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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2010-10, Vol.107 (43), p.18676-18681
• Main Authors: Navarro, Gemma, Moreno, Estefanía, Aymerich, Marisol, Marcellino, Daniel, McCormick, Peter J, Mallol, Josefa, Cortés, Antoni, Casadó, Vicent, Canela, Enric I, Ortiz, Jordi, Fuxe, Kjell, Lluís, Carmen, Ferré, Sergi, Franco, Rafael
• Format: Article
• Language: English
• Subjects: Agonists; Animals; Biological Sciences; Brain - drug effects; Brain - metabolism; Cell Line; Cell membranes; CHO Cells; Cocaine; Cocaine - toxicity; Cocaine-Related Disorders - etiology; Cocaine-Related Disorders - metabolism; Complementary DNA; Cricetinae; Cricetulus; Dimerization; Fluorescence; Humans; Ligands; Male; MAP Kinase Signaling System - drug effects; Mice; Mice, Knockout; Phosphorylation; Protein Structure, Quaternary - drug effects; Receptors; Receptors, Dopamine D1 - chemistry; Receptors, Dopamine D1 - drug effects; Receptors, Dopamine D1 - genetics; Receptors, Dopamine D1 - metabolism; Receptors, sigma - chemistry; Receptors, sigma - drug effects; Receptors, sigma - genetics; Receptors, sigma - metabolism; Recombinant Proteins - chemistry; Recombinant Proteins - drug effects; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Sigma-1 Receptor; Small interfering RNA; Transfection
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1008911107

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) 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, 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-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 σ₁R-D₁R heteromerization, and provide a unique perspective toward understanding the molecular basis of cocaine addiction.