The sex differences revealed in the present study, emanating from the higher levels of D1-D2 heteromer, coupled to lower density of D1 receptor in NAc of female rat, and the resulting sex differences in basal and D1-D2 heteromer-induced signaling through BDNF/TrkB and GSK3/β-catenin pathways may be at the origin, or at least represent an essential role, in the usually reported sex difference in female susceptibility to stress, anxiety, and depression. This evidence concerns the gene BDNF and major depressive disorder.