title: CD40-TNF activation in mice induces extended sickness behavior syndrome co-incident with but not dependent on activation of the kynurenine pathway.
abstract: The similarity between sickness behavior syndrome (SBS) in infection and autoimmune disorders and certain symptoms in major depressive disorder (MDD), and the high co-morbidity of autoimmune disorders and MDD, constitutes some of the major evidence for the immune-inflammation hypothesis of MDD. CD40 ligand-CD40 immune-activation is important in host response to infection and in development of autoimmunity. Mice given a single intra-peritoneal injection of CD40 agonist antibody (CD40AB) develop SBS for 2-3days characterized by weight loss and increased sleep, effects that are dependent on the cytokine, tumor necrosis factor (TNF). Here we report that CD40AB also induces behavioral effects that extend beyond acute SBS and co-occur with but are not mediated by kynurenine pathway activation and recovery. CD40AB led to decreased saccharin drinking (days 1-7) and decreased Pavlovian fear conditioning (days 5-6), and was without effect on physical fatigue (day 5). These behavioral effects co-occurred with increased plasma and brain levels of kynurenine and its metabolites (days 1-7/8). Co-injection of TNF blocker etanercept with CD40AB prevented each of SBS, reduced saccharin drinking, and kynurenine pathway activation in plasma and brain. Repeated oral administration of a selective indoleamine 2,3-dioxygenase (IDO) inhibitor blocked activation of the kynurenine pathway but was without effect on SBS and saccharin drinking. This study provides novel evidence that CD40-TNF activation induces deficits in saccharin drinking and Pavlovian fear learning and activates the kynurenine pathway, and that CD40-TNF activation of the kynurenine pathway is not necessary for induction of the acute or extended SBS effects.
authors.affiliation: Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy & 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: CNS Diseases Research Germany, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.
authors.forename: Rene
authors.initials: R
authors.lastname: Fuertig
authors.affiliation: Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy & Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland.
authors.forename: Hannes
authors.initials: H
authors.lastname: Sigrist
authors.affiliation: Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy & Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland.
authors.forename: Gregory N
authors.initials: GN
authors.lastname: Newman
authors.affiliation: Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy & Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland; ETH Zurich, Institute of Human Movement Sciences and Sport, Zurich, Switzerland.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Hoop
authors.affiliation: Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy & Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland.
authors.forename: Manuela
authors.initials: M
authors.lastname: Bizzozzero
authors.affiliation: Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland; Neuroscience Center, University and ETH Zurich, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Mueller
authors.affiliation: Drug Discovery Support, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Luippold
authors.affiliation: CNS Diseases Research Germany, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.
authors.forename: Angelo
authors.initials: A
authors.lastname: Ceci
authors.affiliation: CNS Diseases Research Germany, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.
authors.forename: Bastian
authors.initials: B
authors.lastname: Hengerer
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: Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland; Neuroscience Center, University and ETH Zurich, Switzerland.
authors.forename: Adriano
authors.initials: A
authors.lastname: Fontana
authors.affiliation: Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy & 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; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D001522:Behavior, Animal / Q000187:drug effects; D019013:CD40 Antigens / Q000819:agonists / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology* / Q000378:metabolism; D003213:Conditioning, Psychological / Q000187:drug effects; D003865:Major Depressive Disorder / Q000276:immunology / Q000378:metabolism; D004327:Drinking Behavior / Q000187:drug effects; D005239:Fear / Q000187:drug effects; D055809:Illness Behavior / Q000187:drug effects / Q000502:physiology*; D007737:Kynurenine / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects; D013577:Syndrome; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology* / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand; D007737:Kynurenine
keywords: CD40; Depression; Fatigue; Fear learning; IDO; Kynurenine pathway; Reward motivation; Sickness behavior syndrome; TNF