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<p>Major Depressive Disorder (MDD) affects around 20% of people globally and is often comorbid with anxiety. This study investigates prucalopride, a serotonin type 4 receptor (5-HT<sub>4</sub>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 mg/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 <i>Ruminococcus</i>, which were depleted by CORT. Our findings highlight prucalopride’s rapid anxiolytic and antidepressant-like effects and its impact on gut microbiota, supporting the potential of 5-HT<sub>4</sub>R-targeting molecules as therapeutic options for psychiatric disorders.</p>

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Prucalopride, a serotonin type 4 receptor agonist, induces fast anxiolytic/antidepressant effects and concomitant changes in the gut microbiota

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月4日

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  • Sofia Cussotto,
  • Salma R. Abdennebi,
  • Isabelle Etting,
  • Christine A. Denny,
  • René Hen,
  • Romain Colle,
  • Emmanuelle Corruble,
  • Jean-Claude Alvarez,
  • Denis J. David,
  • Indira Mendez-David

摘要

Major Depressive Disorder (MDD) affects around 20% of people globally and is often comorbid with anxiety. This study investigates prucalopride, a serotonin type 4 receptor (5-HT4R) 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 mg/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 Ruminococcus, which were depleted by CORT. Our findings highlight prucalopride’s rapid anxiolytic and antidepressant-like effects and its impact on gut microbiota, supporting the potential of 5-HT4R-targeting molecules as therapeutic options for psychiatric disorders.