The glutamatergic system has emerged as a novel pathway for treating major depressive disorder (MDD) with the focus on producing both rapid and sustained antidepressant effects. Dextromethorphan is a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist that has produced antidepressant-like effects in forced swim and tail suspension tests (TST); however, the rapid and sustained antidepressant-like effects of dextromethorphan have not been evaluated. This study evaluated the rapid and sustained (24 h) antidepressant-like effects of dextromethorphan (0–32 mg/kg) in C56BL/6 mice using the novelty-induced hypophagia (NIH) test and TST, respectively. Additionally, we evaluated anxiety-related behavior and locomotor effects of dextromethorphan (0–56.0 mg/kg) using the light-dark and open field tests. Dextromethorphan (32 mg/kg) produced acute (30 min) antidepressant-like effects in TST, but failed to produce antidepressant-like effects 24 h after drug administration. Treatment of dextromethorphan (32 mg/kg) alone or in combination with CYP2D6 enzyme inhibitor Quinidine (32 mg/kg) failed to produce rapid antidepressant-like effects by increasing the latency to drink in the NIH test rather than decreasing the latency to drink. Dextromethorphan (56 mg/kg) produced an anxiogenic-like effect by decreasing the time spent in the light side, number of entries, and latency to enter the light side in the light-dark test. Administration of dextromethorphan (0–56 mg/kg) did not significantly alter locomotor activity. Although dextromethorphan is considered a noncompetitive NMDA receptor antagonist, dextromethorphan binds to several monoaminergic receptors (SERT and NET) and likely produces the antidepressant-like effects through these receptors similar to traditional antidepressant drugs. Additionally, these results suggest that the therapeutic window for dextromethorphan in the clinical population is small as similar doses produce antidepressant-like and anxiogenic-like behaviors.

谷氨酸能系统已成为治疗严重抑郁症（MDD）的新型途径，其重点是产生快速和持续的抗抑郁作用。右美沙芬是一种非竞争性N-甲基-d-天冬氨酸（NMDA）受体拮抗剂，在强迫游泳和尾部悬吊试验（TST）中产生了抗抑郁样作用；然而，尚未评估右美沙芬的快速和持续抗抑郁样作用。这项研究分别使用新颖性诱发的吞咽（NIH）测试和TST评估了C56BL / 6小鼠右美沙芬（0–32 mg / kg）的快速和持续（24 h）抗抑郁样作用。此外，我们使用明暗和露天试验评估了右美沙芬（0-56.0 mg / kg）的焦虑相关行为和运动影响。右美沙芬（32 mg / kg）在TST中产生了急性（30分钟）样的抗抑郁药作用，但在给药后24小时未能产生抗抑郁样的药效。单独使用右美沙芬（32 mg / kg）或与CYP2D6酶抑制剂奎尼丁（32 mg / kg）组合使用时，通过增加NIH测试中的饮酒潜伏期而不是减少饮酒潜伏期未能产生类似抗抑郁药的快速作用。右美沙芬（56 mg / kg）通过减少在明暗试验中花费在亮侧的时间，进入次数和进入亮侧的潜伏期，从而产生了类似焦虑的作用。右美沙芬（0-56 mg / kg）的使用没有显着改变运动能力。尽管右美沙芬被认为是非竞争性NMDA受体拮抗剂，但右美沙芬与几种单胺能受体（SERT和NET）结合，并可能通过这些受体产生类似于传统抗抑郁药的抗抑郁样作用。另外，