Despite years of research, our understanding of the mechanisms by which inflammation induces depression is still limited. As clinical data points to a strong association between depression and motivational alterations, we sought to (1) characterize the motivational changes that are associated with inflammation in mice, and (2) determine if they depend on inflammation-induced activation of indoleamine 2,3 dioxygenase-1 (IDO1). Lipopolysaccharide (LPS)-treated or spared nerve injured (SNI) wild type (WT) and Ido1−/− mice underwent behavioral tests of antidepressant activity (e.g., forced swim test) and motivated behavior, including assessment of (1) reward expectancy using a food-related anticipatory activity task, (2) willingness to work for reward using a progressive ratio schedule of food reinforcement, (3) effort allocation using a concurrent choice task, and (4) ability to associate environmental cues with reward using conditioned place preference. LPS- and SNI-induced deficits in behavioral tests of antidepressant activity in WT but not Ido1−/− mice. Further, LPS decreased food related-anticipatory activity, reduced performance in the progressive ratio task, and shifted effort toward the preferred reward in the concurrent choice task. These effects were observed in both WT and Ido1−/− mice. Finally, SNI mice developed a conditioned place preference based on relief from pain in an IDO1-independent manner. These findings demonstrate that the motivational effects of inflammation do not require IDO1. Further, they indicate that the motivational component of inflammation-induced depression is mechanistically distinct from that measured by behavioral tests of antidepressant activity.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $43.69 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Dantzer R (2018). Psychiatric disorders and inflammation. In: Cavaillon JM, Singer M, editors. Inflammation: from molecular and cellular mechanisms to the clinic. Wiley-VCH, Weinheim Germany.
Kappelmann N, Lewis G, Dantzer R, Jones PB, Khandaker GM. Antidepressant activity of anti-cytokine treatment: a systematic review and meta-analysis of clinical trials of chronic inflammatory conditions. Mol Psychiatry. 2018;23:335–343.
Duivis HE, Vogelzangs N, Kupper N, de Jonge P, Penninx BW. Differential association of somatic and cognitive symptoms of depression and anxiety with inflammation: findings from the Netherlands Study of Depression and Anxiety (NESDA). Psychoneuroendocrinology. 2013;38:1573–1585.
White J, Kivimaki M, Jokela M, Batty GD. Association of inflammation with specific symptoms of depression in a general population of older people: The English Longitudinal Study of Ageing. Brain Behav Immun. 2017;61:27–30.
Case SM, Stewart JC. Race/ethnicity moderates the relationship between depressive symptom severity and C-reactive protein: 2005-2010 NHANES data. Brain Behav Immun. 2014;41:101–108.
Kennard B, Silva S, Vitiello B, Curry J, Kratochvil C, Simons A, et al. Remission and residual symptoms after short-term treatment in the Treatment of Adolescents with Depression Study (TADS). J Am Acad Child Adolesc Psychiatry. 2006;45:1404–1411.
Nierenberg AA, Keefe BR, Leslie VC, Alpert JE, Pava JA, Worthington JJ 3rd, et al. Residual symptoms in depressed patients who respond acutely to fluoxetine. J Clin Psychiatry. 1999;60:221–225.
Felger JC, Li Z, Haroon E, Woolwine BJ, Jung MY, Hu X, et al. Inflammation is associated with decreased functional connectivity within corticostriatal reward circuitry in depression. Mol Psychiatry. 2016;21:1358–1365.
Insel TR. The NIMH Research Domain Criteria (RDoC) Project: precision medicine for psychiatry. Am J Psychiatry. 2014;171:395–397.
Laumet G, Zhou W, Dantzer R, Edralin JD, Huo X, Budac DP, et al. Upregulation of neuronal kynurenine 3-monooxygenase mediates depression-like behavior in a mouse model of neuropathic pain. Brain Behav Immun. 2017;66:94–102.
