Chronic Mild Stress Alters Kynurenine Pathways Changing the Glutamate Neurotransmission in Frontal Cortex of Rats
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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.
KeywordsChronic mild stress Antidepressants Indoleamine 2,3-dioxygenase Kynurenine pathways Glutamate neurotransmission Frontal cortex
Funding for this study was provided by the Instituto de Salud Carlos III (PI13/01102) and Fondos Europeos de Desarrollo Regional (FEDER) and the Ministerio de Economía, Industria y Competitividad (MINECO; SAF2016-75500-R), and CIBERSAM to JCL, including an Intramural Translational Project awarded to JRC from the CIBERSAM (SAM15PINT1514). BGB and JRC are postdoctoral Ramón y Cajal fellows (MINECO). HTB was funded by the CONACYT (Consejo Nacional de Ciencia y Tecnología, Mexico).
Compliance with Ethical Standards
Conflict of Interest
The authors provide full disclosure of any and all biomedical financial interests.
The authors declare that there are not conflicts of interest.
- 1.Marcus M, Yasamy MT, van Ommeren M, Chisholm D (2012) Depression, a global public health concern. WHO Department of Mental Health and Substance Abuse, pp 1–8Google Scholar
- 2.Global Burden of Disease Study C (2015) Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 386(9995):743–800. https://doi.org/10.1016/S0140-6736(15)60692-4 CrossRefGoogle Scholar
- 3.Disease GBD, Injury I, Prevalence C (2016) Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet 388(10053):1545–1602. https://doi.org/10.1016/S0140-6736(16)31678-6 CrossRefGoogle Scholar
- 7.O'Connor JC, Andre C, Wang Y, Lawson MA, Szegedi SS, Lestage J, Castanon N, Kelley KW et al (2009) 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 29(13):4200–4209. https://doi.org/10.1523/JNEUROSCI.5032-08.2009 CrossRefPubMedPubMedCentralGoogle Scholar
- 8.Raison CL, Dantzer R, Kelley KW, Lawson MA, Woolwine BJ, Vogt G, Spivey JR, Saito K 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(4):393–403. https://doi.org/10.1038/mp.2009.116 CrossRefGoogle Scholar
- 14.Martin-Hernandez D, Bris AG, MacDowell KS, Garcia-Bueno B, Madrigal JL, Leza JC, Caso JR (2016) Modulation of the antioxidant nuclear factor (erythroid 2-derived)-like 2 pathway by antidepressants in rats. Neuropharmacology 103:79–91. https://doi.org/10.1016/j.neuropharm.2015.11.029 CrossRefGoogle Scholar
- 18.Patricio P, Mateus-Pinheiro A, Irmler M, Alves ND, Machado-Santos AR, Morais M, Correia JS, Korostynski M et al (2015) Differential and converging molecular mechanisms of antidepressants’ action in the hippocampal dentate gyrus. Neuropsychopharmacology 40(2):338–349. https://doi.org/10.1038/npp.2014.176 CrossRefGoogle Scholar
- 22.Martin-Hernandez D, Caso JR, Bris AG, Maus SR, Madrigal JL, Garcia-Bueno B, MacDowell KS, Alou L et al (2016) Bacterial translocation affects intracellular neuroinflammatory pathways in a depression-like model in rats. Neuropharmacology 103:122–133. https://doi.org/10.1016/j.neuropharm.2015.12.003 CrossRefGoogle Scholar
- 23.Kusmider M, Solich J, Palach P, Dziedzicka-Wasylewska M (2007) Effect of citalopram in the modified forced swim test in rats. Pharmacol Rep 59(6):785–788Google Scholar
- 25.Garate I, Garcia-Bueno B, Madrigal JL, Bravo L, Berrocoso E, Caso JR, Mico JA, Leza JC (2011) Origin and consequences of brain Toll-like receptor 4 pathway stimulation in an experimental model of depression. J Neuroinflammation 8:151. https://doi.org/10.1186/1742-2094-8-151 CrossRefPubMedPubMedCentralGoogle Scholar
