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 ₁ receptors (D ₁ Rs) play a more 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, D ₁ R and σ ₁ R were found to heteromerize in transfected cells, where cocaine robustly potentiated D ₁ R-mediated adenylyl cyclase activation, induced MAPK activation per se and counteracted MAPK activation induced by D ₁ R stimulation in a dopamine transporter-independent and σ ₁ R-dependent manner. Some of these effects were also demonstrated in murine striatal slices and were absent in σ ₁ R KO mice, providing evidence for the existence of σ ₁ R-D ₁ R heteromers in the brain. Therefore, these results provide a molecular explanation for which D ₁ R plays a more significant role in the behavioral effects of cocaine, through σ ₁ R-D ₁ R heteromerization, and provide a unique perspective toward understanding the molecular basis of cocaine addiction.