O’Connor JC, Lawson MA, Andre C, Moreau M, Lestage J, Castanon N, et al. Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice. Mol Psychiatry. 2009;14:511–522.
Zhou W, Dantzer R, Budac DP, Walker AK, Mao-Ying QL, Lee AW, et al. Peripheral indoleamine 2,3-dioxygenase 1 is required for comorbid depression-like behavior but does not contribute to neuropathic pain in mice. Brain Behav Immun. 2015;46:147–153.
Walker AK, Budac DP, Bisulco S, Lee AW, Smith RA, Beenders B, et al. NMDA receptor blockade by ketamine abrogates lipopolysaccharide-induced depressive-like behavior in C57BL/6J mice. Neuropsychopharmacology. 2013;38:1609–1616.
Raison CL, Dantzer R, Kelley KW, Lawson MA, Woolwine BJ, Vogt G, et al. CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-alpha: relationship to CNS immune responses and depression. Mol Psychiatry. 2010;15:393–403.
Steiner J, Walter M, Gos T, Guillemin GJ, Bernstein HG, Sarnyai Z, et al. Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus: evidence for an immune-modulated glutamatergic neurotransmission? J Neuroinflamm. 2011;8:94.
Meier TB, Drevets WC, Teague TK, Wurfel BE, Mueller SC, Bodurka J, et al. Kynurenic acid is reduced in females and oral contraceptive users: Implications for depression. Brain Behav Immun. 2018;67:59–64.
Henry CJ, Huang Y, Wynne A, Hanke M, Himler J, Bailey MT, et al. Minocycline attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia. J Neuroinflamm. 2008;5:15.
Martin SA, Pence BD, Greene RM, Johnson SJ, Dantzer R, Kelley KW, et al. Effects of voluntary wheel running on LPS-induced sickness behavior in aged mice. Brain Behav Immun. 2013;29:113–123.
Godbout JP, Moreau M, Lestage J, Chen J, Sparkman NL, O’Connor J, et al. Aging exacerbates depressive-like behavior in mice in response to activation of the peripheral innate immune system. Neuropsychopharmacology. 2008;33:2341–2351.
Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008;9:46–56.
Laumet G, Garriga J, Chen SR, Zhang Y, Li DP, Smith TM, et al. G9a is essential for epigenetic silencing of K(+) channel genes in acute-to-chronic pain transition. Nat Neurosci. 2015;18:1746–1755.
Salazar A, Gonzalez-Rivera BL, Redus L, Parrott JM, O’Connor JC. Indoleamine 2,3-dioxygenase mediates anhedonia and anxiety-like behaviors caused by peripheral lipopolysaccharide immune challenge. Horm Behav. 2012;62:202–209.
Bodnoff SR, Suranyi-Cadotte B, Aitken DH, Quirion R, Meaney MJ. The effects of chronic antidepressant treatment in an animal model of anxiety. Psychopharmacology. 1988;95:298–302.
Singhmar P, Huo X, Eijkelkamp N, Berciano SR, Baameur F, Mei FC, et al. Critical role for Epac1 in inflammatory pain controlled by GRK2-mediated phosphorylation of Epac1. Proc Natl Acad Sci USA. 2016;113:3036–3041.
Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL. Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods. 1994;53:55–63.
Malek N, Mrugala M, Makuch W, Kolosowska N, Przewlocka B, Binkowski M, et al. A multi-target approach for pain treatment: dual inhibition of fatty acid amide hydrolase and TRPV1 in a rat model of osteoarthritis. Pain. 2015;156:890–903.
Tetreault P, Dansereau MA, Dore-Savard L, Beaudet N, Sarret P. Weight bearing evaluation in inflammatory, neuropathic and cancer chronic pain in freely moving rats. Physiol Behav. 2011;104:495–502.
Grossberg AJ, Zhu X, Leinninger GM, Levasseur PR, Braun TP, Myers MG Jr., et al. Inflammation-induced lethargy is mediated by suppression of orexin neuron activity. J Neurosci. 2011;31:11376–11386.
