title: Antidepressant effects of TrkB ligands on depression-like behavior and dendritic changes in mice after inflammation.
abstract: BACKGROUND
  Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase B (TrkB), signaling represent potential therapeutic targets for major depressive disorder. The purpose of this study is to examine whether TrkB ligands show antidepressant effects in an inflammation-induced model of depression.
  
  
  METHODS
  In this study, we examined the effects of TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) and TrkB antagonist ANA-12 on depression-like behavior and morphological changes in mice previously exposed to lipopolysaccharide (LPS). Protein levels of BDNF, phospho-TrkB (p-TrkB), and TrkB in the brain regions were also examined.
  
  
  RESULTS
  LPS caused a reduction of BDNF in the CA3 and dentate gyrus (DG) of the hippocampus and prefrontal cortex (PFC), whereas LPS increased BDNF in the nucleus accumbens (NAc). Dexamethason suppression tests showed hyperactivity of the hypothalamic-pituitary-adrenal axis in LPS-treated mice. Intraperitoneal (i.p.) administration of 7,8-DHF showed antidepressant effects on LPS-induced depression-like behavior, and i.p. pretreatment with ANA-12 blocked its antidepressant effects. Surprisingly, ANA-12 alone showed antidepressant-like effects on LPS-induced depression-like behavior. Furthermore, bilateral infusion of ANA-12 into the NAc showed antidepressant effects. Moreover, LPS caused a reduction of spine density in the CA3, DG, and PFC, whereas LPS increased spine density in the NAc. Interestingly, 7,8-DHF significantly attenuated LPS-induced reduction of p-TrkB and spine densities in the CA3, DG, and PFC, whereas ANA-12 significantly attenuated LPS-induced increases of p-TrkB and spine density in the NAc.
  
  
  CONCLUSIONS
  The results suggest that LPS-induced inflammation may cause depression-like behavior by altering BDNF and spine density in the CA3, DG, PFC, and NAc, which may be involved in the antidepressant effects of 7,8-DHF and ANA-12, respectively.
authors: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan (Drs Zhang, Wu, Yao, Ren, Yang, Li, Shirayama, Hashimoto, and Ms Fujita); National Institute of Drug Dependence, Peking University, Beijing, China (Dr Li); Department of Psychiatry, Teikyo University Chiba Medical Center, Chiba, Japan (Dr Shirayama).
authors: Ji-chun
authors: JC
authors: Zhang
authors: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan (Drs Zhang, Wu, Yao, Ren, Yang, Li, Shirayama, Hashimoto, and Ms Fujita); National Institute of Drug Dependence, Peking University, Beijing, China (Dr Li); Department of Psychiatry, Teikyo University Chiba Medical Center, Chiba, Japan (Dr Shirayama).
authors: Jin
authors: J
authors: Wu
authors: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan (Drs Zhang, Wu, Yao, Ren, Yang, Li, Shirayama, Hashimoto, and Ms Fujita); National Institute of Drug Dependence, Peking University, Beijing, China (Dr Li); Department of Psychiatry, Teikyo University Chiba Medical Center, Chiba, Japan (Dr Shirayama).
authors: Yuko
authors: Y
authors: Fujita
authors: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan (Drs Zhang, Wu, Yao, Ren, Yang, Li, Shirayama, Hashimoto, and Ms Fujita); National Institute of Drug Dependence, Peking University, Beijing, China (Dr Li); Department of Psychiatry, Teikyo University Chiba Medical Center, Chiba, Japan (Dr Shirayama).
authors: Wei
authors: W
authors: Yao
authors: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan (Drs Zhang, Wu, Yao, Ren, Yang, Li, Shirayama, Hashimoto, and Ms Fujita); National Institute of Drug Dependence, Peking University, Beijing, China (Dr Li); Department of Psychiatry, Teikyo University Chiba Medical Center, Chiba, Japan (Dr Shirayama).
authors: Qian
authors: Q
authors: Ren
authors: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan (Drs Zhang, Wu, Yao, Ren, Yang, Li, Shirayama, Hashimoto, and Ms Fujita); National Institute of Drug Dependence, Peking University, Beijing, China (Dr Li); Department of Psychiatry, Teikyo University Chiba Medical Center, Chiba, Japan (Dr Shirayama).
authors: Chun
authors: C
authors: Yang
authors: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan (Drs Zhang, Wu, Yao, Ren, Yang, Li, Shirayama, Hashimoto, and Ms Fujita); National Institute of Drug Dependence, Peking University, Beijing, China (Dr Li); Department of Psychiatry, Teikyo University Chiba Medical Center, Chiba, Japan (Dr Shirayama).
authors: Su-xia
authors: SX
authors: Li
authors: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan (Drs Zhang, Wu, Yao, Ren, Yang, Li, Shirayama, Hashimoto, and Ms Fujita); National Institute of Drug Dependence, Peking University, Beijing, China (Dr Li); Department of Psychiatry, Teikyo University Chiba Medical Center, Chiba, Japan (Dr Shirayama).
authors: Yukihiko
authors: Y
authors: Shirayama
authors: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan (Drs Zhang, Wu, Yao, Ren, Yang, Li, Shirayama, Hashimoto, and Ms Fujita); National Institute of Drug Dependence, Peking University, Beijing, China (Dr Li); Department of Psychiatry, Teikyo University Chiba Medical Center, Chiba, Japan (Dr Shirayama). hashimoto@faculty.chiba-u.jp.
authors: Kenji
authors: K
authors: Hashimoto
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001381:Azepines / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D049229:Dendritic Spines / Q000187:drug effects* / Q000502:physiology; D003866:Depressive Disorder / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D047309:Flavones / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D008070:Lipopolysaccharides; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects / Q000503:physiopathology; D010766:Phosphorylation / Q000187:drug effects; D017397:Prefrontal Cortex / Q000187:drug effects / Q000503:physiopathology; D020813:Receptor, trkB / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: C485383:6,7-dihydroxyflavone; C559317:ANA 12 compound; D000928:Antidepressive Agents; D001381:Azepines; D001549:Benzamides; D019208:Brain-Derived Neurotrophic Factor; D047309:Flavones; D008070:Lipopolysaccharides; D046912:Multiprotein Complexes; D020813:Receptor, trkB; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
keywords: BDNF-TrkB signaling; hippocampus; inflammation; nucleus accumbens; prefrontal cortex
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