bipolar depression and our preclinical findings, further studies are needed to examine DM's potential as a safe, effective fast acting antidepressant.