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Articles, Cellular/Molecular

Cocaine Disrupts Histamine H3 Receptor Modulation of Dopamine D1 Receptor Signaling: σ1-D1-H3 Receptor Complexes as Key Targets for Reducing Cocaine's Effects

Estefanía Moreno, David Moreno-Delgado, Gemma Navarro, Hanne M. Hoffmann, Silvia Fuentes, Santi Rosell-Vilar, Paola Gasperini, Mar Rodríguez-Ruiz, Mireia Medrano, Josefa Mallol, Antoni Cortés, Vicent Casadó, Carme Lluís, Sergi Ferré, Jordi Ortiz, Enric Canela and Peter J. McCormick
Journal of Neuroscience 5 March 2014, 34 (10) 3545-3558; DOI: https://doi.org/10.1523/JNEUROSCI.4147-13.2014
Estefanía Moreno
1Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED),
2Institute of Biomedicine of the University of Barcelona (IBUB) and
3Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, 08028 Spain,
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David Moreno-Delgado
1Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED),
2Institute of Biomedicine of the University of Barcelona (IBUB) and
3Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, 08028 Spain,
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Gemma Navarro
1Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED),
2Institute of Biomedicine of the University of Barcelona (IBUB) and
3Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, 08028 Spain,
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Hanne M. Hoffmann
4Neuroscience Institute and Department of Biochemistry and Molecular Biology, Faculty of Medicine, Universitat Autónoma de Barcelona, 08193 Bellaterra, Spain,
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Silvia Fuentes
4Neuroscience Institute and Department of Biochemistry and Molecular Biology, Faculty of Medicine, Universitat Autónoma de Barcelona, 08193 Bellaterra, Spain,
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Santi Rosell-Vilar
4Neuroscience Institute and Department of Biochemistry and Molecular Biology, Faculty of Medicine, Universitat Autónoma de Barcelona, 08193 Bellaterra, Spain,
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Paola Gasperini
1Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED),
2Institute of Biomedicine of the University of Barcelona (IBUB) and
3Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, 08028 Spain,
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Mar Rodríguez-Ruiz
1Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED),
2Institute of Biomedicine of the University of Barcelona (IBUB) and
3Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, 08028 Spain,
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Mireia Medrano
1Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED),
2Institute of Biomedicine of the University of Barcelona (IBUB) and
3Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, 08028 Spain,
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Josefa Mallol
1Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED),
2Institute of Biomedicine of the University of Barcelona (IBUB) and
3Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, 08028 Spain,
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Antoni Cortés
1Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED),
2Institute of Biomedicine of the University of Barcelona (IBUB) and
3Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, 08028 Spain,
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Vicent Casadó
1Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED),
2Institute of Biomedicine of the University of Barcelona (IBUB) and
3Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, 08028 Spain,
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Carme Lluís
1Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED),
2Institute of Biomedicine of the University of Barcelona (IBUB) and
3Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, 08028 Spain,
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Sergi Ferré
5National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland 21224, and
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Jordi Ortiz
4Neuroscience Institute and Department of Biochemistry and Molecular Biology, Faculty of Medicine, Universitat Autónoma de Barcelona, 08193 Bellaterra, Spain,
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Enric Canela
1Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED),
2Institute of Biomedicine of the University of Barcelona (IBUB) and
3Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, 08028 Spain,
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Peter J. McCormick
1Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED),
2Institute of Biomedicine of the University of Barcelona (IBUB) and
3Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, 08028 Spain,
6School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich, United Kingdom NR4 7TJ
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Abstract

The general effects of cocaine are not well understood at the molecular level. What is known is that the dopamine D1 receptor plays an important role. Here we show that a key mechanism may be cocaine's blockade of the histamine H3 receptor-mediated inhibition of D1 receptor function. This blockade requires the σ1 receptor and occurs upon cocaine binding to σ1-D1-H3 receptor complexes. The cocaine-mediated disruption leaves an uninhibited D1 receptor that activates Gs, freely recruits β-arrestin, increases p-ERK 1/2 levels, and induces cell death when over activated. Using in vitro assays with transfected cells and in ex vivo experiments using both rats acutely treated or self-administered with cocaine along with mice depleted of σ1 receptor, we show that blockade of σ1 receptor by an antagonist restores the protective H3 receptor-mediated brake on D1 receptor signaling and prevents the cell death from elevated D1 receptor signaling. These findings suggest that a combination therapy of σ1R antagonists with H3 receptor agonists could serve to reduce some effects of cocaine.

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The Journal of Neuroscience: 34 (10)
Journal of Neuroscience
Vol. 34, Issue 10
5 Mar 2014
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Cocaine Disrupts Histamine H3 Receptor Modulation of Dopamine D1 Receptor Signaling: σ1-D1-H3 Receptor Complexes as Key Targets for Reducing Cocaine's Effects
Estefanía Moreno, David Moreno-Delgado, Gemma Navarro, Hanne M. Hoffmann, Silvia Fuentes, Santi Rosell-Vilar, Paola Gasperini, Mar Rodríguez-Ruiz, Mireia Medrano, Josefa Mallol, Antoni Cortés, Vicent Casadó, Carme Lluís, Sergi Ferré, Jordi Ortiz, Enric Canela, Peter J. McCormick
Journal of Neuroscience 5 March 2014, 34 (10) 3545-3558; DOI: 10.1523/JNEUROSCI.4147-13.2014

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Cocaine Disrupts Histamine H3 Receptor Modulation of Dopamine D1 Receptor Signaling: σ1-D1-H3 Receptor Complexes as Key Targets for Reducing Cocaine's Effects
Estefanía Moreno, David Moreno-Delgado, Gemma Navarro, Hanne M. Hoffmann, Silvia Fuentes, Santi Rosell-Vilar, Paola Gasperini, Mar Rodríguez-Ruiz, Mireia Medrano, Josefa Mallol, Antoni Cortés, Vicent Casadó, Carme Lluís, Sergi Ferré, Jordi Ortiz, Enric Canela, Peter J. McCormick
Journal of Neuroscience 5 March 2014, 34 (10) 3545-3558; DOI: 10.1523/JNEUROSCI.4147-13.2014
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