title: Rapid and Sustained Antidepressant Action of the mGlu2/3 Receptor Antagonist MGS0039 in the Social Defeat Stress Model: Comparison with Ketamine.
abstract: Similar to the N-methyl-D-aspartate receptor antagonist ketamine, the metabotropic glutamate 2/3 receptor antagonist, MGS0039, shows antidepressant effects. However, there are no reports comparing these 2 compounds in the social defeat stress model of depression.
  
  
  
  We examined the effects of MGS0039 (1 mg/kg) and ketamine (10 mg/kg) on depression-like behavior in susceptible mice after repeated social defeat stress. Protein levels of brain-derived neurotrophic factor, TrkB, phospho-TrkB, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (GluA1), postsynaptic density protein 95, and dendritic spine density in selected brain regions were measured.
  
  
  
  In the tail suspension and forced swimming tests, both MGS0039 and ketamine significantly attenuated the increased immobility time observed in susceptible mice, compared with vehicle-treated animals, 1 or 2 days after a single dose of drug. In the sucrose preference test, both compounds significantly improved the reduced preference typically seen in susceptible mice at 3 to 7 days after a single dose of drug. Western-blot analyses showed that similar to ketamine, MGS0039 significantly attenuated the reduced brain-derived neurotrophic factor, phospho-TrkB/TrkB ratio, GluA1 and postsynaptic density protein 95 seen in the prefrontal cortex, dentate gyrus, and CA3 of the hippocampus from susceptible mice, 8 days after a single dose. Again, in a similar manner to ketamine, MGS0039 significantly attenuated the reduction of spine density in the prelimbic regions of the medial prefrontal cortex, dentate gyrus, and CA3 of the hippocampus, but not infralimbic regions of the medial prefrontal cortex and CA1, in susceptible mice 8 days after a single dose. In contrast, neither drug elicited an effect on altered brain-derived neurotrophic factor-TrkB signaling, GluA1, and postsynaptic density protein 95 levels and did not increase spine density observed in the nucleus accumbens of susceptible mice.
  
  
  
  Similar to ketamine, MGS0039 shows rapid and sustained antidepressant effects in the social defeat stress model. Long-lasting synaptogenesis in the prelimbic regions of medial prefrontal cortex, dentate gyrus, and CA3 might be implicated in this sustained antidepressant effect.
authors.affiliation: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan; Research Headquarters, Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
authors.forename: Chao
authors.initials: C
authors.lastname: Dong
authors.affiliation: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan; Research Headquarters, Taisho Pharmaceutical Co., Ltd., Saitama, 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, Japan; Research Headquarters, Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
authors.forename: Wei
authors.initials: W
authors.lastname: Yao
authors.affiliation: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan; Research Headquarters, Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
authors.forename: Qian
authors.initials: Q
authors.lastname: Ren
authors.affiliation: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan; Research Headquarters, Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
authors.forename: Min
authors.initials: M
authors.lastname: Ma
authors.affiliation: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan; Research Headquarters, Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
authors.forename: Chun
authors.initials: C
authors.lastname: Yang
authors.affiliation: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan; Research Headquarters, Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Chaki
authors.affiliation: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan; Research Headquarters, Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Hashimoto
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D049229:Dendritic Spines / Q000187:drug effects; D003998:Dicarboxylic Acids / Q000494:pharmacology*; D000076122:Disks Large Homolog 4 Protein / Q000378:metabolism; D005518:Food Preferences / Q000187:drug effects; D046353:Immobility Response, Tonic / Q000187:drug effects; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D051379:Mice; D011494:Protein Kinases / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism
chemical_list: C483757:2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo(3.1.0)hexane-2,6-dicarboxylic acid; D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D001643:Bridged Bicyclo Compounds; D003998:Dicarboxylic Acids; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; D007649:Ketamine; D011494:Protein Kinases; C041311:tropomyosin kinase
keywords: BDNF-TrkB signaling; antidepressant; ketamine; metabotropic glutamate 2/3 (mGlu2/3) receptor antagonist; social defeat stress model; synaptogenesis