Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice

被引:962
作者
O'Connor, J. C. [1 ]
Lawson, M. A. [1 ]
Andre, C. [2 ]
Moreau, M. [2 ]
Lestage, J. [2 ]
Castanon, N. [2 ]
Kelley, K. W. [1 ,3 ]
Dantzer, R. [1 ,3 ]
机构
[1] Univ Illinois, Edward R Madigan Lab 227, Coll Agr Consumer & Environm Sci, Dept Anim Sci, Urbana, IL 61801 USA
[2] Univ Bordeaux 2, CNRS, INRA, F-33076 Bordeaux, France
[3] Univ Illinois, Coll Med, Dept Pathol, Urbana, IL 61801 USA
关键词
1-methyltryptophan; minocycline; kynurenine; tryptophan; tail suspension test; forced-swim test; DENDRITIC CELLS; TRYPTOPHAN DEGRADATION; KYNURENINE PATHWAY; INTERFERON-ALPHA; QUINOLINIC ACID; CANCER-PATIENTS; PROTEIN-KINASE; MINOCYCLINE; EXPRESSION; BRAIN;
D O I
10.1038/sj.mp.4002148
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:511 / 522
页数:12
相关论文
共 54 条
[1]   Monoamine depletion in psychiatric and healthy populations: review [J].
Booij, L ;
Van der Does, AJW ;
Riedel, WJ .
MOLECULAR PSYCHIATRY, 2003, 8 (12) :951-973
[2]   1-METHYL-DL-TRYPTOPHAN, BETA-(3-BENZOFURANYL)-DL-ALANINE (THE OXYGEN ANALOG OF TRYPTOPHAN), AND BETA-[3-BENZO(B)THIENYL]-DL-ALANINE (THE SULFUR ANALOG OF TRYPTOPHAN) ARE COMPETITIVE INHIBITORS FOR INDOLEAMINE 2,3-DIOXYGENASE [J].
CADY, SG ;
SONO, M .
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 1991, 291 (02) :326-333
[3]  
Capuron L, 2003, BRAIN BEHAV IMMUN, V17, pS119
[4]   Association between decreased serum tryptophan concentrations and depressive symptoms in cancer patients undergoing cytokine therapy [J].
Capuron, L ;
Ravaud, A ;
Neveu, PJ ;
Miller, AH ;
Maes, M ;
Dantzer, R .
MOLECULAR PSYCHIATRY, 2002, 7 (05) :468-473
[5]   Neurobehavioral effects of interferon-α in cancer patients:: Phenomenology and paroxetine responsiveness of symptom dimensions [J].
Capuron, L ;
Gumnick, JF ;
Musselman, DL ;
Lawson, DH ;
Reemsnyder, A ;
Nemeroff, CB ;
Miller, AH .
NEUROPSYCHOPHARMACOLOGY, 2002, 26 (05) :643-652
[6]   From inflammation to sickness and depression: when the immune system subjugates the brain [J].
Dantzer, Robert ;
O'Connor, Jason C. ;
Freund, Gregory G. ;
Johnson, Rodney W. ;
Kelley, Keith W. .
NATURE REVIEWS NEUROSCIENCE, 2008, 9 (01) :46-57
[7]   Behavioral responses during the forced swim test are not affected by anti-inflammatory agents or acute illness induced by lipopolysaccharide [J].
Deak, T ;
Bellamy, C ;
D'Agostino, LG ;
Rosanoff, M ;
McElderry, NK ;
Bordner, KA .
BEHAVIOURAL BRAIN RESEARCH, 2005, 160 (01) :125-134
[8]   Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson's disease [J].
Du, YS ;
Ma, ZZ ;
Lin, SZ ;
Dodel, RC ;
Gao, F ;
Bales, KR ;
Triarhou, LC ;
Chernet, E ;
Perry, KW ;
Nelson, DLG ;
Luecke, S ;
Phebus, LA ;
Bymaster, FP ;
Paul, SM .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (25) :14669-14674
[9]   ENDOTOXIN ELICITS NORMAL TRYPTOPHAN AND INDOLEAMINE RESPONSES BUT IMPAIRED CATECHOLAMINE AND PITUITARY-ADRENAL RESPONSES IN ENDOTOXIN-RESISTANT MICE [J].
DUNN, AJ ;
CHULUYAN, HE .
LIFE SCIENCES, 1994, 54 (13) :847-853
[10]   Minocycline for short-term neuroprotection [J].
Elewa, HF ;
Hilali, H ;
Hess, DC ;
Machado, LS ;
Fagan, SC .
PHARMACOTHERAPY, 2006, 26 (04) :515-521