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Contribution of skeletal muscular glycine to rapid antidepressant effects of ketamine in an inflammation-induced mouse model of depression

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Abstract

Rationale

Basic and clinical studies have reported rapid and long-lasting antidepressant effects of ketamine. Although previous studies have proposed several mechanisms underlying the antidepressant effects of ketamine, these mechanisms have not been completely elucidated.

Objectives

The present study evaluated the effects of systemically administered ketamine treatment in a lipopolysaccharide (LPS)-induced mouse model of depression.

Methods

Non-targeted metabolomics, western blotting, and behavioral tests (locomotion, tail suspension, and forced swimming tests) were performed.

Result

Ketamine significantly attenuated the abnormally increased immobility time in a lipopolysaccharide (LPS)-induced mouse model of depression. Aminomalonic acid, glutaraldehyde, glycine, histidine, N-methyl-l-glutamic acid, and ribose levels in skeletal muscle were altered following ketamine administration. Furthermore, ketamine significantly decreased the LPS-induced increase in glycine receptor A1 (GlyA1) levels. However, the glycine receptor antagonist strychnine did not elicit any pharmacological effects on ketamine-induced alterations in behaviors or muscular GlyA1 levels. Exogenous glycine and l-serine significantly improved depression-like symptoms in LPS-induced mice.

Conclusions

Our findings suggest that skeletal muscular glycine contributes to the antidepressant effects of ketamine in inflammation. Effective strategies for improving skeletal muscular glycine levels may be a novel approach to depression treatment.

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References

  • Agudelo LZ, Femenia T, Orhan F, Porsmyr-Palmertz M, Goiny M, Martinez-Redondo V, Correia JC, Izadi M, Bhat M, Schuppe-Koistinen I, Pettersson AT, Ferreira DMS, Krook A, Barres R, Zierath JR, Erhardt S, Lindskog M, Ruas JL (2014) Skeletal muscle PGC-1alpha1 modulates kynurenine metabolism and mediates resilience to stress-induced depression. Cell 159:33–45

    Article  CAS  Google Scholar 

  • Archer T, Josefsson T, Lindwall M (2014) Effects of physical exercise on depressive symptoms and biomarkers in depression. CNS Neurol Disord Drug Targets 13:1640–1653

    Article  Google Scholar 

  • Brunello N, Mendlewicz J, Kasper S, Leonard B, Montgomery S, Nelson J, Paykel E, Versiani M, Racagni G (2002) The role of noradrenaline and selective noradrenaline reuptake inhibition in depression. Eur Neuropsychopharmacol 12:461–475

    Article  CAS  Google Scholar 

  • Bujak R, Struck-Lewicka W, Markuszewski MJ, Kaliszan R (2015) Metabolomics for laboratory diagnostics. J Pharm Biomed Anal 113:108–120

    Article  CAS  Google Scholar 

  • Burgdorf J, Zhang XL, Weiss C, Gross A, Boikess SR, Kroes RA, Khan MA, Burch RM, Rex CS, Disterhoft JF, Stanton PK, Moskal JR (2015) The long-lasting antidepressant effects of rapastinel (GLYX-13) are associated with a metaplasticity process in the medial prefrontal cortex and hippocampus. Neuroscience 308:202–211

    Article  CAS  Google Scholar 

  • Chaki S (2017) Beyond ketamine: new approaches to the development of safer antidepressants. Curr Neuropharmacol 15:963–976

    Article  CAS  Google Scholar 

  • Cryan JF, Mombereau C, Vassout A (2005) The tail suspension test as a model for assessing antidepressant activity: review of pharmacological and genetic studies in mice. Neurosci Biobehav Rev 29:571–625

    Article  CAS  Google Scholar 

  • Dang YH, Ma XC, Zhang JC, Ren Q, Wu J, Gao CG, Hashimoto K (2014) Targeting of NMDA receptors in the treatment of major depression. Curr Pharm Des 20:5151–5159

    Article  CAS  Google Scholar 

  • Danielsson L, Noras AM, Waern M, Carlsson J (2013) Exercise in the treatment of major depression: a systematic review grading the quality of evidence. Physiother Theory Pract 29:573–585

    Article  Google Scholar 

  • Dantzer R, O'Connor JC, Freund GG, Johnson RW, Kelley KW (2008) From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 9:46–56

    Article  CAS  Google Scholar 

  • Dutertre S, Becker CM, Betz H (2012) Inhibitory glycine receptors: an update. J Biol Chem 287:40216–40223

