S1PR2 and major depressive disorder: Knockdown of S1P-related receptors (S1PR2 and S1PR3) increased both anxiety and depression levels (52), while overexpression of S1PR3 not only attenuated anxiety-related and depression-related behaviors, but also promoted the production of adrenocorticotropic hormone (ACTH) to increase the adaptability of rats to stressors (52, 53).