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

Gemma Navarro, Estefanía Moreno, Marisol Aymerich, Daniel Marcellino, Peter J. McCormick, Josefa Mallol, Antoni Cortés, Vicent Casadó, Enric I. Canela, Jordi Ortiz, Kjell Fuxe, Carmen Lluís, Sergi Ferré, Rafael Franco

Research output: Contribution to journalArticlepeer-review

132 Citations (Scopus)

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 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.
Original languageEnglish
Pages (from-to)18676-18681
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America (PNAS)
Volume107
Issue number43
DOIs
Publication statusPublished - 26 Oct 2010

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