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

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

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

120 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 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.

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

Keywords

  • Drug addiction
  • Receptor heteromer

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