NMDA receptor blockade by ketamine abrogates lipopolysaccharide-induced depressive-like behavior in C57BL/6J mice

Neuropsychopharmacology. 2013 Aug;38(9):1609-16. doi: 10.1038/npp.2013.71. Epub 2013 Mar 19.

Abstract

We have previously demonstrated that lipopolysaccharide (LPS) induces depressive-like behavior by activating indoleamine 2,3 dioxygenase (IDO; O'Connor et al, 2009c). IDO degrades tryptophan along the kynurenine pathway. Using mass-spectrometry (LC-MS) analysis of kynurenine metabolites in the brain of mice injected at the periphery with 1 mg/kg LPS, we show that LPS activates the kynurenine 3-monooxygenase pathway that ultimately degrades kynurenine into quinolinic acid. As quinolinic acid acts as an N-methyl-D-aspartate (NMDA) receptor agonist, we used the NMDA receptor antagonist ketamine to assess the role of NMDA receptor activation in LPS-induced depressive-like behavior. Here, we report that a low dose of ketamine (6 mg/kg, intraperitoneally) immediately before administration of LPS (0.83 mg/kg, intraperitoneally) in C57Bl/6 J mice abrogated the development of LPS-induced depressive-like behavior, without altering LPS-induced sickness measured by body weight loss, decreased motor activity, and reduced food intake. Depressive-like behavior was measured 24 h after LPS by decreased sucrose preference and increased immobility in the forced swim test (FST). Ketamine had no effect on LPS-induced cytokine expression in the liver and brain, IDO activation, and brain-derived neurotrophic factor (BDNF) transcripts. The ability of ketamine to abrogate LPS-induced depressive-like behavior independently of a possible interference with LPS-induced inflammatory signaling was confirmed when ketamine was administered 10 h after LPS instead of immediately before LPS. In contrast, ketamine had no effect when administered 24 h before LPS. To confirm that NMDA receptor antagonism by ketamine mediates the antidepressant-like activity of this compound in LPS-treated mice, mice were pretreated with the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline-2,3-dione (NBQX) to block enhanced AMPA receptor glutamatergic neurotransmission after NMDA receptor antagonism by ketamine. NBQX administered at the dose of 10 mg/kg intraperitoneally 15 min before ketamine in mice treated with LPS 24 h earlier restored LPS-induced decreased sucrose preference. These findings indicate that LPS-induced depressive-like behavior is mediated by NMDA receptor activation, probably as a consequence of formation of quinolinic acid.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology
  • Antidepressive Agents / therapeutic use
  • Body Weight / drug effects
  • Brain / drug effects
  • Brain / metabolism
  • Brain-Derived Neurotrophic Factor / biosynthesis
  • Cytokines / metabolism
  • Depression / chemically induced
  • Depression / drug therapy*
  • Drug Administration Schedule
  • Drug Interactions
  • Eating / drug effects
  • Excitatory Amino Acid Antagonists / pharmacology
  • Food Preferences / drug effects
  • Immobility Response, Tonic / drug effects
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism
  • Ketamine / antagonists & inhibitors
  • Ketamine / pharmacology*
  • Ketamine / therapeutic use
  • Lipopolysaccharides / antagonists & inhibitors*
  • Liver / drug effects
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Motor Activity / drug effects
  • Quinoxalines / pharmacology
  • Receptors, AMPA / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Signal Transduction / drug effects

Substances

  • Antidepressive Agents
  • Brain-Derived Neurotrophic Factor
  • Cytokines
  • Excitatory Amino Acid Antagonists
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Lipopolysaccharides
  • Quinoxalines
  • Receptors, AMPA
  • Receptors, N-Methyl-D-Aspartate
  • 2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline
  • Ketamine