and a serotonin/norepinephrine reuptake inhibitor.showed that the regions spanning transmembrane domain (TM)1, TM3, and TM6 form the ligand binding pocket. The compound.bound tightly to the binding pocket of all three monoamine reuptake transporters; however.showed poor docking with DAT. Co-expression of DAT with the dopamine D2 receptor (D2R) significantly inhibited DA-induced endocytosis of D2R probably by reuptaking DA into the cells. Pretreatment of the cells with., which is one of the compounds with good inhibitory activity on DAT, blocked DAT-induced inhibition of D2R endocytosis. In summary, this study identified critical structural features contributing to the selectivity of a molecule for each of the monoamine transporters, critical residues on the compounds that bound to the transporters, and the functional role of a DA reuptake inhibitor in regulating D2R function.