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 |
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| Institution: | 1. CNS Diseases Research Germany, Boehringer Ingelheim Pharma GmbH & Co. KG., Biberach, Germany;2. Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland;3. Department of Psychiatry, Psychotherapy & Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland;4. Neuroscience Center, University and ETH Zurich, Switzerland;5. Pediatric Immunology, University Children’s Hospital Zurich, Switzerland;6. Drug Discovery Support, Boehringer Ingelheim Pharma GmbH & Co. KG., Biberach, Germany;1. Molecular Immunopathology Unit, Bosch Institute and School of Medical Sciences, University of Sydney, Sydney, New South Wales 2006, Australia;2. Discipline of Pharmacology, Sydney Medical School, University of Sydney, Sydney, New South Wales 2006, Australia;3. Vascular Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, 2010, Australia;4. School of Medical Sciences, Faculty of Medicine, University of New South Wales, New South Wales 2052, Australia;5. School of Psychology, Faculty of Science, University of Sydney, Sydney, New South Wales 2006, Australia;1. Laureate Institute for Brain Research, Tulsa, OK, USA;2. Faculty of Community Medicine, University of Tulsa, Tulsa, OK, USA;3. Janssen Research & Development, LLC, of Johnson & Johnson Inc., Titusville, NJ, USA;4. Division of Internal Medicine, Department of Symptom Research, MD Anderson Cancer Center, Houston, TX, USA;5. Departments of Surgery and Psychiatry, University of Oklahoma College of Medicine, Tulsa, OK, USA;6. Department of Pharmaceutical Sciences, University of Oklahoma College of Pharmacy, Tulsa, OK, USA;7. Department of Biochemistry and Microbiology, Oklahoma State University Center for Health Sciences, Tulsa, OK, USA;8. College of Engineering, University of Oklahoma, Tulsa, OK, USA;1. Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77 Stockholm, Sweden;2. Department of Comparative Medicine, Yale School of Medicine, New Haven, CT, USA;1. Center for Translational Psychiatry, Department of Psychiatry and Behavioral Sciences, The University of Texas Medical School at Houston, Houston, TX, USA;2. Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciúma, SC, Brazil;3. Graduate Program in Health and Behavior, Catholic University of Pelotas, Pelotas, RS, Brazil;4. Department of Clinical Medicine and Translational Psychiatry Research Group, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil;5. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA;1. Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy & Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland;2. Neuroscience Center, University and ETH Zurich, Zurich, Switzerland;3. Department of Psychiatry, Psychotherapy & Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland;4. Department of Life Sciences, University of Roehampton, London, United Kingdom;5. Institut de Recherches Internationales Servier (IRIS), Suresnes, France |
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| 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. |
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| Keywords: | Psychosocial stress Fear conditioning Inflammation IDO1 Kynurenine pathway Monoamines Depression Anxiety |
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