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Comparison of ketamine, 7,8-dihydroxyflavone, and ANA-12 antidepressant effects in the social defeat stress model of depression

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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.

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Acknowledgments

This study was supported by a Grant-in-Aid for Scientific Research on Innovative Areas of the Ministry of Education, Culture, Sports, Science and Technology, Japan (to K.H., #24116006).

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Authors and Affiliations

  1. Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan

    Ji-chun Zhang, Wei Yao, Chao Dong, Chun Yang, Qian Ren, Min Ma, Mei Han & Kenji Hashimoto

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  1. Ji-chun Zhang
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  2. Wei Yao
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  3. Chao Dong
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Correspondence to Kenji Hashimoto.

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Supplemental Fig. 1

Ketamine, 7,8-DHF and ANA-12 did not show antidepressant effects in control mice. A: Treatment schedule and behavioral tests. B: LMT, C: TST and D: FST were performed 1 hour, 3 hours, and 5 hours after injection of ketamine (10 mg/kg), 7,8-DHF (10 mg/kg) or ANA-12 (0.5 mg/kg), respectively. E-G: SPT was performed 1 day (day 2), 3 days (day 4) and 7 days (day 8) after injection of ketamine, 7,8-DHF or ANA-12. The values represent the mean ± S.E.M. (n=8-10). Con: control; Veh: vehicle; DHF: 7,8-dihydroxyflavone; ANA: ANA-12; Ket: ketamine; LMT: locomotion test; TST: tail suspension test; FST: forced swimming test; SPT: 1% sucrose preference test.(GIF 109 kb)

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Zhang, Jc., Yao, W., Dong, C. et al. Comparison of ketamine, 7,8-dihydroxyflavone, and ANA-12 antidepressant effects in the social defeat stress model of depression. Psychopharmacology 232, 4325–4335 (2015). https://doi.org/10.1007/s00213-015-4062-3

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