title: Behavioral and biochemical effects of ketamine and dextromethorphan relative to its antidepressant-like effects in Swiss Webster mice.
abstract: Ketamine has been shown to produce rapid and robust antidepressant effects in depressed individuals; however, its abuse potential and adverse psychotomimetic effects limit its widespread use. Dextromethorphan (DM) may serve as a safer alternative on the basis of pharmacodynamic similarities to ketamine. In this proof-of-concept study, behavioral and biochemical analyses were carried out to evaluate the potential involvement of brain-derived neurotrophic factor (BDNF) in the antidepressant-like effects of DM in mice, with comparisons to ketamine and imipramine. Male Swiss, Webster mice were injected with DM, ketamine, or imipramine and their behaviors were evaluated in the forced-swim test and the open-field test. Western blots were used to measure BDNF and its precursor, pro-BDNF, protein expression in the hippocampus and the frontal cortex of these mice. Our results show that both DM and imipramine reduced immobility time in the forced-swim test without affecting locomotor activity, whereas ketamine reduced immobility time and increased locomotor activity. Ketamine also rapidly (within 40 min) increased pro-BDNF expression in an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-dependent manner in the hippocampus, whereas DM and imipramine did not alter pro-BDNF or BDNF levels in either the hippocampus or the frontal cortex within this timeframe. These data show that DM shares some features with both ketamine and imipramine. Additional studies examining DM may aid in the development of more rapid, safe, and efficacious antidepressant treatments.
authors: Departments of aPharmaceutical SciencesbBehavioral Medicine and PsychiatrycPhysiology and PharmacologydNeurosurgery, School of Medicine and Pharmacy, West Virginia University, Morgantown, West VirginiaeCollege of Pharmacy, Touro University California, Vallejo, California, USA.
authors: Linda
authors: L
authors: Nguyen
authors: Brandon P
authors: BP
authors: Lucke-Wold
authors: Aric F
authors: AF
authors: Logsdon
authors: Anna L
authors: AL
authors: Scandinaro
authors: Jason D
authors: JD
authors: Huber
authors: Rae R
authors: RR
authors: Matsumoto
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D003915:Dextromethorphan / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D051379:Mice; D011498:Protein Precursors / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology; D018091:Receptors, AMPA / Q000378:metabolism; D018709:Statistics, Nonparametric; D013550:Swimming / Q000523:psychology
chemical_list: D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D011498:Protein Precursors; D011810:Quinoxalines; D018091:Receptors, AMPA; C426674:brain-derived neurotrophic factor precursor; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D007649:Ketamine; D003915:Dextromethorphan