TY - JOUR
T1 - Cocaine disrupts histamine H3 receptor modulation of dopamine D1 receptor signaling: σ1-D1-H3 receptor complexes as key targets for reducing cocaine's effects
T2 - σ1-D1-H3 receptor complexes as key targets for reducing cocaine's effects
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.
PY - 2014/3/10
Y1 - 2014/3/10
N2 - 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. © 2014 the authors.
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. © 2014 the authors.
UR - http://www.scopus.com/inward/record.url?scp=84895488459&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.4147-13.2014
DO - 10.1523/JNEUROSCI.4147-13.2014
M3 - Article
C2 - 24599455
SN - 0270-6474
VL - 34
SP - 3545
EP - 3558
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 10
ER -