RT Journal Article
SR Electronic
T1 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
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 3545
OP 3558
DO 10.1523/JNEUROSCI.4147-13.2014
VO 34
IS 10
A1 Moreno, Estefanía
A1 Moreno-Delgado, David
A1 Navarro, Gemma
A1 Hoffmann, Hanne M.
A1 Fuentes, Silvia
A1 Rosell-Vilar, Santi
A1 Gasperini, Paola
A1 Rodríguez-Ruiz, Mar
A1 Medrano, Mireia
A1 Mallol, Josefa
A1 Cortés, Antoni
A1 Casadó, Vicent
A1 Lluís, Carme
A1 Ferré, Sergi
A1 Ortiz, Jordi
A1 Canela, Enric
A1 McCormick, Peter J.
YR 2014
UL http://www.jneurosci.org/content/34/10/3545.abstract
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.