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Cocaine disrupts histamine H3 receptor modulation of dopamine D1 receptor signaling: σ1-D1-H3 receptor complexes as key targets for reducing cocaine’s effects

Moreno, E, Moreno-Delgado, D, Navarro, G, Hoffmann, HM, Fuentes, S, Rosell-Vilar, S, Gasperini, P, Rodríguez-Ruiz, M, Medrano, M, Mallol, J, Cortés, A, Casadó, V, Lluís, C, Ferré, S, Ortiz, J, Canela, E and McCormick, P (2014) 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, 34 (10). pp. 3545-3558.

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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.

Item Type: Article
Subjects : Veterinary Medicine
Authors :
NameEmailORCID
Moreno, EUNSPECIFIEDUNSPECIFIED
Moreno-Delgado, DUNSPECIFIEDUNSPECIFIED
Navarro, GUNSPECIFIEDUNSPECIFIED
Hoffmann, HMUNSPECIFIEDUNSPECIFIED
Fuentes, SUNSPECIFIEDUNSPECIFIED
Rosell-Vilar, SUNSPECIFIEDUNSPECIFIED
Gasperini, PUNSPECIFIEDUNSPECIFIED
Rodríguez-Ruiz, MUNSPECIFIEDUNSPECIFIED
Medrano, MUNSPECIFIEDUNSPECIFIED
Mallol, JUNSPECIFIEDUNSPECIFIED
Cortés, AUNSPECIFIEDUNSPECIFIED
Casadó, VUNSPECIFIEDUNSPECIFIED
Lluís, CUNSPECIFIEDUNSPECIFIED
Ferré, SUNSPECIFIEDUNSPECIFIED
Ortiz, JUNSPECIFIEDUNSPECIFIED
Canela, EUNSPECIFIEDUNSPECIFIED
McCormick, Pp.mccormick@surrey.ac.ukUNSPECIFIED
Date : 5 March 2014
Identification Number : https://doi.org/10.1523/JNEUROSCI.4147-13.2014
Copyright Disclaimer : Copyright © 2014 the authors
Depositing User : Symplectic Elements
Date Deposited : 17 May 2017 10:46
Last Modified : 18 May 2017 12:43
URI: http://epubs.surrey.ac.uk/id/eprint/829149

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