FTY720 (Fingolimod), a modulator of sphingosine-1-phosphate receptors, increases baseline hypothalamic-pituitary adrenal axis activity and alters behaviors relevant to affect and anxiety

Abstract

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 angiogenesis. 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 also mitigated restraint-induced increases in ACTH and corticosterone. 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 1, Vegf-B, and Mmp2 in the medial prefrontal cortex, suggesting that FTY720 reduced angiogenesis. The antidepressant-like and anxiolytic-like effects of FTY720 may be attributed to reduced angiogenesis as increased stress-induced blood vessel density in the brain contributes to depression- and anxiety-like behavior in rats. Together, these results suggest that S1PRs regulate baseline HPA axis activity but reduces social anxiety and despair providing further evidence that S1PRs are important and novel regulators of stress-related functions.