Li Guang-Xiang, Yan Jiao-Zhao, Sun Sun-Rui, Hou Xiao-Juan, Yin Yong-Yu, Li Yun-Feng
Beijing Institute of Basic Medical Sciences, Beijing, China.
Beijing Institute of Pharmacology and Toxicology, Beijing Key Laboratory of Neuropsychopharmacology, Beijing, China.
Front Pharmacol. 2024 Sep 6;15:1428485. doi: 10.3389/fphar.2024.1428485. eCollection 2024.
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.
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 and two behavioral assays (tail suspension test and forced swimming test) to evaluate antidepressant-like activity.
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.
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.
重度抑郁症（MDD）是一种常见且使人致残的心理健康状况；目前用于治疗MDD的方法因其疗效有限和起效缓慢，不足以满足临床需求。盐酸海吡酮（YL - 0919）是一种σ-1受体激动剂，也是一种目前正在进行临床开发的新型速效抗抑郁药。
为了进一步了解YL - 0919的速效抗抑郁活性，本研究聚焦于小鼠中缝背核（DRN）中5-羟色胺能神经元的作用。使用光纤光度法评估神经活动，并通过两种行为测试（悬尾试验和强迫游泳试验）来评估抗抑郁样活性。
发现YL - 0919治疗3天或7天可显著激活DRN中的5-羟色胺（5-HT）能神经元，并对小鼠行为产生显著的抗抑郁样作用。对DRN中5-羟色胺能神经元进行化学遗传学抑制可显著阻断YL - 0919的抗抑郁样作用。此外，YL - 0919治疗可显著提高前额叶皮质（PFC）中的5-HT水平。这些变化与选择性5-羟色胺再摄取抑制剂（SSRI）氟西汀的变化截然不同，这表明这两种化合物的抗抑郁样作用在机制上有所不同。
总之，这些结果揭示了DRN中5-羟色胺能神经元在介导YL - 0919的速效抗抑郁样作用中的新作用，表明这些神经元是开发用于MDD临床治疗的速效抗抑郁药的潜在新靶点。
