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

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.

Putative Neuroprotective and Neurotoxic Kynurenine Pathway Metabolites Are Associated with Hippocampal and Amygdalar Volumes in Subjects with Major Depressive Disorder

“…In support of this hypothesis, Raison et al (2010) reported that INFa-treated hepatitis C patients showed both plasma and CSF increases in KYN and QA that correlated with depressive symptoms. Furthermore, peripheral administration of KYN has been shown to induce behavioral analogs of depression in rodents (O'Connor et al, 2009), andLaugeray et al (2011) reported that mice subjected to chronic mild stress showed a peripheral increase in kynurenine pathway activity that was inversely correlated with KA concentration in the amygdala.…”

Mouse chronic social stress increases blood and brain kynurenine pathway activity and fear behaviour: Both effects are reversed by inhibition of indoleamine 2,3-dioxygenase

“…Pre-treatment of mice with the competitive IDO inhibitor 1-methyltryptophan (1-MT) decreased the effectseverity of repeated acoustic + restraint stress on physical condition and motor inactivity (Kiank et al, 2010). Pre-treatment with 1-MT prevented systemic LPS, which activates the IDO1-KYN pathway, from decreasing mouse activity in FST and TST (O'Connor et al, 2009b).…”

Minocycline modulates neuropathic pain behaviour and cortical M1–M2 microglial gene expression in a rat model of depression

“…Antidepressant-like effects of minocycline have been demonstrated in several animal models (Henry et al, 2008, O'Connor et al, 2009, Hinwood et al, 2012, Arakawa et al, 2012, with recent data expanding this to include the OB rat. Specifically, chronic minocycline has been demonstrated to attenuate OB-related hyperactivity, behavioural despair (forced swim test) and spatial memory deficits (Borre et al, 2012, Rinwa andKumar, 2013).…”

“…Antidepressant efficacy of minocycline, a second-generation antibiotic that also inhibits microglial activation, has been reported both clinically (Miyaoka et al, 2012) and in animal models (Henry et al, 2008, O'Connor et al, 2009, Arakawa et al, 2012, Hinwood et al, 2012. Furthermore, minocycline has been shown to be beneficial in pain states such as rheumatoid arthritis (Langevitz et al, 2000) and sciatica (Sumracki et al, 2012).…”