Nguyen Linda, Matsumoto Rae R
Department of Pharmaceutical Sciences, West Virginia University, Morgantown, WV, USA; Department of Behavioral Medicine and Psychiatry, West Virginia University, Morgantown, WV, USA.
Department of Pharmaceutical Sciences, West Virginia University, Morgantown, WV, USA; Department of Behavioral Medicine and Psychiatry, West Virginia University, Morgantown, WV, USA; College of Pharmacy, Touro University California, Vallejo, CA, USA.
Behav Brain Res. 2015 Dec 15;295:26-34. doi: 10.1016/j.bbr.2015.03.024. Epub 2015 Mar 21.
Dextromethorphan (DM) is an antitussive with rapid acting antidepressant potential based on pharmacodynamic similarities to ketamine. Building upon our previous finding that DM produces antidepressant-like effects in the mouse forced swim test (FST), the present study aimed to establish the antidepressant-like actions of DM in the tail suspension test (TST), another well-established model predictive of antidepressant efficacy. Additionally, using the TST and FST, we investigated the role of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors in the antidepressant-like properties of DM because accumulating evidence suggests that AMPA receptors play an important role in the pathophysiology of depression and may contribute to the efficacy of antidepressant medications, including that of ketamine. We found that DM displays antidepressant-like effects in the TST similar to the conventional and fast acting antidepressants characterized by imipramine and ketamine, respectively. Moreover, decreasing the first-pass metabolism of DM by concomitant administration of quinidine (CYP2D6 inhibitor) potentiated antidepressant-like actions, implying DM itself has antidepressant efficacy. Finally, in both the TST and FST, pretreatment with the AMPA receptor antagonist NBQX (2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide) significantly attenuated the antidepressant-like behavior elicited by DM. Together, the data show that DM exerts antidepressant-like actions through AMPA receptors, further suggesting DM may act as a safe and effective fast acting antidepressant drug.
右美沙芬（DM）是一种镇咳药，基于其与氯胺酮的药效学相似性，具有快速起效的抗抑郁潜力。基于我们之前发现DM在小鼠强迫游泳试验（FST）中产生抗抑郁样作用，本研究旨在确定DM在悬尾试验（TST）中的抗抑郁样作用，TST是另一种预测抗抑郁疗效的成熟模型。此外，利用TST和FST，我们研究了α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体在DM抗抑郁样特性中的作用，因为越来越多的证据表明AMPA受体在抑郁症的病理生理学中起重要作用，并且可能有助于包括氯胺酮在内的抗抑郁药物的疗效。我们发现，DM在TST中显示出抗抑郁样作用，类似于分别以丙咪嗪和氯胺酮为特征的传统和快速起效的抗抑郁药。此外，通过同时给予奎尼丁（CYP2D6抑制剂）降低DM的首过代谢可增强抗抑郁样作用，这意味着DM本身具有抗抑郁疗效。最后，在TST和FST中，用AMPA受体拮抗剂NBQX（2,3-二氧代-6-硝基-1,2,3,4-四氢苯并[f]喹喔啉-7-磺酰胺）预处理可显著减弱DM引起的抗抑郁样行为。总之，数据表明DM通过AMPA受体发挥抗抑郁样作用，进一步表明DM可能作为一种安全有效的快速起效抗抑郁药物。
