title: Interferon-alpha treatment induces depression-like behaviour accompanied by elevated hippocampal quinolinic acid levels in rats.
abstract: Immunotherapy with the cytokine interferon-alpha (IFN-α) can induce symptoms of depression, and it is likely that the tryptophan-kynurenine pathway may be involved in this regard. In this study we investigated the effects of IFN-α on depression-like behaviour and central metabolites of the tryptophan-kynurenine pathway in rats. Secondly, we explored the modulating effects of an antidepressant (imipramine) and anti-inflammatory drug (celecoxib) on IFN-α-induced behavioural and pathophysiological changes in the brain. The following treatment groups were used: Control (saline), IFN-α (6×10(4)IU/kg s.c.), IFN-α+imipramine or IFN-α+celecoxib. Drugs were administered daily for 1 week. IFN-α treatment induced depression-like behaviour by increasing immobility in the forced swim test (FST), and decreased tryptophan levels in the brain. There was a trend for an increased kynurenine/tryptophan ratio, indicative of indoleamine 2,3-dioxygenase (IDO) activation, and increased quinolinic acid in the hippocampus. Imipramine decreased immobility in the FST, but did not reverse the IFN-α-induced changes in the tryptophan-kynurenine pathway. There was a trend for celecoxib to decrease immobility and to reverse the IFN-α-induced increase in the kynurenine/tryptophan ratio. Thus, our study provides further evidence for IFN-α-induced depression-like behaviour through central changes of the tryptophan-kynurenine pathway.
authors.affiliation: Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Risskov, Denmark. Electronic address: Christinawfischer@gmail.com.
authors.forename: Christina Weide
authors.initials: CW
authors.lastname: Fischer
authors.affiliation: Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Risskov, Denmark. Electronic address: Amandaeskelund@msn.com.
authors.forename: Amanda
authors.initials: A
authors.lastname: Eskelund
authors.affiliation: Lundbeck Research USA, Paramus, NJ, USA. Electronic address: Dpbu@lundbeck.com.
authors.forename: David P
authors.initials: DP
authors.lastname: Budac
authors.affiliation: Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Risskov, Denmark. Electronic address: Sti@clin.au.dk.
authors.forename: Sandra
authors.initials: S
authors.lastname: Tillmann
authors.affiliation: Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Risskov, Denmark. Electronic address: Nico.liebenberg@clin.au.dk.
authors.forename: Nico
authors.initials: N
authors.lastname: Liebenberg
authors.affiliation: Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Risskov, Denmark. Electronic address: Betielfv@rm.dk.
authors.forename: Betina
authors.initials: B
authors.lastname: Elfving
authors.affiliation: Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Risskov, Denmark. Electronic address: Wegener@dadlnet.dk.
authors.forename: Gregers
authors.initials: G
authors.lastname: Wegener
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use; D002853:Chromatography, Liquid; D003863:Depression / Q000139:chemically induced* / Q000188:drug therapy / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D004563:Electrochemistry; D005518:Food Preferences / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D055809:Illness Behavior / Q000187:drug effects; D016898:Interferon-alpha / Q000633:toxicity*; D008297:Male; D017378:Quinolinic Acid / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012439:Saccharin / Q000008:administration & dosage; D018709:Statistics, Nonparametric; D013549:Sweetening Agents / Q000008:administration & dosage; D013550:Swimming / Q000523:psychology; D014364:Tryptophan / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D016898:Interferon-alpha; D013549:Sweetening Agents; D014364:Tryptophan; D017378:Quinolinic Acid; D012439:Saccharin
keywords: Animal models; Depression; Interferon-alpha; Tryptophan–kynurenine pathway