- 28.Savitz J, Drevets WC, Wurfel BE, Ford BN, Bellgowan PS, Victor TA, Bodurka J, Teague TK et al (2015) Reduction of kynurenic acid to quinolinic acid ratio in both the depressed and remitted phases of major depressive disorder. Brain Behav Immun 46:55–59. https://doi.org/10.1016/j.bbi.2015.02.007 CrossRefPubMedPubMedCentralGoogle Scholar
- 30.Liu YN, Peng YL, Liu L, Wu TY, Zhang Y, Lian YJ, Yang YY, Kelley KW et al (2015) TNFalpha mediates stress-induced depression by upregulating indoleamine 2,3-dioxygenase in a mouse model of unpredictable chronic mild stress. Eur Cytokine Netw 26(1):15–25. https://doi.org/10.1684/ecn.2015.0362 CrossRefPubMedPubMedCentralGoogle Scholar
- 35.Garcia-Bueno B, Caso JR, Perez-Nievas BG, Lorenzo P, Leza JC (2007) Effects of peroxisome proliferator-activated receptor gamma agonists on brain glucose and glutamate transporters after stress in rats. Neuropsychopharmacology 32(6):1251–1260. https://doi.org/10.1038/sj.npp.1301252 CrossRefGoogle Scholar
- 36.Madrigal JL, Caso JR, de Cristobal J, Cardenas A, Leza JC, Lizasoain I, Lorenzo P, Moro MA (2003) Effect of subacute and chronic immobilisation stress on the outcome of permanent focal cerebral ischaemia in rats. Brain Res 979(1–2):137–145. https://doi.org/10.1016/S0006-8993(03)02892-0 CrossRefGoogle Scholar
- 37.Choudary PV, Molnar M, Evans SJ, Tomita H, Li JZ, Vawter MP, Myers RM, Bunney WE Jr et al (2005) Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression. Proc Natl Acad Sci U S A 102:15653–15658. https://doi.org/10.1073/pnas.0507901102 CrossRefPubMedPubMedCentralGoogle Scholar
- 38.Zink M, Vollmayr B, Gebicke-Haerter PJ, Henn FA (2010) Reduced expression of glutamate transporters vGluT1, EAAT2 and EAAT4 in learned helpless rats, an animal model of depression. Neuropharmacology 58(2):465–473. https://doi.org/10.1016/j.neuropharm.2009.09.005 CrossRefPubMedPubMedCentralGoogle Scholar
- 39.Zhang XH, Jia N, Zhao XY, Tang GK, Guan LX, Wang D, Sun HL, Li H et al (2013) Involvement of pGluR1, EAAT2 and EAAT3 in offspring depression induced by prenatal stress. Neuroscience 250:333–341. https://doi.org/10.1016/j.neuroscience.2013.04.031 CrossRefGoogle Scholar
- 40.Golembiowska K, Dziubina A (2000) Effect of acute and chronic administration of citalopram on glutamate and aspartate release in the rat prefrontal cortex. Pol J Pharmacol 52(6):441–448Google Scholar
- 42.Musazzi L, Milanese M, Farisello P, Zappettini S, Tardito D, Barbiero VS, Bonifacino T, Mallei A et al (2010) Acute stress increases depolarization-evoked glutamate release in the rat prefrontal/frontal cortex: the dampening action of antidepressants. PLoS One 5(1):e8566. https://doi.org/10.1371/journal.pone.0008566 CrossRefPubMedPubMedCentralGoogle Scholar
- 47.Ampuero E, Rubio FJ, Falcon R, Sandoval M, Diaz-Veliz G, Gonzalez RE, Earle N, Dagnino-Subiabre A et al (2010) Chronic fluoxetine treatment induces structural plasticity and selective changes in glutamate receptor subunits in the rat cerebral cortex. Neuroscience 169(1):98–108. https://doi.org/10.1016/j.neuroscience.2010.04.035 CrossRefGoogle Scholar
- 48.Erburu M, Munoz-Cobo I, Diaz-Perdigon T, Mellini P, Suzuki T, Puerta E, Tordera RM (2017) SIRT2 inhibition modulate glutamate and serotonin systems in the prefrontal cortex and induces antidepressant-like action. Neuropharmacology 117:195–208. https://doi.org/10.1016/j.neuropharm.2017.01.033 CrossRefGoogle Scholar
- 49.Burgdorf J, Zhang XL, Nicholson KL, Balster RL, Leander JD, Stanton PK, Gross AL, Kroes RA et al (2013) GLYX-13, a NMDA receptor glycine-site functional partial agonist, induces antidepressant-like effects without ketamine-like side effects. Neuropsychopharmacology 38(5):729–742. https://doi.org/10.1038/npp.2012.246 CrossRefPubMedPubMedCentralGoogle Scholar