Comparison of ketamine, 7,8-dihydroxyflavone, and ANA-12 antidepressant effects in the social defeat stress model of depression.
BACKGROUND
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.
Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.
Ji-chun
JC
Zhang
Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.
Wei
W
Yao
Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.
Chao
C
Dong
Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.
Chun
C
Yang
Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.
Qian
Q
Ren
Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.
Min
M
Ma
Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.
Mei
M
Han
Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan. hashimoto@faculty.chiba-u.jp.
Kenji
K
Hashimoto
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D001381:Azepines / Q000494:pharmacology / Q000627:therapeutic use*; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D003863:Depression / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D004195:Disease Models, Animal; D047309:Flavones / Q000494:pharmacology / Q000627:therapeutic use*; D019417:Hindlimb Suspension / Q000523:psychology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007649:Ketamine / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D013315:Stress, Psychological / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D013550:Swimming / Q000523:psychology
C485383:6,7-dihydroxyflavone; C559317:ANA 12 compound; D000928:Antidepressive Agents; D001381:Azepines; D001549:Benzamides; D019208:Brain-Derived Neurotrophic Factor; D047309:Flavones; D007649:Ketamine
AMPA receptor; Accumbens; Animal model; Antidepressant; BDNF; Dentate gyrus; Frontal cortex; Glutamate receptor; NMDA receptor; Stress