PT - JOURNAL ARTICLE AU - Moreno, Estefanía AU - Moreno-Delgado, David AU - Navarro, Gemma AU - Hoffmann, Hanne M. AU - Fuentes, Silvia AU - Rosell-Vilar, Santi AU - Gasperini, Paola AU - Rodríguez-Ruiz, Mar AU - Medrano, Mireia AU - Mallol, Josefa AU - Cortés, Antoni AU - Casadó, Vicent AU - Lluís, Carme AU - Ferré, Sergi AU - Ortiz, Jordi AU - Canela, Enric AU - McCormick, Peter J. 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.