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|Title:||Cocaine disrupts histamine H3 receptor modulation of dopamine D1 receptor signaling: σ1-D1-H3 receptor complexes as key targets for reducing cocaine's effects|
|Author:||Moreno Guillén, Estefanía|
Navarro Brugal, Gemma
Mallol Montero, Josefa
Cortés Tejedor, Antonio
Lluís i Biset, Carme
Canela Campos, Enric I.
McCormick, Peter J.
|Publisher:||The Society for Neuroscience|
|Abstract:||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.|
|Note:||Reproducció del document publicat a: https://doi.org/10.1523/JNEUROSCI.4147-13.2014|
|It is part of:||Journal of Neuroscience, 2014, vol. 34, num. 10, p. 3545-3558|
|Appears in Collections:||Articles publicats en revistes (Bioquímica i Biomedicina Molecular)|
Articles publicats en revistes (Bioquímica i Fisiologia)
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