Chronic Mild Stress Alters Kynurenine Pathways Changing the Glutamate Neurotransmission in Frontal Cortex of Rats

Mol Neurobiol. 2019 Jan;56(1):490-501. doi: 10.1007/s12035-018-1096-7. Epub 2018 May 3.


Immune stimulation might be involved in the pathophysiology of major depressive disorder (MDD). This stimulation induces indoleamine 2,3-dioxygenase (IDO), an enzyme that reduces the tryptophan bioavailability to synthesize serotonin. IDO products, kynurenine metabolites, exert neurotoxic/neuroprotective actions through glutamate receptors. Thus, we study elements of these pathways linked to kynurenine metabolite activity examining whether antidepressants (ADs) can modulate them. Male Wistar rats were exposed to chronic mild stress (CMS), and some of them were treated with ADs. The expression of elements of the IDO pathway, including kynurenine metabolites, and their possible modulation by ADs was studied in the frontal cortex (FC). CMS increased IDO expression in FC compared to control group, and ADs restored the IDO expression levels to control values. CMS-induced IDO expression led to increased levels of the excitotoxic quinolinic acid (QUINA) compared to control, and ADs prevented the rise in such levels. Neither CMS nor ADs changed significantly the antiexcitotoxic kynurenic acid (KYNA) levels. The QUINA/KYNA ratio, calculated as excitotoxicity risk indicator, increased after CMS and ADs prevented this increase. CMS lowered excitatory amino acid transporter (EAAT)-1 and EAAT-4 expression, and some ADs restored their expression levels. Furthermore, CMS decreased N-methyl-D-aspartate receptor (NMDAR)-2A and 2B protein expression, and ADs mitigated this decrease. Our research examines the link between CMS-induced pro-inflammatory cytokines and the kynurenine pathway; it shows that CMS alters the kynurenine pathway in rat FC. Importantly, it also reveals the ability of classic ADs to prevent potentially harmful situations related to the brain scenario caused by CMS.

Keywords: Antidepressants; Chronic mild stress; Frontal cortex; Glutamate neurotransmission; Indoleamine 2,3-dioxygenase; Kynurenine pathways.

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology
  • Antidepressive Agents / therapeutic use
  • Chronic Disease
  • Cytokines / metabolism
  • Frontal Lobe / drug effects
  • Frontal Lobe / pathology*
  • Frontal Lobe / physiopathology*
  • Glutamate Plasma Membrane Transport Proteins / genetics
  • Glutamate Plasma Membrane Transport Proteins / metabolism
  • Glutamic Acid / metabolism*
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism
  • Inflammation Mediators / metabolism
  • Kynurenic Acid / metabolism
  • Kynurenine / metabolism*
  • Male
  • Metabolic Networks and Pathways / drug effects
  • Quinolinic Acid / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Wistar
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Stress, Psychological / drug therapy
  • Stress, Psychological / metabolism*
  • Stress, Psychological / physiopathology*
  • Synaptic Transmission* / drug effects
  • Tryptophan / metabolism


  • Antidepressive Agents
  • Cytokines
  • Glutamate Plasma Membrane Transport Proteins
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Inflammation Mediators
  • RNA, Messenger
  • Receptors, N-Methyl-D-Aspartate
  • Kynurenine
  • Glutamic Acid
  • Tryptophan
  • Quinolinic Acid
  • Kynurenic Acid