Department of Biological Sciences, Columbia University, New York State Psychiatric Institute, New York, New York; Division of Integrative Neuroscience, New York State Psychiatric Institute, New York, New York.
Department of Psychiatry, Columbia University, New York State Psychiatric Institute, New York, New York; Division of Integrative Neuroscience, New York State Psychiatric Institute, New York, New York.
Biol Psychiatry. 2022 Dec 15;92(12):952-963. doi: 10.1016/j.biopsych.2022.05.030. Epub 2022 Jun 14.
Selective serotonin reuptake inhibitors such as fluoxetine have a limited treatment efficacy. The mechanism by which some patients respond to fluoxetine while others do not remains poorly understood, limiting treatment effectiveness. We have found the opioid system to be involved in the responsiveness to fluoxetine treatment in a mouse model for anxiety- and depressive-like behavior.
We analyzed gene expression changes in the dentate gyrus of mice chronically treated with corticosterone and fluoxetine. After identifying a subset of genes of interest, we studied their expression patterns in relation to treatment responsiveness. We further characterized their expression through in situ hybridization and the analysis of a single-cell RNA sequencing dataset. Finally, we behaviorally tested mu and delta opioid receptor knockout mice in the novelty suppressed feeding test and the forced swim test after chronic corticosterone and fluoxetine treatment.
Chronic fluoxetine treatment upregulates proenkephalin expression in the dentate gyrus, and this upregulation is associated with treatment responsiveness. The expression of several of the most significantly upregulated genes, including proenkephalin, is localized to an anatomically and transcriptionally specialized subgroup of mature granule cells in the dentate gyrus. We have also found that the delta opioid receptor contributes to some, but not all, of the behavioral effects of fluoxetine.
These data indicate that the opioid system is involved in the antidepressant effects of fluoxetine, and this effect may be mediated through the upregulation of proenkephalin in a subpopulation of mature granule cells.
选择性 5-羟色胺再摄取抑制剂（如氟西汀）的治疗效果有限。一些患者对氟西汀有反应而另一些患者没有反应的机制仍知之甚少，这限制了治疗效果。我们发现阿片系统参与了焦虑和抑郁样行为的小鼠模型中对氟西汀治疗的反应。
我们分析了慢性皮质酮和氟西汀治疗的小鼠齿状回中的基因表达变化。在确定了一组感兴趣的基因后，我们研究了它们的表达模式与治疗反应的关系。我们通过原位杂交和单细胞 RNA 测序数据集的分析进一步表征了它们的表达。最后，我们在慢性皮质酮和氟西汀处理后，通过新奇抑制喂养试验和强迫游泳试验对 μ 和 δ 阿片受体敲除小鼠进行了行为测试。
慢性氟西汀治疗上调了齿状回中的前强啡肽表达，这种上调与治疗反应有关。几个表达最显著上调的基因的表达，包括前强啡肽，定位于齿状回中成熟颗粒细胞的一个解剖学和转录上专门的亚群。我们还发现 δ 阿片受体参与了氟西汀的一些但不是所有的行为效应。
这些数据表明阿片系统参与了氟西汀的抗抑郁作用，这种作用可能是通过成熟颗粒细胞亚群中前强啡肽的上调介导的。
