The review emphasizes the role of endogenous phospho-SERT and phospho-NET in animal behavior with the intent of shining a light on the underlying compromised neuronal mechanisms to help us better understand the etiology of mental illnesses and psychostimulant substance use disorder (SUD), and to open the door for developing alternative pharmacological strategies targeting specific regulatory motifs for treating neuropsychiatric disorders such as depression and SUD. The gene discussed is SLC6A4; the disease is major depressive disorder.