Nguyen Linda, Robson Matthew J, Healy Jason R, Scandinaro Anna L, Matsumoto Rae R
Department of Basic Pharmaceutical Sciences, and Department of Behavioral Medicine and Psychiatry, West Virginia University, Morgantown, West Virginia, United States of America.
PLoS One. 2014 Feb 28;9(2):e89985. doi: 10.1371/journal.pone.0089985. eCollection 2014.
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 (3)H-pentazocine binding to σ1 receptors. Taken together, these data suggest that dextromethorphan exerts some of its antidepressant actions through σ1 receptors.
右美沙芬是一种安全性高的止咳药，基于其与N-甲基-D-天冬氨酸（NMDA）受体拮抗剂氯胺酮的药效学相似性，有人推测它可能具有快速起效的抗抑郁活性。除了与NMDA受体结合外，右美沙芬还与σ1受体结合，而σ1受体被认为是一类潜在新型抗抑郁药物的蛋白质靶点。本研究的目的是确定右美沙芬是否能产生类抗抑郁作用，以及σ1受体是否参与介导其类抗抑郁作用。采用强迫游泳试验，在雄性瑞士韦伯斯特小鼠中评估右美沙芬的类抗抑郁作用。接下来，将σ1受体拮抗剂（BD1063和BD1047）与右美沙芬联合使用，以确定σ受体是否参与其类抗抑郁作用。还将细胞色素P450（CYP）2D6抑制剂奎尼丁与右美沙芬联合使用，以提高右美沙芬的生物利用度并减少对其他代谢产物的暴露。最后，进行饱和结合试验，以评估右美沙芬与σ1受体相互作用的方式。我们的结果显示，右美沙芬在强迫游泳试验中表现出类抗抑郁作用，而预先使用σ1受体拮抗剂可减弱这种作用，BD1063可使右美沙芬剂量反应曲线向右移动。奎尼丁与右美沙芬同时给药可增强其类抗抑郁作用。饱和结合试验表明，右美沙芬的Ki浓度可降低[（3）H]（+）-喷他佐辛与σ受体结合的Kd和Bmax。综上所述，这些数据表明右美沙芬通过σ1受体发挥其部分抗抑郁作用。
