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This study investigates prucalopride, a serotonin type 4 receptor (5-HT\n                    <jats:sub>4<\/jats:sub>\n                    R) agonist approved for constipation, as a fast-acting anxiolytic\/antidepressant using a mouse model of stress, based on corticosterone (CORT) administration. Behavioral effects of prucalopride (0.5 and 1.5\u2009mg\/kg\/day) were compared to fluoxetine, a common SSRI, over 7 (subchronic) and 28 (chronic) days. Prucalopride showed faster and more significant improvements in emotionality scores than fluoxetine, reversing CORT-induced behavioral changes within 7 days. Gut microbiota analysis revealed CORT-induced changes at the subchronic timepoint. While chronic prucalopride did not alter microbial alpha diversity, it significantly shifted microbial composition (beta-diversity). Notably, prucalopride restored levels of the genus\n                    <jats:italic>Ruminococcus<\/jats:italic>\n                    , which were depleted by CORT. Our findings highlight prucalopride\u2019s rapid anxiolytic and antidepressant-like effects and its impact on gut microbiota, supporting the potential of 5-HT\n                    <jats:sub>4<\/jats:sub>\n                    R-targeting molecules as therapeutic options for psychiatric disorders.\n                  <\/jats:p>","DOI":"10.1038\/s41522-026-00928-6","type":"journal-article","created":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T10:09:30Z","timestamp":1770199770000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Prucalopride, a serotonin type 4 receptor agonist, induces fast anxiolytic\/antidepressant effects and concomitant changes in the gut microbiota"],"prefix":"10.1038","volume":"12","author":[{"given":"Sofia","family":"Cussotto","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salma R.","family":"Abdennebi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Etting","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine A.","family":"Denny","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ren\u00e9","family":"Hen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romain","family":"Colle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuelle","family":"Corruble","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Claude","family":"Alvarez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denis J.","family":"David","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Indira","family":"Mendez-David","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,4]]},"reference":[{"key":"928_CR1","doi-asserted-by":"publisher","first-page":"2299","DOI":"10.1016\/S0140-6736(18)31948-2","volume":"392","author":"GS Malhi","year":"2018","unstructured":"Malhi, G. 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