Chronic stress contributes to the pathogenesis of major depressive disorder (MDD). In the kynurenine pathway (KP), kynurenine is metabolized to 3-hydroxykynurenine (3-HK) by kynurenine 3-monooxygenase (KMO) and to kynurenic acid (KA) by kynurenine aminotransferase. KP alternation has been reported to be associated with the pathogenesis of MDD. We investigated the involvement of KP in the depressive-like behavior induced by chronic unpredictable mild stress (CUMS). Mice were randomly exposed to 9 kinds of mild stressors for 4 weeks. Corticosterone level in the serum and corticotropin-releasing hormone (CRH) mRNA level in the hypothalamus (HT) elevated immediately after CUMS. Further, KMO mRNA level was decreased, but KA content was increased in the prefrontal cortex (PFC). Because KA is α7 nicotinic acetylcholine receptor (α7nAChR) antagonist, we investigated the effects of nicotine (Nic) and galantamine (Gal :α7nAChR agonist) on the depressive-like behavior and dysregulation of HPA axis induced by CUMS. When Nic and Gal were administrated before exposure to each stressor during CUMS, they attenuated CUMS-induced decreased sociability. Although Nic failed to inhibit elevated corticosterone level in the serum immediately after CUMS, but suppressed that sustained elevation 1 week after CUMS. Alternation of KP from 3-HK to KA through downregulation of KMO may be involved in the depressive-like behavior and the sustained elevation of serum corticosterone 1 week after CUMS.