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

Psychopharmacology (Berl). 2019 Dec;236(12):3513-3523. doi: 10.1007/s00213-019-05319-8. Epub 2019 Jul 18.


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.

Keywords: Depression; Glycine; Ketamine; Skeletal muscle.

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology
  • Antidepressive Agents / therapeutic use
  • Depression / chemically induced
  • Depression / drug therapy*
  • Depression / metabolism*
  • Disease Models, Animal
  • Glycine / metabolism*
  • Inflammation / chemically induced
  • Inflammation / drug therapy
  • Inflammation / metabolism
  • Ketamine / pharmacology
  • Ketamine / therapeutic use*
  • Lipopolysaccharides / toxicity*
  • Locomotion / drug effects
  • Locomotion / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism*


  • Antidepressive Agents
  • Lipopolysaccharides
  • Ketamine
  • Glycine