Moreno Guillén, EstefaníaMoreno-Delgado, DavidNavarro Brugal, GemmaHoffmann, HanneFuentes, SilviaRosell-Vilar, SantiGasperini, PaolaRodríguez Ruiz, MarMedrano Moya, MireiaMallol Montero, JosefaCortés Tejedor, AntonioCasadó, VicentLluís i Biset, CarmeFerré, SergiOrtiz, JordiCanela Campos, Enric I. (Enric Isidre), 1949-McCormick, Peter J.2018-05-252018-05-252014-03-050270-6474https://hdl.handle.net/2445/122586The 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.14 p.application/pdfengcc-by-nc-sa (c) Moreno Guillén, Estefanía et al., 2014http://creativecommons.org/licenses/by-nc-sa/3.0/esCocaïnaReceptors cel·lularsDopaminaCocaineCell receptorsDopamineinfo:eu-repo/semantics/article6349162018-05-25info:eu-repo/semantics/openAccess24599455