Resumen:
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 sigma-1 receptors, the physiological role of which is largely unknown. In the present study, D1R and sigma R-1 were found to heteromerize in transfected cells, where cocaine robustly potentiated D1R-mediated adenylyl cyclase activation, induced MAPK activation per se and counteracted MAPK activation induced by D1R stimulation in a dopamine transporter-independent and sigma R-1-dependent manner. Some of these effects were also demonstrated in murine striatal slices and were absent in sigma R-1 KO mice, providing evidence for the existence of sigma R-1-D1R heteromers in the brain. Therefore, these results provide a molecular explanation for which D1R plays a more significant role in the behavioral effects of cocaine, through sigma R-1-D1R heteromerization, and provide a unique perspective toward understanding the molecular basis of cocaine addiction.
