Skip to main content

Advertisement

SpringerLink
Log in

Is there a role for glutamate-mediated excitotoxicity in inflammation-induced depression?

  • Translational Neurosciences - Review article
  • Published:
Journal of Neural Transmission Aims and scope Submit manuscript

Abstract

Chronic inflammation in physically ill patients is often associated with the development of symptoms of depression. The mechanisms that are responsible for inflammation-associated depression have been elucidated over the last few years. Kynurenine produced from tryptophan in a reaction catabolized by indoleamine 2,3 dioxygenase is transported into the brain where it is metabolized by microglial enzymes into a number of neurotropic compounds including quinolinic acid, an agonist of N-methyl-d-aspartate receptors. Quinolinic acid can synergize with glutamate released by activated microglia. This chain of events opens the possibility to treat inflammation-induced depression using therapies that target the transport of kynurenine through the blood–brain barrier, the production of quinolinic acid and glutamate by activated microglia, or the efflux of glutamate from the brain to the blood.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Andreetta F, Barnes NM, Wren PB, Carboni L (2013) p38 MAP kinase activation does not stimulate serotonin transport in rat brain: implications for sickness behaviour mechanisms. Life Sci 93:30–37. doi:10.1016/j.lfs.2013.05.014

    Article  CAS  PubMed  Google Scholar 

  • Benton T, Staab J, Evans DL (2007) Medical co-morbidity in depressive disorders. Ann Clin Psychiatry Off J Am Acad Clin Psychiatr 19:289–303. doi:10.1080/10401230701653542

    Article  Google Scholar 

  • Berman RM et al (2000) Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 47:351–354

    Article  CAS  PubMed  Google Scholar 

  • Boado RJ, Li JY, Nagaya M, Zhang C, Pardridge WM (1999) Selective expression of the large neutral amino acid transporter at the blood–brain barrier. Proc Natl Acad Sci USA 96:12079–12084

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Campos F et al (2011) Neuroprotection by glutamate oxaloacetate transaminase in ischemic stroke: an experimental study. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab 31:1378–1386. doi:10.1038/jcbfm.2011.3

    Article  CAS  Google Scholar 

  • Capuron L et al (2002a) Neurobehavioral effects of interferon-alpha in cancer patients: phenomenology and paroxetine responsiveness of symptom dimensions. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol 26:643–652. doi:10.1016/S0893-133X(01)00407-9

    Article  CAS  Google Scholar 

  • Capuron L et al (2002b) Association between decreased serum tryptophan concentrations and depressive symptoms in cancer patients undergoing cytokine therapy. Mol Psychiatry 7:468–473. doi:10.1038/sj.mp.4000995

    Article  CAS  PubMed  Google Scholar 

  • Cohen-Kashi-Malina K, Cooper I, Teichberg VI (2012) Mechanisms of glutamate efflux at the blood-brain barrier: involvement of glial cells. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab 32:177–189. doi:10.1038/jcbfm.2011.121

    Article  CAS  Google Scholar 

  • Conrad M, Sato H (2012) The oxidative stress-inducible cystine/glutamate antiporter, system x(c) (−): cystine supplier and beyond. Amino Acids 42:231–246. doi:10.1007/s00726-011-0867-5

    Article  CAS  PubMed  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. doi:10.1038/nrn2297

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Denicoff KD et al (1987) The neuropsychiatric effects of treatment with interleukin-2 and lymphokine-activated killer cells. Ann Intern Med 107:293–300

    Article  CAS  PubMed  Google Scholar 

  • Eastman CL, Guilarte TR (1989) Cytotoxicity of 3-hydroxykynurenine in a neuronal hybrid cell line. Brain Res 495:225–231

    Article  CAS  PubMed  Google Scholar 

  • Elovainio M et al (2011) Moderating effect of indoleamine 2,3-dioxygenase (IDO) activation in the association between depressive symptoms and carotid atherosclerosis: evidence from the Young Finns study. J Affect Disord 133:611–614. doi:10.1016/j.jad.2011.04.025

    Article  CAS  PubMed  Google Scholar 

  • Erhardt S et al (2013) Connecting inflammation with glutamate agonism in suicidality. Neuropsychopharmacology 38:743–752. doi:10.1038/npp.2012.248

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Eugenin EA et al (2001) Microglia at brain stab wounds express connexin 43 and in vitro form functional gap junctions after treatment with interferon-gamma and tumor necrosis factor-alpha. Proc Natl Acad Sci USA 98:4190–4195. doi:10.1073/pnas.051634298

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Evans DL et al (2005) Mood disorders in the medically ill: scientific review and recommendations. Biol Psychiatry 58:175–189. doi:10.1016/j.biopsych.2005.05.001

