Evidence for a key role of the peripheral kynurenine pathway in the modulation of anxiety- and depression-like behaviours in mice: focus on individual differences.

We previously reported that confronting mice to the Unpredictable Chronic Mild Stress procedure (UCMS) resulted in peripheral and cerebral alterations of the kynurenine pathway (KP). The present study tested whether KP disturbances are associated with differences in anxiety- and depressive-like behaviors in both naïve and UCMS mice. Non-stressed and UCMS mice were subjected to the elevated plus maze test and to the forced swim test. Mice were then sacrificed for quantification of tryptophan (TRP)-serotonin (5-HT) and TRP-kynurenine (KYN) metabolites in two corticolimbic structures involved in the regulation of mood (cingulate cortex=CC; amygdala=AMY). We showed that an elevated peripheral (lung) KYN/TRP ratio is correlated to the magnitude of anxiodepressive-like phenotypes only in UCMS mice. We also observed, in UCMS mice, that a high peripheral (lung) KYN/TRP ratio is associated with an increased metabolism of 5-HT in CC and a reduced level of kynurenic acid (KYNA) in AMY. Our results suggest that elevated peripheral KP might underlie cerebral biochemical changes and might consequently be involved in the modulation of behavior but only in UCMS mice. These findings make more complete the comprehension of the KP involvement in behavioral changes induced by chronic stress and suggest that it could play a crucial role in the modulation of emotional states.