Modified dextromethorphan displays antidepressant‐like effects in the forced swim test

Abstract

Dextromethorphan (DM) may serve as a safer alternative to ketamine as a fast acting antidepressant due to overlapping pharmacology. Our lab has previously shown DM produces antidepressant‐like effects through sigma‐1 (σ1) receptors in the forced swim test (FST) in male Swiss, Webster mice. However DM's rapid metabolism poses a challenge in its use as a routine clinical drug. Two approaches to inhibit its metabolism are 1) addition of the CYP2D6 inhibitor, quinidine, and 2) chemically modifying DM. The present study aimed to determine if modified DM (MDM) by itself and in the presence of quinidine elicits antidepressant‐like effects and if σ1 receptors are involved. Our results showed MDM (3‐30 mg/kg, i.p.) produces a dose‐dependent decrease in immobility time in the FST, indicative of antidepressant‐like effects. MDM also had stimulatory effects, but they cannot account for its antidepressant‐like effects because there was no correlation between the two measures. Pretreatment with BD1063 (σ1 receptor antagonist) to examine the potential role of σ1 receptors failed to block MDM's antidepressant‐like effects. Co‐administration of quinidine to slow the metabolism of MDM produced a similar dose‐dependent decrease in immobility time in the FST compared to MDM alone. Quinidine with MDM, however, had no stimulatory effects. In conclusion, MDM has antidepressant‐like effects independent of σ1 receptors in the FST. Addition of quinidine does not alter the antidepressant‐like effects of MDM, but reduces its stimulant effects, suggesting a possible way to reduce the abuse potential and increase the safety of MDM.