    Article  PubMed  Google Scholar 

  • Fu X et al (2010) Central administration of lipopolysaccharide induces depressive-like behavior in vivo and activates brain indoleamine 2,3 dioxygenase in murine organotypic hippocampal slice cultures. J Neuroinflamm 7:43. doi:10.1186/1742-2094-7-43

    Article  Google Scholar 

  • Fukui S, Schwarcz R, Rapoport SI, Takada Y, Smith QR (1991) Blood-brain barrier transport of kynurenines: implications for brain synthesis and metabolism. J Neurochem 56:2007–2017

    Article  CAS  PubMed  Google Scholar 

  • Gabbay V, Ely BA, Babb J, Liebes L (2012) The possible role of the kynurenine pathway in anhedonia in adolescents. J Neural Transm 119:253–260. doi:10.1007/s00702-011-0685-7

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Garcia LS et al (2008) Acute administration of ketamine induces antidepressant-like effects in the forced swimming test and increases BDNF levels in the rat hippocampus. Progr Neuropsychopharmacol Biol Psychiatry 32:140–144

    Article  CAS  Google Scholar 

  • Gold AB et al (2011) The relationship between indoleamine 2,3-dioxygenase activity and post-stroke cognitive impairment. J Neuroinflamm 8:17. doi:10.1186/1742-2094-8-17

    Article  CAS  Google Scholar 

  • Goldberg D (2010) The detection and treatment of depression in the physically ill. World Psychiatry Off J World Psychiatr Assoc 9:16–20

    Google Scholar 

  • Gras G et al (2012) EAAT expression by macrophages and microglia: still more questions than answers. Amino Acids 42:221–229. doi:10.1007/s00726-011-0866-6

    Article  CAS  PubMed  Google Scholar 

  • Helms HC, Madelung R, Waagepetersen HS, Nielsen CU, Brodin B (2012) In vitro evidence for the brain glutamate efflux hypothesis: brain endothelial cells cocultured with astrocytes display a polarized brain-to-blood transport of glutamate. Glia 60:882–893. doi:10.1002/glia.22321

    Article  PubMed  Google Scholar 

  • Heyes MP, Quearry BJ, Markey SP (1989) Systemic endotoxin increases l-tryptophan, 5-hydroxyindoleacetic acid, 3-hydroxykynurenine and quinolinic acid content of mouse cerebral cortex. Brain Res 491:173–179

    Article  CAS  PubMed  Google Scholar 

  • Hosoya K, Sugawara M, Asaba H, Terasaki T (1999) Blood-brain barrier produces significant efflux of l-aspartic acid but not d-aspartic acid: in vivo evidence using the brain efflux index method. J Neurochem 73:1206–1211

    Article  CAS  PubMed  Google Scholar 

  • Irwin MR, Miller AH (2007) Depressive disorders and immunity: 20 years of progress and discovery. Brain Behav Immun 21:374–383. doi:10.1016/j.bbi.2007.01.010

    Article  CAS  PubMed  Google Scholar 

  • Kigerl KA et al (2012) System x(c)(−) regulates microglia and macrophage glutamate excitotoxicity in vivo. Exp Neurol 233:333–341. doi:10.1016/j.expneurol.2011.10.025

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kita T, Morrison PF, Heyes MP, Markey SP (2002) Effects of systemic and central nervous system localized inflammation on the contributions of metabolic precursors to the l-kynurenine and quinolinic acid pools in brain. J Neurochem 82:258–268

    Article  CAS  PubMed  Google Scholar 

  • Kurz K, Schroecksnadel S, Weiss G, Fuchs D (2011) Association between increased tryptophan degradation and depression in cancer patients. Curr Opin Clin Nutr Metab Care 14:49–56. doi:10.1097/MCO.0b013e328340d849

    Article  CAS  PubMed  Google Scholar 

  • Larkin GL, Beautrais A (2011) A preliminary naturalistic study of low-dose ketamine for depression and suicide ideation. Int J Neuropsychopharmacol 14:1127–1131

    Article  CAS  PubMed  Google Scholar 

  • Lawson MA et al (2013) Intracerebroventricular administration of lipopolysaccharide induces indoleamine-2,3-dioxygenase-dependent depression-like behaviors. J Neuroinflamm 10:87. doi:10.1186/1742-2094-10-87

    Article  CAS  Google Scholar 

  • Leibowitz A, Boyko M, Shapira Y, Zlotnik A (2012) Blood glutamate scavenging: insight into neuroprotection. Int J Mol Sci 13:10041–10066. doi:10.3390/ijms130810041

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Maeng S, Zarate CA Jr (2007) The role of glutamate in mood disorders: results from the ketamine in major depression study and the presumed cellular mechanism underlying its antidepressant effects. Curr Psychiatry Rep 9:467–474

