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

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

Full text not available from this repository.

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
Related URLs:
Depositing User: Pure Connector
Date Deposited: 12 May 2014 16:02
Last Modified: 21 Apr 2020 22:58
URI: https://ueaeprints.uea.ac.uk/id/eprint/48279
DOI: 10.1523/JNEUROSCI.4147-13.2014

Actions (login required)

View Item View Item