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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/122586
Cocaine disrupts histamine H3 receptor modulation of dopamine D1 receptor signaling: σ1-D1-H3 receptor complexes as key targets for reducing cocaine's effects
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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.
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MORENO GUILLÉN, Estefanía, MORENO-DELGADO, David, NAVARRO BRUGAL, Gemma, HOFFMANN, Hanne, FUENTES, Silvia, ROSELL-VILAR, Santi, GASPERINI, Paola, RODRÍGUEZ RUIZ, Mar, MEDRANO MOYA, Mireia, MALLOL MONTERO, Josefa, CORTÉS TEJEDOR, Antonio, CASADÓ, Vicent, LLUÍS I BISET, Carme, FERRÉ, Sergi, ORTIZ, Jordi, CANELA CAMPOS, Enric i. (enric isidre), MCCORMICK, Peter j.. Cocaine disrupts histamine H3 receptor modulation of dopamine D1 receptor signaling: σ1-D1-H3 receptor complexes as key targets for reducing cocaine's effects. _Journal of Neuroscience_. 2014. Vol. 34, núm. 10, pàgs. 3545-3558. [consulta: 24 de gener de 2026]. ISSN: 0270-6474. [Disponible a: https://hdl.handle.net/2445/122586]