FTY720 (fingolimod) is an analog of sphingosine, a ubiquitous sphingolipid. Phosphorylated FTY720 (FTY720-P) non-selectively binds to sphingosine-1-phosphate receptors (S1PRs) and regulates multiple cellular processes including cell proliferation, inflammation, and vascular remodeling. We recently demonstrated that S1PR3 expression in the medial prefrontal cortex (mPFC) of rats promotes stress resilience and that S1PR3 expression in blood may serve as a biomarker for PTSD. Here we investigate the effects of FTY720 in regulating the stress response. We found that single and repeated intraperitoneal injections of FTY720 increased baseline plasma adrenocorticotropic hormone (ACTH) and corticosterone concentrations. FTY720 reduced social anxiety- and despair-like behavior as assessed by increased social interaction time and reduced time spent immobile in the Porsolt forced swim test. In blood, FTY720 administration reduced lymphocyte and reticulocyte counts, but raised erythrocyte counts. FTY720 also reduced mRNA of angiopoietin 1, endothelin 1, plasminogen, TgfB2, Pdgfa, and Mmp2 in the medial prefrontal cortex, suggesting that FTY720 reduced vascular remodeling. The antidepressant-like and anxiolytic-like effects of FTY720 may be attributed to reduced vascular remodeling as increased stress-induced blood vessel density in the brain contributes to behavior associated with vulnerability in rats. Together, these results demonstrate that FTY720 regulates baseline HPA axis activity but reduces social anxiety and despair, providing further evidence that S1PRs are important and novel regulators of stress-related functions.

FTY720（芬戈莫德）是鞘氨醇的类似物，鞘氨醇是一种普遍存在的鞘脂。磷酸化 FTY720 (FTY720-P) 非选择性结合 1-磷酸鞘氨醇受体 (S1PR)，调节多种细胞过程，包括细胞增殖、炎症和血管重塑。我们最近证明，大鼠内侧前额皮质（mPFC）中的 S1PR3 表达可促进应激恢复能力，并且血液中的 S1PR3 表达可作为 PTSD 的生物标志物。在这里，我们研究 FTY720 在调节应激反应中的作用。我们发现单次和重复腹腔注射 FTY720 会增加基线血浆促肾上腺皮质激素 (ACTH) 和皮质酮浓度。在 Porsolt 强迫游泳测试中，通过增加社交互动时间和减少不动时间来评估，FTY720 减少了社交焦虑和绝望样行为。在血液中，FTY720 给药减少了淋巴细胞和网织红细胞计数，但增加了红细胞计数。FTY720 还减少内侧前额皮质中血管生成素 1、内皮素 1、纤溶酶原、TgfB2、Pdgfa和Mmp2的 mRNA ，表明 FTY720 减少血管重塑。FTY720 的抗抑郁样和抗焦虑样作用可能归因于血管重塑的减少，因为应激诱导的大脑血管密度增加会导致与大鼠脆弱性相关的行为。总之，这些结果表明 FTY720 调节基线 HPA 轴活动，但减少社交焦虑和绝望，进一步证明 S1PR 是压力相关功能的重要且新颖的调节剂。