    Article  PubMed  Google Scholar 

  • Mattox ML, D’Angelo JA, Grimes ZM, Fiebiger E, Dickinson BL (2012) The cystine/glutamate antiporter regulates indoleamine 2,3-dioxygenase protein levels and enzymatic activity in human dendritic cells. Am J Clin Exp Immunol 1:113–123

    PubMed Central  PubMed  Google Scholar 

  • Miller AH, Ancoli-Israel S, Bower JE, Capuron L, Irwin MR (2008) Neuroendocrine-immune mechanisms of behavioral comorbidities in patients with cancer. J Clin Oncol Off J Am Soc Clin Oncol 26:971–982. doi:10.1200/JCO.2007.10.7805

    CAS  Google Scholar 

  • Moreau M et al (2008) Inoculation of Bacillus Calmette–Guerin to mice induces an acute episode of sickness behavior followed by chronic depressive-like behavior. Brain Behav Immun 22:1087–1095. doi:10.1016/j.bbi.2008.04.001

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Nagy D et al (2010) Effects of blood glutamate scavenging on cortical evoked potentials. Cell Mol Neurobiol 30:1101–1106. doi:10.1007/s10571-010-9542-8

    Article  CAS  PubMed  Google Scholar 

  • Nosyreva E et al (2013) Acute suppression of spontaneous neurotransmission drives synaptic potentiation. J Neurosci 33:6990–7002

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • O’Connor JC et al (2009a) Interferon-gamma and tumor necrosis factor-alpha mediate the upregulation of indoleamine 2,3-dioxygenase and the induction of depressive-like behavior in mice in response to bacillus Calmette–Guerin. J Neurosci Off J Soc Neurosci 29:4200–4209. doi:10.1523/JNEUROSCI.5032-08.2009

    Google Scholar 

  • O’Connor JC et al (2009b) Induction of IDO by bacille Calmette–Guerin is responsible for development of murine depressive-like behavior. J Immunol 182:3202–3212. doi:10.4049/jimmunol.0802722

    Article  PubMed Central  PubMed  Google Scholar 

  • O’Connor JC et al (2009c) Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice. Mol Psychiatry 14:511–522. doi:10.1038/sj.mp.4002148

    Article  PubMed Central  PubMed  Google Scholar 

  • Obrenovitch TP, Urenjak J (2003) Accumulation of quinolinic acid with neuroinflammation: does it mean excitotoxicity? Adv Exp Med Biol 527:147–154

    Article  CAS  PubMed  Google Scholar 

  • Omidi Y, Barar J, Ahmadian S, Heidari HR, Gumbleton M (2008) Characterization and astrocytic modulation of system L transporters in brain microvasculature endothelial cells. Cell Biochem Funct 26:381–391. doi:10.1002/cbf.1455

    Article  CAS  PubMed  Google Scholar 

  • Piani D, Spranger M, Frei K, Schaffner A, Fontana A (1992) Macrophage-induced cytotoxicity of N-methyl-d-aspartate receptor positive neurons involves excitatory amino acids rather than reactive oxygen intermediates and cytokines. Eur J Immunol 22:2429–2436. doi:10.1002/eji.1830220936

    Article  CAS  PubMed  Google Scholar 

  • Raison CL, Miller AH (2013) Do cytokines really sing the blues? Cerebrum Dana Forum Brain Sci 2013:10

    Google Scholar 

  • Raison CL et al (2010) CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-alpha: relationship to CNS immune responses and depression. Mol Psychiatry 15:393–403. doi:10.1038/mp.2009.116

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Raison CL et al (2013) A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. J Am Med Assoc Psychiatry 70:31–41. doi:10.1001/2013.jamapsychiatry.4

    CAS  Google Scholar 

  • Renault PF et al (1987) Psychiatric complications of long-term interferon alfa therapy. Arch Intern Med 147:1577–1580

    Article  CAS  PubMed  Google Scholar 

  • Ruban A, Mohar B, Jona G, Teichberg VI (2013) Blood glutamate scavenging as a novel neuroprotective treatment for paraoxon intoxication. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab. doi:10.1038/jcbfm.2013.186

    Google Scholar 

  • Saito K, Markey SP, Heyes MP (1992) Effects of immune activation on quinolinic acid and neuroactive kynurenines in the mouse. Neuroscience 51:25–39

    Article  CAS  PubMed  Google Scholar 

  • Schwarcz R, Bruno JP, Muchowski PJ, Wu HQ (2012) Kynurenines in the mammalian brain: when physiology meets pathology. Nat Rev Neurosci 13:465–477. doi:10.1038/nrn3257

