title: Comparison of R-ketamine and rapastinel antidepressant effects in the social defeat stress model of depression.
abstract: The N-methyl-D-aspartate (NMDA) receptor antagonists, including R-ketamine and rapastinel (formerly GLYX-13), show rapid antidepressant effects in animal models of depression.
  
  
  
  We compared the rapid and sustained antidepressant effects of R-ketamine and rapastinel in the social defeat stress model.
  
  
  
  In the tail suspension and forced swimming tests, R-ketamine (10 mg/kg, intraperitoneal (i.p.)) or rapastinel (10 mg/kg, i.p.) significantly attenuated the increased immobility time in the susceptible mice, compared with the vehicle-treated group. In the sucrose preference test, both compounds significantly enhanced the reduced preference in susceptible mice 2, 4, or 7 days after a single injection. All mice were sacrificed 8 days after a single injection. Western blot analyses showed that R-ketamine, but not rapastinel, significantly attenuated the reduced brain-derived neurotrophic factor (BDNF)-TrkB signaling, postsynaptic density protein 95 (PSD-95), and GluA1 (a subtype of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor) in the prefrontal cortex, dentate gyrus, and CA3 of the hippocampus in the susceptible mice. In contrast, both compounds had no effect against the increased BDNF-TrkB signaling, PSD-95, and GluA1 seen in the nucleus accumbens of susceptible mice. Moreover, sustained antidepressant effect of R-ketamine (3 mg/kg, intravenous (i.v.)), but not rapastinel (3 mg/kg, i.v.), was detected 7 days after a single dose.
  
  
  
  These results highlight R-ketamine as a longer lasting antidepressant compared with rapastinel in social defeat stress model. It is likely that synaptogenesis including BDNF-TrkB signaling in the prefrontal cortex (PFC) and hippocampus may be required for the mechanisms promoting this sustained antidepressant effect.
authors.affiliation: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, 260-8670, Japan.|Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, People's Republic of China.
authors.forename: Bangkun
authors.initials: B
authors.lastname: Yang
authors.affiliation: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, 260-8670, Japan.
authors.forename: Ji-Chun
authors.initials: JC
authors.lastname: Zhang
authors.affiliation: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, 260-8670, Japan.
authors.forename: Mei
authors.initials: M
authors.lastname: Han
authors.affiliation: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, 260-8670, Japan.
authors.forename: Wei
authors.initials: W
authors.lastname: Yao
authors.affiliation: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, 260-8670, Japan.
authors.forename: Chun
authors.initials: C
authors.lastname: Yang
authors.affiliation: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, 260-8670, Japan.
authors.forename: Qian
authors.initials: Q
authors.lastname: Ren
authors.affiliation: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, 260-8670, Japan.
authors.forename: Min
authors.initials: M
authors.lastname: Ma
authors.affiliation: Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, People's Republic of China.
authors.forename: Qian-Xue
authors.initials: QX
authors.lastname: Chen
authors.affiliation: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, 260-8670, Japan. hashimoto@faculty.chiba-u.jp.
authors.forename: Kenji
authors.initials: K
authors.lastname: Hashimoto
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000187:drug effects* / Q000378:metabolism; D056654:CA3 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism; D018891:Dentate Gyrus / Q000187:drug effects / Q000378:metabolism; D003863:Depression / Q000188:drug therapy; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein / Q000187:drug effects / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D019417:Hindlimb Suspension; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D020813:Receptor, trkB / Q000187:drug effects / Q000378:metabolism; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism; D013315:Stress, Psychological / Q000378:metabolism*; D013550:Swimming
chemical_list: D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D000076122:Disks Large Homolog 4 Protein; D018691:Excitatory Amino Acid Antagonists; D007649:Ketamine; D009842:Oligopeptides; D020813:Receptor, trkB; D018091:Receptors, AMPA; C501447:Dlg4 protein, mouse; C507283:GLYX-13 peptide
keywords: Antidepressant; Brain-derived neurotrophic factor; R-ketamine; Rapastinel; Synaptogenesis