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Effects of IDO1 and TDO2 inhibition on cognitive deficits and anxiety following LPS-induced neuroinflammation

Published online by Cambridge University Press:  20 December 2019

Sophie Imbeault Open the ORCID record for Sophie Imbeault [Opens in a new window] ,
Michel Goiny ,
Xicong Liu  and
Sophie Erhardt
Sophie Imbeault
Affiliation:
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
Michel Goiny
Affiliation:
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
Xicong Liu
Affiliation:
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
Sophie Erhardt*
Affiliation:
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
*
Author for correspondence: Sophie Erhardt, Email: [email protected]
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Abstract

Objective:

Sustained immune activation leads to cognitive dysfunctions, depression-, and anxiety-like behaviours in humans and rodents. It is modelled by administration of lipopolysaccharides (LPS) to induce expression of pro-inflammatory cytokines that then activate indoleamine 2,3 dioxygenase (IDO1), the rate-limiting enzyme in the kynurenine pathway of tryptophan metabolism. Here, we ask whether chronic IDO1 inhibition by 1-methyl-tryptophan (1-MT, added at 2 g/l in the drinking water) or chronic inhibition of tryptophan 2,3 dioxygenase (TDO2), another enzyme capable of converting tryptophan to kynurenine, by 680C91 (15 mg/kg per os), can rescue LPS-induced (0.83-mg/kg intraperitoneally) anxiety and cognitive deficits. We also investigate the acute effects of 680C91 on serotonergic, dopaminergic, and kynurenine pathway metabolites.

Methods:

We examined LPS-induced deficits in trace fear conditioning and anxiety in the light–dark box and elevated plus maze (EPM) in group-housed C57Bl6/N mice. Kynurenine pathway metabolites and monoamine levels were measured via high-performance liquid chromatography.

Results:

Chronic blockade of IDO1 with 1-MT did not rescue cognitive deficits or abrogate the anxiogenic behaviour caused by LPS despite a decrease in the brain kynurenine:tryptophan ratio. However, 1-MT by itself demonstrated anxiolytic properties in the EPM. Acute and chronic inhibition of TDO2 elevated brain levels of tryptophan, while chronic inhibition of TDO2 was unsuccessful in rescuing cognitive deficits and abrogating the anxiety caused by LPS.

Conclusions:

In line with previous studies, we show that LPS administration induces anxiety and cognitive dysfunctions in mice that however were not reversed by chronic blockade of IDO1 or TDO2 at the doses used.

Keywords

lipopolysaccharideskynureninefear conditioning1-MT680C91
Type
Original Article
Information
Acta Neuropsychiatrica , Volume 32 , Issue 1 , February 2020 , pp. 43 - 53
Copyright
© Scandinavian College of Neuropsychopharmacology 2019 

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