PT  - JOURNAL ARTICLE
AU  - Estefanía Moreno
AU  - David Moreno-Delgado
AU  - Gemma Navarro
AU  - Hanne M. Hoffmann
AU  - Silvia Fuentes
AU  - Santi Rosell-Vilar
AU  - Paola Gasperini
AU  - Mar Rodríguez-Ruiz
AU  - Mireia Medrano
AU  - Josefa Mallol
AU  - Antoni Cortés
AU  - Vicent Casadó
AU  - Carme Lluís
AU  - Sergi Ferré
AU  - Jordi Ortiz
AU  - Enric Canela
AU  - Peter J. McCormick
TI  - Cocaine Disrupts Histamine H<sub>3</sub> Receptor Modulation of Dopamine D<sub>1</sub> Receptor Signaling: σ<sub>1</sub>-D<sub>1</sub>-H<sub>3</sub> Receptor Complexes as Key Targets for Reducing Cocaine's Effects
AID  - 10.1523/JNEUROSCI.4147-13.2014
DP  - 2014 Mar 05
TA  - The Journal of Neuroscience
PG  - 3545--3558
VI  - 34
IP  - 10
4099  - http://www.jneurosci.org/content/34/10/3545.short
4100  - http://www.jneurosci.org/content/34/10/3545.full
SO  - J. Neurosci.2014 Mar 05; 34
AB  - 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.