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Accumulating evidence suggests that the activation of the pituitary adenylate cyclase-activating polypeptide and its receptor PAC1 are involved in the stress axis and the development of stress-related disorders. We recently developed PA-915, a small-molecule, non-peptide, high-affinity PAC1 antagonist, and demonstrated that it significantly suppresses anxiety-like behavior in acute stress-induced mice. In this study, we aimed to investigate the behavioral effects of PA-915 in chronic stress-induced mouse models of depression, which included repeated social defeat stress, repeated corticosterone administration, and social isolation rearing. PA-915 ameliorated the increased immobility time in the forced swim test in these stress-induced mice. In repeated social defeat stress mice, PA-915 improved anxiety-like and depression-like behaviors and cognitive dysfunction, as assessed by the light-dark, open field, elevated plus maze, sucrose preference, forced swim, Y-maze, and novel object recognition tests. In addition, we evaluated the usefulness of PA-915 as an antidepressant and compared it with ketamine and fluoxetine. In the sucrose preference test, an antidepressant-like effect was observed for 8 weeks in mice that received a single dose of PA-915, which was a similar effect observed with ketamine. In non-stressed control mice, PA-915 did not induce behavioral abnormalities, such as hyperlocomotion, cognitive dysfunction, or dependency. The present results show that PA-915 improves anxiety-like behaviors and cognitive impairment and exerts rapid and long-lasting antidepressant effects in chronic stress-induced mouse models of anxiety and depression, proposing a promising treatment option for stress-related disorders.<\/jats:p>","DOI":"10.1038\/s41380-025-03209-4","type":"journal-article","created":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T10:58:32Z","timestamp":1756983512000},"page":"1014-1026","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Rapid and long-lasting antidepressant-like effects of the pituitary adenylate cyclase-activating polypeptide receptor antagonist PA-915 in chronic stress mouse models"],"prefix":"10.1038","volume":"31","author":[{"given":"Yusuke","family":"Shintani","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4992-2845","authenticated-orcid":false,"given":"Atsuko","family":"Hayata-Takano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ichiro","family":"Takasaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4001-6771","authenticated-orcid":false,"given":"Takashi","family":"Kurihara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsuro","family":"Miyata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yui","family":"Yamano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manato","family":"Ikuta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rei","family":"Takeshita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenichiro","family":"Murata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taisei","family":"Oguri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiaki","family":"Asaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuto","family":"Nunomura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bangzhong","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinsaku","family":"Nakagawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuya","family":"Okada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoki","family":"Toyooka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7153-266X","authenticated-orcid":false,"given":"Toru","family":"Takumi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7562-4000","authenticated-orcid":false,"given":"Yukio","family":"Ago","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhiro","family":"Takuma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6548-4016","authenticated-orcid":false,"given":"Hitoshi","family":"Hashimoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,4]]},"reference":[{"key":"3209_CR1","first-page":"1789","volume":"392","author":"GBD 2017 Disease and Injury Incidence and Prevalence Collaborators","year":"2017","unstructured":"GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. 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