Lack of dopamine D1 receptors in the antidepressant actions of (R)-ketamine in a chronic social defeat stress model

  • Lijia Chang
  • Kai Zhang
  • Yaoyu Pu
  • Youge Qu
  • Si-ming Wang
  • Zhongwei Xiong
  • Yukihiko Shirayama
  • Kenji HashimotoEmail author
Short Communication


It is reported that dopamine D1 receptors in the medial prefrontal cortex play a role in the antidepressant actions of (R,S)-ketamine. However, its role in the antidepressant actions of (R)-ketamine, which is more potent than (S)-ketamine, is unknown. In the locomotion test, tail suspension test, forced swimming test and 1% sucrose preference test, pretreatment with dopamine D1 receptor antagonist SCH-23390 did not block the antidepressant effects of (R)-ketamine in the susceptible mice after chronic social defeat stress. These findings suggest that dopamine D1 receptors may not play a major role in the antidepressant actions of (R)-ketamine.


Antidepressant (R)-ketamine Dopamine D1 receptor Social defeat stress 



This study was supported by AMED (to K.H., JP18dm0107119). Dr. Hashimoto is an inventor on a filed patent application on “The use of (R)-ketamine in the treatment of psychiatric diseases” by Chiba University. Dr. Hashimoto has received research support from Dainippon-Sumitomo, Otsuka, and Taisho.

Compliance with ethical standards

Conflict of interest

All authors declare that they have no conflict of interest.


