Dept. of Psychology, Sapienza University, Via Dei Marsi, 78, 00184, Rome, Italy; IRCCS Fondazione Santa Lucia, Via del Fosso di Fiorano, 64, 00143, Roma, Italy.
Dept. of Psychology, Sapienza University, Via Dei Marsi, 78, 00184, Rome, Italy; Behavioral Neuroscience PhD Programme, Sapienza University, Piazzale Aldo Moro 5, 00184, Rome, Italy.
Neuropharmacology. 2021 Jun 1;190:108559. doi: 10.1016/j.neuropharm.2021.108559. Epub 2021 Apr 15.
Selective serotonin reuptake inhibitors (SSRIs) are designed to improve mood by raising extracellular serotonin levels through the blockade of the serotonin transporter. However, they exhibit a slow onset of action, suggesting the involvement of adaptive regulatory mechanisms. We hypothesized that the microRNA-34 family facilitates the therapeutic activity of SSRIs. We show that genetic deletion of these microRNAs in mice impairs the response to chronic, but not acute, fluoxetine treatment, with a specific effect on behavioral constructs that are related to depression, rather than anxiety. Moreover, using a pharmacological strategy, we found that an increased expression of the serotonin 2C (5-HT2C) receptor in the dorsal raphe region of the brain contributes to this phenotype. The onset of the therapeutic efficacy of SSRIs is paralleled by the desensitization of the 5-HT2C receptor in the dorsal raphe, and 5-HT2C is a putative target of microRNA-34. In this study, acute and chronic fluoxetine treatment differentially alters the expression of 5-HT2C and microRNA-34a in the dorsal raphe. Moreover, by in vitro luciferase assay, we demonstrated the repressive regulatory activity of microRNA-34a against 5-HT2C mRNA. Specific blockade of this interaction through local infusion of a target site blocker was sufficient to prevent the behavioral effects of chronic fluoxetine. Our results demonstrate a new miR-34a-mediated regulatory mechanism of 5-HT2C expression in the dorsal raphe and implicate it in eliciting the behavioral responses to chronic fluoxetine treatment.
选择性 5-羟色胺再摄取抑制剂（SSRIs）旨在通过阻断 5-羟色胺转运体来提高细胞外 5-羟色胺水平，从而改善情绪。然而，它们表现出起效缓慢，这表明存在适应性调节机制。我们假设 microRNA-34 家族促进了 SSRIs 的治疗活性。我们表明，在小鼠中这些 microRNAs 的基因缺失会损害对慢性而非急性氟西汀治疗的反应，对与抑郁相关而非焦虑相关的行为结构有特定影响。此外，我们使用药理学策略发现，大脑中背缝核区域 5-羟色胺 2C（5-HT2C）受体的表达增加有助于这种表型。SSRIs 治疗效果的出现与背缝核中 5-HT2C 受体的脱敏同时发生，而 5-HT2C 是 microRNA-34 的一个潜在靶点。在这项研究中，急性和慢性氟西汀处理以不同的方式改变了背缝核中 5-HT2C 和 microRNA-34a 的表达。此外，通过体外荧光素酶测定，我们证明了 microRNA-34a 对 5-HT2C mRNA 的抑制性调节活性。通过局部输注靶向抑制剂特异性阻断这种相互作用足以防止慢性氟西汀的行为影响。我们的结果表明，在背缝核中存在一种新的 microRNA-34a 介导的 5-HT2C 表达调节机制，并暗示它在引发对慢性氟西汀治疗的行为反应中起作用。
