• Ji-chun Zhang, Jin Wu, Yuko Fujita, Wei Yao, Qian Ren, Chun Yang, Su-xia Li, Yukihiko Shirayama, and Kenji Hashimoto.
• 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).
• Int. J. Neuropsychopharmacol. 2014 Oct 31; 18 (4).

BackgroundBrain-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.MethodsIn 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.ResultsLPS 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.ConclusionsThe 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.© The Author 2015. Published by Oxford University Press on behalf of CINP.

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