The current study aims to evaluate the role of Protein Kinase (PKA)- cAMP response element-binding protein (CREB)- brain derived neurotropic factor (BDNF) signaling pathway in depression and the effects of roflumilast (PDE4 inhibitor) as potential antidepressant on the activity of the PKA-CREB-BDNF signaling pathway, histology, and pro-inflammatory cytokine production. Here, PDE4A is linked to depressive disorder.