Cocaine disrupts histamine H<inf>3</inf> receptor modulation of dopamine D<inf>1</inf> receptor signaling: σ<inf>1</inf>-D<inf>1</inf>-H<inf>3</inf> receptor complexes as key targets for reducing cocaine's effects: σ1-D1-H3 receptor complexes as key targets for reducing cocaine's effects

Estefanía Moreno, David Moreno-Delgado, Gemma Navarro, Hanne M. Hoffmann, Silvia Fuentes, Santi Rosell-Vilar, Paola Gasperini, Mar Rodríguez-Ruiz, Mireia Medrano, Josefa Mallol, Antoni Cortés, Vicent Casadó, Carme Lluís, Sergi Ferré, Jordi Ortiz, Enric Canela, Peter J. McCormick

Research output: Contribution to journalArticleResearchpeer-review

48 Citations (Scopus)

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. © 2014 the authors.
Original languageEnglish
Pages (from-to)3545-3558
Number of pages14
JournalJournal of Neuroscience
Volume34
Issue number10
DOIs
Publication statusPublished - 10 Mar 2014

Fingerprint Dive into the research topics of 'Cocaine disrupts histamine H<inf>3</inf> receptor modulation of dopamine D<inf>1</inf> receptor signaling: σ<inf>1</inf>-D<inf>1</inf>-H<inf>3</inf> receptor complexes as key targets for reducing cocaine's effects: σ<sub>1</sub>-D<sub>1</sub>-H<sub>3</sub> receptor complexes as key targets for reducing cocaine's effects'. Together they form a unique fingerprint.

Cite this