title: Involvement of AMPA receptors in the antidepressant-like effects of dextromethorphan in mice.
abstract: 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.
authors: Department of Pharmaceutical Sciences, West Virginia University, Morgantown, WV, USA; Department of Behavioral Medicine and Psychiatry, West Virginia University, Morgantown, WV, USA.
authors: Linda
authors: L
authors: Nguyen
authors: 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. Electronic address: rae.matsumoto@tu.edu.
authors: Rae R
authors: RR
authors: Matsumoto
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D003863:Depression / Q000188:drug therapy / Q000378:metabolism; D003866:Depressive Disorder / Q000188:drug therapy; D003915:Dextromethorphan / Q000494:pharmacology*; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019417:Hindlimb Suspension; D007099:Imipramine / Q000494:pharmacology; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D051379:Mice; D011802:Quinidine / Q000494:pharmacology; D018091:Receptors, AMPA / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013550:Swimming
chemical_list: D000928:Antidepressive Agents; D018691:Excitatory Amino Acid Antagonists; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine; D003915:Dextromethorphan; D011802:Quinidine; D007099:Imipramine
keywords: AMPA receptor; Antidepressant; Dextromethorphan; Forced swim test; Ketamine; Tail suspension test