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Smith AJ, Smith RA, Stone TW (2009) 5-Hydroxyanthranilic acid, a tryptophan metabolite, generates oxidative stress and neuronal death via p38 activation in cultured cerebellar granule neurones. Neurotox Res 15:303–310. doi:10.1007/s12640-009-9034-0

    Article  CAS  PubMed  Google Scholar 

  • Steiner J et al (2011) Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus: evidence for an immune-modulated glutamatergic neurotransmission? J Neuroinflamm 8:94. doi:10.1186/1742-2094-8-94

    Article  CAS  Google Scholar 

  • Sublette ME, Postolache TT (2012) Neuroinflammation and depression: the role of indoleamine 2,3-dioxygenase (IDO) as a molecular pathway. Psychosom Med 74:668–672. doi:10.1097/PSY.0b013e318268de9f

    Article  PubMed  Google Scholar 

  • Swardfager W et al (2009) Indoleamine 2,3-dioxygenase activation and depressive symptoms in patients with coronary artery disease. Psychoneuroendocrinology 34:1560–1566. doi:10.1016/j.psyneuen.2009.05.019

    Article  CAS  PubMed  Google Scholar 

  • Takaki J et al (2012) l-Glutamate released from activated microglia downregulates astrocytic l-glutamate transporter expression in neuroinflammation: the ‘collusion’ hypothesis for increased extracellular l-glutamate concentration in neuroinflammation. J Neuroinflamm 9:275. doi:10.1186/1742-2094-9-275

    Article  CAS  Google Scholar 

  • Takeuchi H et al (2006) Tumor necrosis factor-alpha induces neurotoxicity via glutamate release from hemichannels of activated microglia in an autocrine manner. J Biol Chem 281:21362–21368. doi:10.1074/jbc.M600504200

    Article  CAS  PubMed  Google Scholar 

  • Teichberg VI, Cohen-Kashi-Malina K, Cooper I, Zlotnik A (2009) Homeostasis of glutamate in brain fluids: an accelerated brain-to-blood efflux of excess glutamate is produced by blood glutamate scavenging and offers protection from neuropathologies. Neuroscience 158:301–308. doi:10.1016/j.neuroscience.2008.02.075

    Article  CAS  PubMed  Google Scholar 

  • Tyring S et al (2006) Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase III trial. Lancet 367:29–35. doi:10.1016/S0140-6736(05)67763-X

    Article  CAS  PubMed  Google Scholar 

  • van Heesch F et al (2013) Lipopolysaccharide-induced anhedonia is abolished in male serotonin transporter knockout rats: an intracranial self-stimulation study. Brain Behav Immun 29:98–103. doi:10.1016/j.bbi.2012.12.013

    Article  PubMed  Google Scholar 

  • Widner B, Laich A, Sperner-Unterweger B, Ledochowski M, Fuchs D (2002) Neopterin production, tryptophan degradation, and mental depression—what is the link? Brain Behav Immun 16:590–595

    Article  CAS  PubMed  Google Scholar 

  • Walker AK et al (2013) NMDA receptor blockade by ketamine abrogates lipopolysaccharide-induced depressive-like behavior in C57BL/6J mice. Neuropsychopharmacology Off Publ Am Coll Neuropsychopharmacol 38:1609–1616. doi:10.1038/npp.2013.71

    Article  CAS  Google Scholar 

  • Yawata I et al (2008) Macrophage-induced neurotoxicity is mediated by glutamate and attenuated by glutaminase inhibitors and gap junction inhibitors. Life Sci 82:1111–1116. doi:10.1016/j.lfs.2008.03.010

    Article  CAS  PubMed  Google Scholar 

  • Zhu CB et al (2010) Interleukin-1 receptor activation by systemic lipopolysaccharide induces behavioral despair linked to MAPK regulation of CNS serotonin transporters. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol 35:2510–2520. doi:10.1038/npp.2010.116

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the University of Texas MD Anderson Cancer Center and grants from the National Institute of Neurological Diseases and Stroke of the National Institutes of Health (Grants R01 NS073939; R01 NS074999). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Conflict of interest

Robert Dantzer works as a consultant for Ironwood Pharma.

Author information

Authors and Affiliations

  1. Division of Internal Medicine, Department of Symptom Research, MD Anderson Cancer Center, 1400 Pressler Street, Houston, TX, 77030, USA

    Robert Dantzer & Adam K. Walker

Authors
  1. Robert Dantzer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Adam K. Walker
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert Dantzer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dantzer, R., Walker, A.K. Is there a role for glutamate-mediated excitotoxicity in inflammation-induced depression?. J Neural Transm 121, 925–932 (2014). https://doi.org/10.1007/s00702-014-1187-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00702-014-1187-1

Keywords

Search

Navigation