{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T18:00:40Z","timestamp":1771956040806,"version":"3.50.1"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,9,6]],"date-time":"2024-09-06T00:00:00Z","timestamp":1725580800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82304462"],"award-info":[{"award-number":["82304462"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Major depressive disorder (MDD) is a common and disabling mental health condition; the currently available treatments for MDD are insufficient to meet clinical needs due to their limited efficacy and slow onset of action. Hypidone hydrochloride (YL-0919) is a sigma-1 receptor agonist and a novel fast-acting antidepressant that is currently under clinical development.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To further understand the fast-acting antidepressant activity of YL-0919, this study focused on the role of 5-HTergic neurons in the dorsal raphe nucleus (DRN) in mice. Using fiber photometry to assess neural activity <jats:italic>in vivo<\/jats:italic> and two behavioral assays (tail suspension test and forced swimming test) to evaluate antidepressant-like activity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>It was found that 3 or 7 days of YL-0919 treatment significantly activated serotonin (5-HT) neurons in the DRN and had significant antidepressant-like effects on mouse behaviors. Chemogenetic inhibition of 5-HTergic neurons in the DRN significantly blocked the antidepressant-like effect of YL-0919. In addition, YL-0919 treatment significantly increased the 5-HT levels in the prefrontal cortex (PFC). These changes were drastically different from those of the selective serotonin reuptake inhibitor (SSRI) fluoxetine, which suggested that the antidepressant-like effects of the two compounds were mechanistically different.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Together, these results reveal a novel role of 5-HTergic neurons in the DRN in mediating the fast-acting antidepressant-like effects of YL-0919, revealing that these neurons are potential novel targets for the development of fast-acting antidepressants for the clinical management of MDD.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2024.1428485","type":"journal-article","created":{"date-parts":[[2024,9,6]],"date-time":"2024-09-06T04:34:31Z","timestamp":1725597271000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["The role of 5-HTergic neuron activation in the rapid antidepressant-like effects of hypidone hydrochloride (YL-0919) in mice"],"prefix":"10.3389","volume":"15","author":[{"given":"Guang-Xiang","family":"Li","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiao-Zhao","family":"Yan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sun-Rui","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiao-Juan","family":"Hou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yong-Yu","family":"Yin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yun-Feng","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2024,9,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1016\/j.ejphar.2017.05.035","article-title":"Psychopharmacology of combined activation of the serotonin(1A) and \u03c3(1) receptors","volume":"809","author":"Ago","year":"2017","journal-title":"Eur. 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