Direct involvement of σ-1 receptors in the dopamine D1 receptor-mediated effects of cocaine

Abstract

It is well known that cocaine blocks the dopamine transporter. This mechanism should lead to a general increase in dopaminergic neurotransmission, and yet dopamine D1 receptors (D1Rs) 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, D1R and σ1R 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 σ1R-dependent manner. Some of these effects were also demonstrated in murine striatal slices and were absent in σ1R KO mice, providing evidence for the existence of σ1R-D 1R heteromers in the brain. Therefore, these results provide a molecular explanation for which D1R playsamore significant role in the behavioral effects of cocaine, through σ1R-D1R heteromerization, and provide a unique perspective toward understanding the molecular basis of cocaine addiction.