title: Mouse chronic social stress increases blood and brain kynurenine pathway activity and fear behaviour: Both effects are reversed by inhibition of indoleamine 2,3-dioxygenase.
abstract: Psychosocial stress is a major risk factor for mood and anxiety disorders, in which excessive reactivity to aversive events/stimuli is a major psychopathology. In terms of pathophysiology, immune-inflammation is an important candidate, including high blood and brain levels of metabolites belonging to the kynurenine pathway. Animal models are needed to study causality between psychosocial stress, immune-inflammation and hyper-reactivity to aversive stimuli. The present mouse study investigated effects of psychosocial stress as chronic social defeat (CSD) versus control-handling (CON) on: Pavlovian tone-shock fear conditioning, activation of the kynurenine pathway, and efficacy of a specific inhibitor (IDOInh) of the tryptophan-kynurenine catabolising enzyme indoleamine 2,3-dioxygenase (IDO1), in reversing CSD effects on the kynurenine pathway and fear. CSD led to excessive fear learning and memory, whilst repeated oral escitalopram (antidepressant and anxiolytic) reversed excessive fear memory, indicating predictive validity of the model. CSD led to higher blood levels of TNF-α, IFN-γ, kynurenine (KYN), 3-hydroxykynurenine (3-HK) and kynurenic acid, and higher KYN and 3-HK in amygdala and hippocampus. CSD was without effect on IDO1 gene or protein expression in spleen, ileum and liver, whilst increasing liver TDO2 gene expression. Nonetheless, oral IDOInh reduced blood and brain levels of KYN and 3-HK in CSD mice to CON levels, and we therefore infer that CSD increases IDO1 activity by increasing its post-translational activation. Furthermore, repeated oral IDOInh reversed excessive fear memory in CSD mice to CON levels. IDOInh reversal of CSD-induced hyper-activity in the kynurenine pathway and fear system contributes significantly to the evidence for a causal pathway between psychosocial stress, immune-inflammation and the excessive fearfulness that is a major psychopathology in stress-related neuropsychiatric disorders.
authors.affiliation: CNS Diseases Research Germany, Boehringer Ingelheim Pharma GmbH & Co. KG., Biberach, Germany.
authors.forename: René
authors.initials: R
authors.lastname: Fuertig
authors.affiliation: Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland; Neuroscience Center, University and ETH Zurich, Switzerland.
authors.forename: Damiano
authors.initials: D
authors.lastname: Azzinnari
authors.affiliation: Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland; Neuroscience Center, University and ETH Zurich, Switzerland.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Bergamini
authors.affiliation: Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland; Department of Psychiatry, Psychotherapy & Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland.
authors.forename: Flurin
authors.initials: F
authors.lastname: Cathomas
authors.affiliation: Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland.
authors.forename: Hannes
authors.initials: H
authors.lastname: Sigrist
authors.affiliation: Department of Psychiatry, Psychotherapy & Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland; Neuroscience Center, University and ETH Zurich, Switzerland.
authors.forename: Erich
authors.initials: E
authors.lastname: Seifritz
authors.affiliation: Pediatric Immunology, University Children's Hospital Zurich, Switzerland.
authors.forename: Stefano
authors.initials: S
authors.lastname: Vavassori
authors.affiliation: Drug Discovery Support, Boehringer Ingelheim Pharma GmbH & Co. KG., Biberach, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Luippold
authors.affiliation: CNS Diseases Research Germany, Boehringer Ingelheim Pharma GmbH & Co. KG., Biberach, Germany.
authors.forename: Bastian
authors.initials: B
authors.lastname: Hengerer
authors.affiliation: CNS Diseases Research Germany, Boehringer Ingelheim Pharma GmbH & Co. KG., Biberach, Germany.
authors.forename: Angelo
authors.initials: A
authors.lastname: Ceci
authors.affiliation: Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland; Neuroscience Center, University and ETH Zurich, Switzerland. Electronic address: christopher.pryce@bli.uzh.ch.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Pryce
mesh_terms: D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D015283:Citalopram / Q000494:pharmacology*; D005239:Fear / Q000187:drug effects; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007736:Kynurenic Acid / Q000378:metabolism; D007737:Kynurenine / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D013315:Stress, Psychological / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism* / Q000523:psychology; D014364:Tryptophan / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D018687:Antidepressive Agents, Second-Generation; C576710:IDO1 protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D014409:Tumor Necrosis Factor-alpha; D015283:Citalopram; C005045:3-hydroxykynurenine; D007737:Kynurenine; D014364:Tryptophan; D007736:Kynurenic Acid
keywords: Anxiety; Depression; Fear conditioning; IDO1; Inflammation; Kynurenine pathway; Monoamines; Psychosocial stress