1. ¹Integrative Immunology and Behavior, Department of Animal Sciences, College of Agricultural, Consumer and Environmental Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, USA
2. ²INRA/CNRS—University Victor Segalen Bordeaux II, Bordeaux, France
3. ³Department of Pathology, College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, USA

Correspondence: Dr R Dantzer, Medical Pathology and Animal Sciences, University of Illinois at Urbana-Champaign, 227 Edward R Madigan Laboratory, 1201 W Gregory Dr. Urbana, IL, USA. E-mail: dantzer@uiuc.edu

Received 26 August 2007; Revised 13 November 2007; Accepted 12 December 2007; Published online 15 January 2008.

Abstract

Although elevated activity of the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) has been proposed to mediate comorbid depression in inflammatory disorders, its causative role has never been tested. We report that peripheral administration of lipopolysaccharide (LPS) activates IDO and culminates in a distinct depressive-like behavioral syndrome, measured by increased duration of immobility in both the forced-swim and tail suspension tests. Blockade of IDO activation either indirectly with the anti-inflammatory tetracycline derivative minocycline, that attenuates LPS-induced expression of proinflammatory cytokines, or directly with the IDO antagonist 1-methyltryptophan (1-MT), prevents development of depressive-like behavior. Both minocycline and 1-MT normalize the kynurenine/tryptophan ratio in the plasma and brain of LPS-treated mice without changing the LPS-induced increase in turnover of brain serotonin. Administration of L-kynurenine, a metabolite of tryptophan that is generated by IDO, to naive mice dose dependently induces depressive-like behavior. These results implicate IDO as a critical molecular mediator of inflammation-induced depressive-like behavior, probably through the catabolism of tryptophan along the kynurenine pathway.