  1. 1.
    Newport DJ, Carpenter LL, McDonald WM, Potash JB, Tohen M, Nemeroff CB (2015) Ketamine and other NMDA antagonists: early clinical trials and possible mechanisms in depression. Am J Psychiatry 172(10):950–966CrossRefGoogle Scholar
  2. 2.
    Kishimoto T, Chawla JM, Hagi K, Zarate CA, Kane JM, Bauer M, Correll CU (2016) Single-dose infusion ketamine and non-ketamine N-methyl-d-aspartate receptor antagonists for unipolar and bipolar depression: a meta-analysis of efficacy, safety and time trajectories. Psychol Med 46(7):1459–1472CrossRefGoogle Scholar
  3. 3.
    Zhang K, Hashimoto K (2019) An update on ketamine and its two enantiomers as rapid-acting antidepressants. Expert Rev Neurother 19(1):83–92CrossRefGoogle Scholar
  4. 4.
    Ebert B, Mikkelsen S, Thorkildsen C, Borgbjerg FM (1997) Norketamine, the main metabolite of ketamine, is a non-competitive NMDA receptor antagonist in the rat cortex and spinal cord. Eur J Pharmacol 333(1):99–104CrossRefGoogle Scholar
  5. 5.
    Fukumoto K, Toki H, Iijima M, Hashihayata T, J-i Yamaguchi, Hashimoto K, Chaki S (2017) Antidepressant potential of (R)-ketamine in rodent models: comparison with (S)-ketamine. J Pharmacol Exp Ther 36(1):9–16CrossRefGoogle Scholar
  6. 6.
    Zhang JC, Li SX, Hashimoto K (2014) R(−)-ketamine shows greater potency and longer lasting antidepressant effects than S(+)-ketamine. Pharmacol Biochem Behav 116:137–141CrossRefGoogle Scholar
  7. 7.
    Yang C, Shirayama Y, Jc Zhang, Ren Q, Yao W, Ma M, Dong C, Hashimoto K (2015) R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects. Transl Psychiatry 5:e632CrossRefGoogle Scholar
  8. 8.
    Yang C, Qu Y, Abe M, Nozawa D, Chaki S, Hashimoto K (2017) (R)-ketamine shows greater potency and longer lasting antidepressant effects than its metabolite (2R,6R)-hydroxynorketamine. Biol Psychiatry 82(5):e43–e44CrossRefGoogle Scholar
  9. 9.
    Yang C, Qu Y, Fujita Y, Ren Q, Ma M, Dong C, Hashimoto K (2017) Possible role of the gut microbiota-brain axis in the antidepressant effects of (R)-ketamine in a social defeat stress model. Transl Psychiatry 7(12):1294CrossRefGoogle Scholar
  10. 10.
    Yang C, Ren Q, Qu Y, Zhang J-C, Ma M, Dong C, Hashimoto K (2018) Mechanistic target of rapamycin–independent antidepressant effects of (R)-ketamine in a social defeat stress model. Biol Psychiatry 83(1):18–28CrossRefGoogle Scholar
  11. 11.
    Zhang K, Ma M, Dong C, Hashimoto K (2018) Role of inflammatory bone markers in the antidepressant actions of (R)-ketamine in a chronic social defeat stress model. Int J Neuropsychopharmacol 21(11):1025–1030Google Scholar
  12. 12.
    Hashimoto K (2016) Letter to the Editor: R-ketamine: a rapid-onset and sustained antidepressant without risk of brain toxicity. Psychol Med 46(11):2449–2451CrossRefGoogle Scholar
  13. 13.
    Yang C, Han M, J-c Zhang, Ren Q, Hashimoto K (2016) Loss of parvalbumin-immunoreactivity in mouse brain regions after repeated intermittent administration of esketamine, but not R-ketamine. Psychiatry Res 239:281–283CrossRefGoogle Scholar
  14. 14.
    Hashimoto K, Kakiuchi T, Ohba H, Nishiyama S, Tsukada H (2017) Reduction of dopamine D2/3 receptor binding in the striatum after a single administration of esketamine, but not R-ketamine: a PET study in conscious monkeys. Eur Arch Psychiatry Clin Neurosci 267(2):173–176CrossRefGoogle Scholar
  15. 15.
    Tian Z, Dong C, Fujita A, Fujita Y, Hashimoto K (2018) Expression of heat shock protein HSP-70 in the retrosplenial cortex of rat brain after administration of (R, S)-ketamine and (S)-ketamine, but not (R)-ketamine. Pharmacol Biochem Behav 172:17–21CrossRefGoogle Scholar
  16. 16.
    Fuchikami M, Thomas A, Liu R, Wohleb ES, Land BB, DiLeone RJ, Aghajanian GK, Duman RS (2015) Optogenetic stimulation of infralimbic PFC reproduces ketamine’s rapid and sustained antidepressant actions. Proc Nat Acad Sci USA 112(26):8106–8111CrossRefGoogle Scholar
  17. 17.
    Shirayama Y, Hashimoto K (2017) Effects of a single bilateral infusion of R-ketamine in the rat brain regions of a learned helplessness model of depression. Eur Arch Psychiatry Clin Neurosci 267(2):177–182CrossRefGoogle Scholar
  18. 18.
    Hare BD, Shinohara R, Liu RJ, Pothula S, DiLeone RJ, Duman RS (2019) Optogenetic stimulation of medial prefrontal cortex Drd1 neurons produces rapid and long-lasting antidepressant effects. Nat Commun 10(1):223CrossRefGoogle Scholar
  19. 19.
    Li Y, Zhu ZR, Ou BC, Wang YQ, Tan ZB, Deng CM, Gao YY, Tang M, So JH, Mu YL, Zhang LQ (2015) Dopamine D2/D3 but not dopamine D1 receptors are involved in the rapid antidepressant-like effects of ketamine in the forced swim test. Behav Brain Res 279:100–105CrossRefGoogle Scholar
  20. 20.
    Hashimoto K, Shirayama Y (2018) What are the causes for discrepancies of antidepressant actions of (2R,6R)-hydroxynorketamine? Biol Psychiatry 84(1):e7–e8CrossRefGoogle Scholar
  21. 21.
    Chang L, Toki H, Qu Y, Fujita Y, Mizuno-Yasuhira A, Yamaguchi JI, Chaki S, Hashimoto K (2018) No sex-specific differences in the acute antidepressant actions of (R)-ketamine in an inflammation model. Int J Neuropsychopharmacol 21(10):932–937CrossRefGoogle Scholar
  22. 22.
    Nugent AC, Ballard ED, Gould TD, Park LT, Moaddel R, Brutsche NE, Zarate CA Jr (2018) Ketamine has distinct electrophysiological and behavioral effects in depressed and healthy subjects. Mol Psychiatry. Google Scholar
  23. 23.
    Moghaddam B, Adams B, Verma A, Daly D (1997) Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci 17(8):2921–2927CrossRefGoogle Scholar
  24. 24.
    Ago Y, Tanabe W, Higuchi M, Tsukada S, Hashimoto K, Hashimoto H (2018) (R)-ketmaine, (S)-ketamine and their metabolites affect differentially in vivo monoamine release in the prefrontal cortex of mice: different involvement of AMPA receptor. Poster W-131 at 57th annual meeting of The American College of Neuropsychopharmacology, Hollywood, FL, 12 Dec 2018Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Lijia Chang
    • 1
  • Kai Zhang
    • 1
  • Yaoyu Pu
    • 1
  • Youge Qu
    • 1
  • Si-ming Wang
    • 1
  • Zhongwei Xiong
    • 1
  • Yukihiko Shirayama
    • 1
    • 2
  • Kenji Hashimoto
    • 1
    Email author
  1. 1.Division of Clinical NeuroscienceChiba University Center for Forensic Mental HealthChibaJapan
  2. 2.Department of PsychiatryTeikyo University Chiba Medical CenterIchiharaJapan

Personalised recommendations