Ji-chun Zhang1, Wei Yao1, Chao Dong1, Chun Yang1, Qian Ren1, Min Ma1, Mei Han1, Kenji Hashimoto2. 1. Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan. 2. Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan. hashimoto@faculty.chiba-u.jp.
Abstract
RATIONALE: Brain-derived neurotrophic factor (BDNF) and signaling at its receptor, tropomyosin-related kinase B (TrkB), are implicated in the rapid and long-lasting antidepressant effects of ketamine. Moreover, a TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF), and/or TrkB antagonist, ANA-12, shows antidepressant effects in animal models of depression. OBJECTIVE: The objective of this study is to compare the influence of ketamine, 7,8-DHF, and ANA-12 on antidepressant activity in the social defeat stress model. RESULTS: In the tail suspension and forced swimming tests, ketamine, 7,8-DHF, or ANA-12 markedly attenuated the increased immobility time in depressed mice compared with the vehicle-treated group. In the sucrose preference test, all drugs significantly improved the reduced preference in depressed mice at both 1 and 3 days after a single dose. Antidepressant effect of ketamine, but not 7,8-DHF or ANA-12, was still detectable 7 days after a single dose. Western blot analyses showed that ketamine, but not 7,8-DHF or ANA-12, markedly attenuated reduced levels of BDNF and postsynaptic density protein 95 (PSD-95) in the prefrontal cortex (PFC), dentate gyrus (DG), and CA3 of the hippocampus in depressed mice 8 days after a single dose. Furthermore, ketamine markedly increased reduced levels of GluA1 in the PFC and DG of depressed mice. In contrast, ketamine showed no effect against increased levels of BDNF, PSD-95, and GluA1 observed in the nucleus accumbens of depressed mice. CONCLUSIONS: Compared with 7,8-DHF and ANA-12, ketamine is a longer-lasting antidepressant in the social defeat stress model, and synaptogenesis may be required for the mechanisms that promote sustained antidepressant effects of ketamine.
RATIONALE: Brain-derived neurotrophic factor (BDNF) and signaling at its receptor, tropomyosin-related kinase B (TrkB), are implicated in the rapid and long-lasting antidepressant effects of ketamine. Moreover, a TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF), and/or TrkB antagonist, ANA-12, shows antidepressant effects in animal models of depression. OBJECTIVE: The objective of this study is to compare the influence of ketamine, 7,8-DHF, and ANA-12 on antidepressant activity in the social defeat stress model. RESULTS: In the tail suspension and forced swimming tests, ketamine, 7,8-DHF, or ANA-12 markedly attenuated the increased immobility time in depressed mice compared with the vehicle-treated group. In the sucrose preference test, all drugs significantly improved the reduced preference in depressed mice at both 1 and 3 days after a single dose. Antidepressant effect of ketamine, but not 7,8-DHF or ANA-12, was still detectable 7 days after a single dose. Western blot analyses showed that ketamine, but not 7,8-DHF or ANA-12, markedly attenuated reduced levels of BDNF and postsynaptic density protein 95 (PSD-95) in the prefrontal cortex (PFC), dentate gyrus (DG), and CA3 of the hippocampus in depressed mice 8 days after a single dose. Furthermore, ketamine markedly increased reduced levels of GluA1 in the PFC and DG of depressed mice. In contrast, ketamine showed no effect against increased levels of BDNF, PSD-95, and GluA1 observed in the nucleus accumbens of depressed mice. CONCLUSIONS: Compared with 7,8-DHF and ANA-12, ketamine is a longer-lasting antidepressant in the social defeat stress model, and synaptogenesis may be required for the mechanisms that promote sustained antidepressant effects of ketamine.
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Authors: Qian Ren; Min Ma; Tamaki Ishima; Christophe Morisseau; Jun Yang; Karen M Wagner; Ji-Chun Zhang; Chun Yang; Wei Yao; Chao Dong; Mei Han; Bruce D Hammock; Kenji Hashimoto Journal: Proc Natl Acad Sci U S A Date: 2016-03-14 Impact factor: 11.205