Abstract
Dextromethorphan is an antitussive with a high margin of safety that has been hypothesized to display rapid-acting antidepressant activity based on pharmacodynamic similarities to the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine. In addition to binding to NMDA receptors, dextromethorphan binds to sigma-1 (σ1) receptors, which are believed to be protein targets for a potential new class of antidepressant medications. The purpose of this study was to determine whether dextromethorphan elicits antidepressant-like effects and the involvement of σ1 receptors in mediating its antidepressant-like actions. The antidepressant-like effects of dextromethorphan were assessed in male, Swiss Webster mice using the forced swim test. Next, σ1 receptor antagonists (BD1063 and BD1047) were evaluated in conjunction with dextromethorphan to determine the involvement of σ receptors in its antidepressant-like effects. Quinidine, a cytochrome P450 (CYP) 2D6 inhibitor, was also evaluated in conjunction with dextromethorphan to increase the bioavailability of dextromethorphan and reduce exposure to additional metabolites. Finally, saturation binding assays were performed to assess the manner in which dextromethorphan interacts at the σ1 receptor. Our results revealed dextromethorphan displays antidepressant-like effects in the forced swim test that can be attenuated by pretreatment with σ1 receptor antagonists, with BD1063 causing a shift to the right in the dextromethorphan dose response curve. Concomitant administration of quinidine potentiated the antidepressant-like effects of dextromethorphan. Saturation binding assays revealed that a Ki concentration of dextromethorphan reduces both the Kd and the Bmax of [3H](+)-pentazocine binding to σ1 receptors. Taken together, these data suggest that dextromethorphan exerts some of its antidepressant actions through σ1 receptors.
Highlights
Depression affects up to one fifth of the world population, stands as the second leading cause of disability worldwide, and imposes a substantial economic burden [1,2]
A hypothesis was offered that dextromethorphan may have fast-acting antidepressant activity based on pharmacodynamic similarities to the N-methyl-D-aspartate (NMDA) antagonist ketamine [5], a drug repeatedly shown in human populations to display rapid antidepressant effects but whose use is severely limited by the need for intravenous administration and the presence of notable adverse effects [6,7,8]
This study is the first to show that dextromethorphan has antidepressant-like effects in vivo, in addition to implicating s1 receptors as a mechanism contributing to its antidepressant actions
Summary
Depression affects up to one fifth of the world population, stands as the second leading cause of disability worldwide, and imposes a substantial economic burden [1,2]. A hypothesis was offered that dextromethorphan may have fast-acting antidepressant activity based on pharmacodynamic similarities to the N-methyl-D-aspartate (NMDA) antagonist ketamine [5], a drug repeatedly shown in human populations to display rapid antidepressant effects but whose use is severely limited by the need for intravenous administration and the presence of notable adverse effects (e.g., hallucinations and dissociations) [6,7,8]. Dextromethorphan has a high margin of safety; it has been used as a nonprescription antitussive over the past 40 years and may serve as a safer alternative to ketamine. It readily undergoes first-pass metabolism by cytochrome P450 (CYP) 2D6 to its major active metabolite dextrorphan [11]. Dextromethorphan in combination with quinidine, which raises the plasma concentration and bioavailability of dextromethorphan through the inhibition of CYP2D6 metabolism [12], is approved by the U.S Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of pseudobulbar affect and is thought to produce part of its therapeutic effects through s1 receptors [13]
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