Mistlberger RE. Circadian food-anticipatory activity: formal models and physiological mechanisms. Neurosci Biobehav Rev. 1994;18:171–195.
Stephan FK. The “other” circadian system: food as a zeitgeber. J Biol Rhythms. 2002;17:284–292.
Grossberg AJ, Vichaya EG, Christian DL, Molkentine JM, Vermeer DW, Gross PS, et al. Tumor-associated fatigue in cancer patients develops independently of IL1 signaling. Cancer Res. 2018;78:695–705.
Sharma S, Hryhorczuk C, Fulton S. Progressive-ratio responding for palatable high-fat and high-sugar food in mice. J Vis Exp. 2012;63:e3754.
Salamone JD, Steinpreis RE, McCullough LD, Smith P, Grebel D, Mahan K. Haloperidol and nucleus accumbens dopamine depletion suppress lever pressing for food but increase free food consumption in a novel food choice procedure. Psychopharmacology. 1991;104:515–521.
Vichaya EG, Hunt SC, Dantzer R. Lipopolysaccharide reduces incentive motivation while boosting preference for high reward in mice. Neuropsychopharmacology. 2014;39:2884–2890.
King T, Vera-Portocarrero L, Gutierrez T, Vanderah TW, Dussor G, Lai J, et al. Unmasking the tonic-aversive state in neuropathic pain. Nat Neurosci. 2009;12:1364–1366.
Sufka KJ. Conditioned place preference paradigm: a novel approach for analgesic drug assessment against chronic pain. Pain. 1994;58:355–366.
Yang Q, Wu Z, Hadden JK, Odem MA, Zuo Y, Crook RJ, et al. Persistent pain after spinal cord injury is maintained by primary afferent activity. J Neurosci. 2014;34:10765–10769.
Krukowski K, Ma J, Golonzhka O, Laumet GO, Gutti T, van Duzer JH, et al. HDAC6 inhibition effectively reverses chemotherapy-induced peripheral neuropathy. Pain. 2017;158:1126–1137.
Cady SG, Sono M. 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. Arch Biochem Biophys. 1991;291:326–333.
Diaz-Munoz M, Vazquez-Martinez O, Aguilar-Roblero R, Escobar C. Anticipatory changes in liver metabolism and entrainment of insulin, glucagon, and corticosterone in food-restricted rats. Am J Physiol Regul Integr Comp Physiol. 2000;279:R2048–2056.
Sheward WJ, Maywood ES, French KL, Horn JM, Hastings MH, Seckl JR, et al. Entrainment to feeding but not to light: circadian phenotype of VPAC2 receptor-null mice. J Neurosci. 2007;27:4351–4358.
Nunes EJ, Randall PA, Estrada A, Epling B, Hart EE, Lee CA, et al. Effort-related motivational effects of the pro-inflammatory cytokine interleukin 1-beta: studies with the concurrent fixed ratio 5/ chow feeding choice task. Psychopharmacology. 2014;231:727–736.
Yohn SE, Arif Y, Haley A, Tripodi G, Baqi Y, Muller CE, et al. Effort-related motivational effects of the pro-inflammatory cytokine interleukin-6: pharmacological and neurochemical characterization. Psychopharmacology. 2016;233:3575–3586.
Lasselin J, Treadway MT, Lacourt TE, Soop A, Olsson MJ, Karshikoff B, et al. Lipopolysaccharide alters motivated behavior in a monetary reward task: a randomized trial. Neuropsychopharmacology. 2017;42:801–810.
Harrison NA, Cercignani M, Voon V, Critchley HD. Effects of inflammation on hippocampus and substantia nigra responses to novelty in healthy human participants. Neuropsychopharmacology. 2015;40:831–838.