    Article  CAS  Google Scholar 

  • Halket JM, Przyborowska A, Stein SE, Mallard WG, Down S, Chalmers RA (1999) Deconvolution gas chromatography/mass spectrometry of urinary organic acids--potential for pattern recognition and automated identification of metabolic disorders. Rapid Commun Mass Spectrom 13:279–284

    Article  CAS  Google Scholar 

  • Hashimoto K (2014) Targeting of NMDA receptors in new treatments for schizophrenia. Expert Opin Ther Targets 18:1049–1063

    Article  CAS  Google Scholar 

  • Heyman E, Gamelin FX, Goekint M, Piscitelli F, Roelands B, Leclair E, Di Marzo V, Meeusen R (2012) Intense exercise increases circulating endocannabinoid and BDNF levels in humans--possible implications for reward and depression. Psychoneuroendocrinology 37:844–851

    Article  CAS  Google Scholar 

  • Huang N, Hua D, Zhan G, Li S, Zhu B, Jiang R, Yang L, Bi J, Xu H, Hashimoto K, Luo A, Yang C (2019) Role of Actinobacteria and Coriobacteriia in the antidepressant effects of ketamine in an inflammation model of depression. Pharmacol Biochem Behav 176:93–100

    Article  CAS  Google Scholar 

  • Ito S (2016) GABA and glycine in the developing brain. J Physiol Sci 66:375–379

    Article  CAS  Google Scholar 

  • Kind T, Wohlgemuth G, Lee DY, Lu Y, Palazoglu M, Shahbaz S, Fiehn O (2009) FiehnLib: mass spectral and retention index libraries for metabolomics based on quadrupole and time-of-flight gas chromatography/mass spectrometry. Anal Chem 81:10038–10048

    Article  CAS  Google Scholar 

  • Koopman R, Caldow MK, Ham DJ, Lynch GS (2017) Glycine metabolism in skeletal muscle: implications for metabolic homeostasis. Curr Opin Clin Nutr Metab Care 20:237–242

    Article  CAS  Google Scholar 

  • Kvam S, Kleppe CL, Nordhus IH, Hovland A (2016) Exercise as a treatment for depression: a meta-analysis. J Affect Disord 202:67–86

    Article  Google Scholar 

  • Li H, Cai J, Chen R, Zhao Z, Ying Z, Wang L, Chen J, Hao K, Kinney PL, Chen H, Kan H (2017) Particulate matter exposure and stress hormone levels: a randomized, double-blind, crossover trial of air purification. Circulation 136:618–627

    Article  CAS  Google Scholar 

  • Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, Li XY, Aghajanian G, Duman RS (2010a) mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329:959–964

    Article  CAS  Google Scholar 

  • Li ZY, Zheng XY, Gao XX, Zhou YZ, Sun HF, Zhang LZ, Guo XQ, Du GH, Qin XM (2010b) Study of plasma metabolic profiling and biomarkers of chronic unpredictable mild stress rats based on gas chromatography/mass spectrometry. Rapid Commun Mass Spectrom 24:3539–3546

    Article  CAS  Google Scholar 

  • Lynch JW (2004) Molecular structure and function of the glycine receptor chloride channel. Physiol Rev 84:1051–1095

    Article  CAS  Google Scholar 

  • Lynch JW, Zhang Y, Talwar S, Estrada-Mondragon A (2017) Glycine receptor drug discovery. Adv Pharmacol 79:225–253

    Article  CAS  Google Scholar 

  • Ni Y, Su M, Lin J, Wang X, Qiu Y, Zhao A, Chen T, Jia W (2008) Metabolic profiling reveals disorder of amino acid metabolism in four brain regions from a rat model of chronic unpredictable mild stress. FEBS Lett 582:2627–2636

    Article  CAS  Google Scholar 

  • Nong Y, Huang YQ, Ju W, Kalia LV, Ahmadian G, Wang YT, Salter MW (2003) Glycine binding primes NMDA receptor internalization. Nature 422:302–307

    Article  CAS  Google Scholar 

  • 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 267:177–182

    Article  Google Scholar 

  • Smith K (2014) Mental health: a world of depression. Nature 515:181

    PubMed  Google Scholar 

  • Wohleb ES, Gerhard D, Thomas A, Duman RS (2017) Molecular and cellular mechanisms of rapid-acting antidepressants ketamine and scopolamine. Curr Neuropharmacol 15:11–20

