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

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 and Franco, Rafael (2010) Direct involvement of σ-1 receptors in the dopamine D receptor-mediated effects of cocaine. Proceedings of the National Academy of Sciences of the United States of America (PNAS), 107 (43). pp. 18676-18681. ISSN 0027-8424

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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.

Item Type: Article
Faculty \ School: Faculty of Science > School of Pharmacy
Related URLs:
Depositing User: Pure Connector
Date Deposited: 13 Jan 2014 13:28
Last Modified: 19 Mar 2020 02:25
URI: https://ueaeprints.uea.ac.uk/id/eprint/47157
DOI: 10.1073/pnas.1008911107

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