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

doi:10.1073/pnas.1008911107

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 journal › Article › Research › peer-review

142 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 language	American English
Pages (from-to)	18676-18681
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	107
Issue number	43
DOIs	https://doi.org/10.1073/pnas.1008911107
Publication status	Published - 26 Oct 2010

Keywords

Drug addiction
Receptor heteromer

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10.1073/pnas.1008911107

Cite this

Navarro, G., Moreno, E., Aymerich, M., Marcellino, D., McCormick, P. J., Mallol, J., Cortésa, A., Casadó, V., Canela, E. I., Ortiz, J., Fuxe, K., Lluís, C., Ferré, S., & Franco, R. (2010). Direct involvement of σ-1 receptors in the dopamine D₁ receptor-mediated effects of cocaine. Proceedings of the National Academy of Sciences of the United States of America, 107(43), 18676-18681. https://doi.org/10.1073/pnas.1008911107

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title = "Direct involvement of σ-1 receptors in the dopamine D1 receptor-mediated effects of cocaine",

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.",

keywords = "Drug addiction, Receptor heteromer",

author = "Gemma Navarro and Estefan{\'i}a Moreno and Marisol Aymerich and Daniel Marcellino and McCormick, {Peter J.} and Josefa Mallol and Antoni Cort{\'e}sa and Vicent Casad{\'o} and Canela, {Enric I.} and Jordi Ortiz and Kjell Fuxe and Carmen Llu{\'i}s and Sergi Ferr{\'e} and Rafael Franco",

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Navarro, G, Moreno, E, Aymerich, M, Marcellino, D, McCormick, PJ, Mallol, J, Cortésa, A, Casadó, V, Canela, EI, Ortiz, J, Fuxe, K, Lluís, C, Ferré, S & Franco, R 2010, 'Direct involvement of σ-1 receptors in the dopamine D₁ receptor-mediated effects of cocaine', Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 43, pp. 18676-18681. https://doi.org/10.1073/pnas.1008911107

TY - JOUR

T1 - Direct involvement of σ-1 receptors in the dopamine D1 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 - Cortésa, 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 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.

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 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.

KW - Drug addiction

KW - Receptor heteromer

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DO - 10.1073/pnas.1008911107

M3 - Artículo

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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

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