Capuron L, Pagnoni G, Drake DF, Woolwine BJ, Spivey JR, Crowe RJ, et al. Dopaminergic mechanisms of reduced basal ganglia responses to hedonic reward during interferon alfa administration. Arch Gen Psychiatry. 2012;69:1044–1053.
Herrera AJ, Castano A, Venero JL, Cano J, Machado A. The single intranigral injection of LPS as a new model for studying the selective effects of inflammatory reactions on dopaminergic system. Neurobiol Dis. 2000;7:429–447.
Castano A, Herrera AJ, Cano J, Machado A. The degenerative effect of a single intranigral injection of LPS on the dopaminergic system is prevented by dexamethasone, and not mimicked by rh-TNF-alpha, IL-1beta and IFN-gamma. J Neurochem. 2002;81:150–157.
Blednov YA, Benavidez JM, Geil C, Perra S, Morikawa H, Harris RA. Activation of inflammatory signaling by lipopolysaccharide produces a prolonged increase of voluntary alcohol intake in mice. Brain Behav Immun. 2011;25:Suppl 1S92–S105.
van Heesch F, Prins J, Konsman JP, Korte-Bouws GA, Westphal KG, Rybka J, et al. Lipopolysaccharide increases degradation of central monoamines: an in vivo microdialysis study in the nucleus accumbens and medial prefrontal cortex of mice. Eur J Pharmacol. 2014;725:55–63.
Coffeen U, Ortega-Legaspi JM, de Gortari P, Simon-Arceo K, Jaimes O, Amaya MI, et al. Inflammatory nociception diminishes dopamine release and increases dopamine D2 receptor mRNA in the rat’s insular cortex. Mol Pain. 2010;6:75.
Chung ES, Chung YC, Bok E, Baik HH, Park ES, Park JY, et al. Fluoxetine prevents LPS-induced degeneration of nigral dopaminergic neurons by inhibiting microglia-mediated oxidative stress. Brain Res. 2010;1363:143–150.
Qin L, Liu Y, Hong JS, Crews FT. NADPH oxidase and aging drive microglial activation, oxidative stress, and dopaminergic neurodegeneration following systemic LPS administration. Glia. 2013;61:855–868.
Korotkova TM, Sergeeva OA, Eriksson KS, Haas HL, Brown RE. Excitation of ventral tegmental area dopaminergic and nondopaminergic neurons by orexins/hypocretins. J Neurosci. 2003;23:7–11.
Calipari ES, Espana RA. Hypocretin/orexin regulation of dopamine signaling: implications for reward and reinforcement mechanisms. Front Behav Neurosci. 2012;6:54.
Center for Behavioral Health Statistics and Quality. (2015). Behavioral health trends in the United States: Results from the 2014 National Survey on Drug Use and Health (HHS Publication No. SMA 15-4927, NSDUH Series H-50). Retrieved from https://www.samhsa.gov/data/
Yalcin I, Bohren Y, Waltisperger E, Sage-Ciocca D, Yin JC, Freund-Mercier MJ, et al. A time-dependent history of mood disorders in a murine model of neuropathic pain. Biol Psychiatry. 2011;70:946–953.
This research was supported by the National Institutes of Health (R01 CA193522 and R21 MH104694 to R.D., R01 NS073939 to A.K., R.D., and C.J.H., and an MD Anderson Cancer Center Support Grant (P30 CA016672)).
R.D. has received honoraria from Danone Nutricia Research that is unrelated to the present study. All remaining authors declare no competing interests.
Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
About this article
Cisplatin educates CD8+ T cells to prevent and resolve chemotherapy-induced peripheral neuropathy in mice
Oxidative stress and neurobehavioural changes in rats following copper exposure and their response to MiADMSA and d-penicillamine
Toxicology Research and Application (2019)
Brain Kynurenine and BH4 Pathways: Relevance to the Pathophysiology and Treatment of Inflammation-Driven Depressive Symptoms
Frontiers in Neuroscience (2018)