    Article  CAS  Google Scholar 

  • Wu H, Yu B, Meng G, Liu F, Guo Q, Wang J, Du H, Zhang W, Shen S, Han P, Dong R, Wang X, Ma Y, Chen X, Niu K (2017a) Both muscle mass and muscle strength are inversely associated with depressive symptoms in an elderly Chinese population. Int J Geriatr Psychiatry 32:769–778

    Article  Google Scholar 

  • Wu Y, Li Y, Jia Y, Wei C, Xu H, Guo R, Li Y, Jia J, Qi X, Gao X (2017b) Imbalance in amino acid and purine metabolisms at the hypothalamus in inflammation-associated depression by GC-MS. Mol BioSyst 13:2715–2728

    Article  CAS  Google Scholar 

  • Xia CY, Wang ZZ, Yamakuni T, Chen NH (2018) A novel mechanism of depression: role for connexins. Eur Neuropsychopharmacol 28:483–498

    Article  CAS  Google Scholar 

  • Yang C, Kobayashi S, Nakao K, Dong C, Han M, Qu Y, Ren Q, Zhang JC, Ma M, Toki H, Yamaguchi JI, Chaki S, Shirayama Y, Nakazawa K, Manabe T, Hashimoto K (2018a) AMPA receptor activation-independent antidepressant actions of ketamine metabolite (S)-Norketamine. Biol Psychiatry 84:591–600

    Article  CAS  Google Scholar 

  • 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 7:1294

    Article  Google Scholar 

  • Yang C, Ren Q, Qu Y, Zhang JC, Ma M, Dong C, Hashimoto K (2018b) Mechanistic target of rapamycin-independent antidepressant effects of (R)-ketamine in a social defeat stress model. Biol Psychiatry 83:18–28

    Article  CAS  Google Scholar 

  • Yang C, Shirayama Y, Zhang JC, 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:e632

    Article  CAS  Google Scholar 

  • Zhan G, Huang N, Li S, Hua D, Zhang J, Fang X, Yang N, Luo A, Yang C (2018) PGC-1alpha-FNDC5-BDNF signaling pathway in skeletal muscle confers resilience to stress in mice subjected to chronic social defeat. Psychopharmacology 235:3351–3358

    Article  CAS  Google Scholar 

  • Zhang JC, Yao W, Hashimoto K (2016) Brain-derived neurotrophic factor (BDNF)-TrkB signaling in inflammation-related depression and potential therapeutic targets. Curr Neuropharmacol 14:721–731

    Article  CAS  Google Scholar 

  • Zhang XY, Ji F, Wang N, Chen LL, Tian T, Lu W (2014) Glycine induces bidirectional modifications in N-methyl-D-aspartate receptor-mediated synaptic responses in hippocampal CA1 neurons. J Biol Chem 289:31200–31211

    Article  CAS  Google Scholar 

  • Zhu W, Ding Z, Zhang Y, Shi J, Hashimoto K, Lu L (2016) Risks associated with misuse of ketamine as a rapid-acting antidepressant. Neurosci Bull 32:557–564

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by grants from the National Natural Science Foundation of China (A.L. [81771159 and 81571047]; C.Y. [81703482]) and supported in part by the Program of the Bureau of Science and Technology Foundation of Changzhou (B.Z. [CJ20159022]; L.Y. [CJ20160030]) and Major Science and Technology Projects of Changzhou Municipal Committee of Health and Family Planning (B.Z. [ZD201505]; L.Y. [ZD201407]).

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Author notes

  1. Niannian Huang and Yue Wang contributed equally to this work.

Authors and Affiliations

  1. Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan, 430030, China

    Niannian Huang, Yue Wang, Gaofeng Zhan, Shan Li, Dongyu Hua, Shiyong Li, Ailin Luo & Chun Yang

  2. Department of Endocrinology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, China

    Fan Yu & Fei Hua

  3. Department of Radiation Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, China

    Riyue Jiang

  4. Department of Cardiology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, China

    Yeshun Wu & Ling Yang

  5. Department of Critical Care Medicine, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, China

    Bin Zhu

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  1. Niannian Huang
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Corresponding authors

Correspondence to Ailin Luo or Chun Yang.

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Conflict of interest

Dr. Chun Yang received research support from B. Braun Medical Inc. Other authors have no conflicts of interest to declare.

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Huang, N., Wang, Y., Zhan, G. et al. Contribution of skeletal muscular glycine to rapid antidepressant effects of ketamine in an inflammation-induced mouse model of depression. Psychopharmacology 236, 3513–3523 (2019). https://doi.org/10.1007/s00213-019-05319-8

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  • DOI: https://doi.org/10.1007/s00213-019-05319-8

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