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We have shown that deficiency of kynurenine 3\u2010monooxygenase (KMO) induces depression\u2010like behaviour via kynurenic acid (KYNA; \u03b17nACh antagonist). In this study, we investigated the involvement of the TRP\u2010KYN pathway in stress\u2010induced behavioural changes and the regulation of the HPA axis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Mice were exposed to chronic unpredictable mild stress (CUMS) and subjected to behavioural tests. We measured TRP\u2010KYN metabolites and the expression of their enzymes in the hippocampus. KMO heterozygous mice were used to investigate stress vulnerability. We also evaluated the effect of nicotine (s.c.) on CUMS\u2010induced behavioural changes and an increase in serum corticosterone (CORT) concentration.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>CUMS decreased social interaction time but increased immobility time under tail suspension associated with increased serum corticosterone concentration. CUMS increased KYNA levels via KMO suppression with microglial decline in the hippocampus. <jats:italic>Kmo<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup> mice were vulnerable to stress: they exhibited social impairment and increased serum corticosterone concentration even after short\u2010term CUMS. Nicotine attenuated CUMS\u2010induced behavioural changes and increased serum corticosterone concentration by inhibiting the increase in corticotropin\u2010releasing hormone. Methyllycaconitine (\u03b17nACh antagonist) inhibited the attenuating effect of nicotine.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>CUMS\u2010induced behavioural changes and the HPA axis dysregulation could be induced by the increased levels of KYNA via KMO suppression. KYNA plays an important role in the pathophysiology of MDD as an \u03b17nACh antagonist. Therefore, \u03b17nACh receptor is an attractive therapeutic target for MDD.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.17407","type":"journal-article","created":{"date-parts":[[2024,12,11]],"date-time":"2024-12-11T03:12:42Z","timestamp":1733886762000},"page":"1466-1486","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Chronic stress induces behavioural changes through increased kynurenic acid by downregulation of kynurenine\u20103\u2010monooxygenase with microglial decline"],"prefix":"10.1111","volume":"182","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-5125-314X","authenticated-orcid":false,"given":"Masaya","family":"Hasegawa","sequence":"first","affiliation":[{"name":"Department of Regulatory Science for Evaluation and Development of Pharmaceuticals and Devices Fujita Health University Graduate School of Medical Sciences  Aichi 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