TY - JOUR
T1 - Direct involvement of σ-1 receptors in the dopamine D receptor-mediated effects of cocaine
AU - Navarro, Gemma
AU - Moreno, Estefanía
AU - Aymerich, Marisol
AU - Marcellino, Daniel
AU - McCormick, Peter J.
AU - Mallol, Josefa
AU - Cortés, Antoni
AU - Casadó, Vicent
AU - Canela, Enric I.
AU - Ortiz, Jordi
AU - Fuxe, Kjell
AU - Lluís, Carmen
AU - Ferré, Sergi
AU - Franco, Rafael
PY - 2010/10/26
Y1 - 2010/10/26
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=78649863658&partnerID=8YFLogxK
U2 - 10.1073/pnas.1008911107
DO - 10.1073/pnas.1008911107
M3 - Article
AN - SCOPUS:78649863658
VL - 107
SP - 18676
EP - 18681
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 43
ER -