It is well known that cocaine blocks the dopamine transporter. This mechanism should lead to a general increase in dopaminergic neurotransmission, and yet dopamine D receptors (DRs) playamore significant role in the behavioral effects of cocaine than the other dopamine receptor subtypes. Cocaine also binds to σ-1 receptors, the physiological role of which is largely unknown. In the present study, DR and σR were found to heteromerize in transfected cells, where cocaine robustly potentiated DR-mediated adenylyl cyclase activation, induced MAPK activation per se and counteracted MAPK activation induced by DR stimulation in a dopamine transporter-independent and σR-dependent manner. Some of these effects were also demonstrated in murine striatal slices and were absent in σR KO mice, providing evidence for the existence of σR-D R heteromers in the brain. Therefore, these results provide a molecular explanation for which DR playsamore significant role in the behavioral effects of cocaine, through σR-DR heteromerization, and provide a unique perspective toward understanding the molecular basis of cocaine addiction.