PMID- 25628381 OWN - NLM STAT- MEDLINE DCOM- 20151120 LR - 20220309 IS - 1469-5111 (Electronic) IS - 1461-1457 (Print) IS - 1461-1457 (Linking) VI - 18 IP - 4 DP - 2014 Oct 31 TI - Antidepressant effects of TrkB ligands on depression-like behavior and dendritic changes in mice after inflammation. LID - pyu077 [pii] LID - 10.1093/ijnp/pyu077 [doi] AB - 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. CI - (c) The Author 2015. Published by Oxford University Press on behalf of CINP. FAU - Zhang, Ji-chun AU - Zhang JC AD - 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). FAU - Wu, Jin AU - Wu J AD - 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). FAU - Fujita, Yuko AU - Fujita Y AD - 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). FAU - Yao, Wei AU - Yao W AD - 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). FAU - Ren, Qian AU - Ren Q AD - 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). FAU - Yang, Chun AU - Yang C AD - 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). FAU - Li, Su-xia AU - Li SX AD - 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). FAU - Shirayama, Yukihiko AU - Shirayama Y AD - 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). FAU - Hashimoto, Kenji AU - Hashimoto K AD - 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. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20141031 PL - England TA - Int J Neuropsychopharmacol JT - The international journal of neuropsychopharmacology JID - 9815893 RN - 0 (6,7-dihydroxyflavone) RN - 0 (ANA 12 compound) RN - 0 (Antidepressive Agents) RN - 0 (Azepines) RN - 0 (Benzamides) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Flavones) RN - 0 (Lipopolysaccharides) RN - 0 (Multiprotein Complexes) RN - EC 2.7.10.1 (Receptor, trkB) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Animals MH - Antidepressive Agents/*pharmacology MH - Azepines/pharmacology MH - Benzamides/pharmacology MH - Brain-Derived Neurotrophic Factor/metabolism MH - Dendritic Spines/*drug effects/physiology MH - Depressive Disorder/*drug therapy/physiopathology MH - Disease Models, Animal MH - Flavones/pharmacology MH - Hippocampus/drug effects/physiopathology MH - Lipopolysaccharides MH - Male MH - Mechanistic Target of Rapamycin Complex 1 MH - Mice, Inbred C57BL MH - Multiprotein Complexes/metabolism MH - Nucleus Accumbens/drug effects/physiopathology MH - Phosphorylation/drug effects MH - Prefrontal Cortex/drug effects/physiopathology MH - Receptor, trkB/*agonists/*antagonists & inhibitors/metabolism MH - TOR Serine-Threonine Kinases/metabolism PMC - PMC4360225 OTO - NOTNLM OT - BDNF-TrkB signaling OT - hippocampus OT - inflammation OT - nucleus accumbens OT - prefrontal cortex EDAT- 2015/01/30 06:00 MHDA- 2015/12/15 06:00 PMCR- 2015/01/26 CRDT- 2015/01/29 06:00 PHST- 2015/01/29 06:00 [entrez] PHST- 2015/01/30 06:00 [pubmed] PHST- 2015/12/15 06:00 [medline] PHST- 2015/01/26 00:00 [pmc-release] AID - pyu077 [pii] AID - 10.1093/ijnp/pyu077 [doi] PST - epublish SO - Int J Neuropsychopharmacol. 2014 Oct 31;18(4):pyu077. doi: 10.1093/ijnp/pyu077.