Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice
Mol Psychiatry. 2008-01-15; 14(5): 511-522
DOI: 10.1038/sj.mp.4002148
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1. Mol Psychiatry. 2009 May;14(5):511-22. doi: 10.1038/sj.mp.4002148. Epub 2008 Jan
15.
Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine
2,3-dioxygenase activation in mice.
O’Connor JC(1), Lawson MA, André C, Moreau M, Lestage J, Castanon N, Kelley KW,
Dantzer R.
Author information:
(1)Integrative Immunology and Behavior, Department of Animal Sciences, College of
Agricultural, Consumer and Environmental Sciences, University of Illinois at
Urbana-Champaign, Urbana, IL, USA.
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.
DOI: 10.1038/sj.mp.4002148
PMCID: PMC2683474
PMID: 18195714 [Indexed for MEDLINE]