This study investigates the role of indoleamine 2,3-dioxygenase (IDO) in the development of depressive-like behavior induced by lipopolysaccharide (LPS) in mice. The authors found that peripheral administration of LPS activates IDO, leading to increased kynurenine levels and a distinct depressive-like behavioral syndrome, as measured by increased immobility in forced swim and tail suspension tests. Blockade of IDO activation, either indirectly with the anti-inflammatory drug minocycline or directly with the IDO antagonist 1-methyltryptophan (1-MT), prevented the development of depressive-like behavior. Both minocycline and 1-MT normalized the kynurenine/tryptophan ratio in plasma and brain without affecting brain serotonin turnover. Administration of L-kynurenine, a metabolite of tryptophan, dose-dependently induced depressive-like behavior in naive mice. These findings suggest that IDO plays a critical role in mediating inflammation-induced depressive-like behavior through the catabolism of tryptophan along the kynurenine pathway.This study investigates the role of indoleamine 2,3-dioxygenase (IDO) in the development of depressive-like behavior induced by lipopolysaccharide (LPS) in mice. The authors found that peripheral administration of LPS activates IDO, leading to increased kynurenine levels and a distinct depressive-like behavioral syndrome, as measured by increased immobility in forced swim and tail suspension tests. Blockade of IDO activation, either indirectly with the anti-inflammatory drug minocycline or directly with the IDO antagonist 1-methyltryptophan (1-MT), prevented the development of depressive-like behavior. Both minocycline and 1-MT normalized the kynurenine/tryptophan ratio in plasma and brain without affecting brain serotonin turnover. Administration of L-kynurenine, a metabolite of tryptophan, dose-dependently induced depressive-like behavior in naive mice. These findings suggest that IDO plays a critical role in mediating inflammation-induced depressive-like behavior through the catabolism of tryptophan along the kynurenine pathway.