Cocaine disrupts histamine H3 receptor modulation of dopamine D1 receptor signaling: σ1-D1-H3 receptor complexes as key targets for reducing cocaine’s effects

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Moreno, Estefanía, Moreno-Delgado, David, Navarro, Gemma, Hoffmann, Hanne M., Fuentes, Silvia, Rosell-Vilar, Santi, Rodriguez-Ruiz, Mar, Medrano, Mireia, Mallol, Josefa, Cortes, Antoni, Casado, Vicent, Lluis, Carme, Ferre, Sergi, Ortiz, Jordi, Canela, Enric and Mccormick, Peter (2014) Cocaine disrupts histamine H3 receptor modulation of dopamine D1 receptor signaling: σ1-D1-H3 receptor complexes as key targets for reducing cocaine’s effects. The Journal of Neuroscience, 34 (10). pp. 3545-3558. ISSN 1529-2401

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Abstract

The general effects of cocaine are not well understood at the molecular level. What is known is that 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.

Item Type: Article
Additional Information: The Journal of Neuroscience, 5 March 2014, 34(10): 3545-3558; doi: 10.1523/JNEUROSCI.4147-13.2014
Faculty \ School: Faculty of Science > School of Pharmacy
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Depositing User: Pure Connector
Date Deposited: 12 May 2014 16:02
Last Modified: 24 Oct 2022 06:14
URI: https://ueaeprints.uea.ac.uk/id/eprint/48279
DOI: 10.1523/JNEUROSCI.4147-13.2014

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