Considering the crucial role of HPA axis in the pathophysiology and therapy of stress-induced depression, in the present study, we used CMS model, a paradigm causing prolonged HPA axis hyperactivity, to investigate whether chronic XBXT-2 (25, 50 mg kg−1, p.o., the effective doses for behavioral responses) administration could decrease the elevated corticosterone and ACTH levels induced by stress, and also, we assessed the effect of XBXT-2 on hippocampal GRs expression in chronically stressed rats. This evidence concerns the gene POMC and major depressive disorder.