In addition, PDE4D seems to be involved in depression, with PDE4DIs able to reverse the depression-like behaviors induced by chronic unpredictable stress (CUS) through restoring cAMP, PKA, the phosphorylation of CREB (pCREB), and GLT1 (glutamate transporter 1) levels in the hippocampus of rats [62]. This evidence concerns the gene CREB1 and major depressive disorder.