Indoleamine 2, 3-dioxygenase is responsible for low stress tolerance after intracerebral hemorrhage

In the chronic phase after intracerebral hemorrhage (ICH), the aftereffect-associated lowering of motivation burdens many patients; however, the pathogenic mechanism is unclear. Here, we revealed for the first time that indoleamine 2, 3-dioxygenase (IDO) expression and enzyme activity are increased in the collagenase-induced murine ICH model. IDO is a rate-limiting enzyme situated at the beginning of the kynurenine pathway and converts tryptophan, a source of serotonin (5-hydroxytryptamine; 5-HT), to kynurenine. In this study, we showed that IDO is localized in 5-HTergic neurons. After ICH, the synaptosomal 5-HT level decreased, but this effect was neutralized by subcutaneous injections of 1-methyl tryptophan (MT), a specific IDO inhibitor. These results suggest that ICH-induced IDO weakens the activity of 5-HTergic neurons. Accordingly, we next investigated whether the IDO increase contributes to the depression-like behaviors of ICH mice. The immobility times of tail suspension and forced swimming tests were significantly prolonged after ICH but shortened by the administration of 1-MT. In conclusion, the increased IDO after ICH was found to decrease 5-HT levels and subsequently reduce stress tolerance. These findings indicate that IDO is a novel therapeutic target for the ICH aftereffect-associated lowering of motivation.