Tryptophan (TRP) is metabolized via the kynurenine (KYN) pathway, which is related to the pathogenesis of major depressive disorder (MDD). Kynurenine 3-monooxygenase (KMO) is a pivotal enzyme in the metabolism of KYN to 3-hydroxykynurenine. In rodents, KMO deficiency induces a depression-like behavior and increases the levels of kynurenic acid (KA), a KYN metabolite formed by kynurenine aminotransferases (KATs). We will introduce the involvement of TRP metabolism in the depression-like behavior induced by chronic unpredictable mild stress (CUMS). Corticosterone level in the serum and corticosterone-releasing hormone (CRH) mRNA level in the hypothalamus (HT) were elevated immediately after CUMS. Associated with the dysregulation of hypothalamic-pituitary-adrenal (HPA) axis, KMO mRNA level was decreased, and KA content was increased in the prefrontal cortex (PFC). Microglia marker Iba-1 was decreased immediately after CUMS. Because KMO is mainly found in microglia in the central nervous system, these results suggests that CUMS increased KA contents via alternation of kynurenine metabolic enzyme from KMO to KATs due to the reduction of microglia. Because KA is α7 nicotinic acetylcholine receptor (α7nAChR) antagonist, we investigated the effect of nicotine and galantamine (allosteric potentiating ligand for α7nAChR ) on the depression-like behavior and dysregulation of HPA axis induced by CUMS. When nicotine and galantamine were administrated before exposure to each stressor, they attenuated CUMS-induced depression-like behaviors. Although nicotine didn‘t affect elevated corticosterone level in the serum immediately after CUMS, it suppressed the sustained elevation 1 week after CUMS. Increase of KA associative with downregulation of KMO in microglia was involved in the depressive-like behavior and the sustained elevation of serum corticosterone after CUMS. The ameliorating effects of nicotine and galantamine on depression-like behaviors induced by CUMS are associated with the activation of α7nAChR.