Impairment of cocaine-mediated behaviours in mice by clinically relevant Ras-ERK inhibitors

Papale, Alessandro ORCID: https://orcid.org/0000-0002-8794-0171, Morella, Ilaria Maria ORCID: https://orcid.org/0000-0001-5691-5400, Indrigo, Marzia Tina, Bernardi, Rick Eugene, Marrone, Livia, Marchisella, Francesca, Brancale, Andrea ORCID: https://orcid.org/0000-0002-9728-3419, Spanagel, Rainer, Brambilla, Riccardo ORCID: https://orcid.org/0000-0003-3569-5706 and Fasano, Stefania ORCID: https://orcid.org/0000-0002-3696-7139 2016. Impairment of cocaine-mediated behaviours in mice by clinically relevant Ras-ERK inhibitors. eLife 5 , e17111. 10.7554/eLife.17111

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Abstract

Ras-ERK signalling in the brain plays a central role in drug addiction. However, to date, no clinically relevant inhibitor of this cascade has been tested in experimental models of addiction, a necessary step toward clinical trials. We designed two new cell-penetrating peptides - RB1 and RB3 - that penetrate the brain and, in the micromolar range, inhibit phosphorylation of ERK, histone H3 and S6 ribosomal protein in striatal slices. Furthermore, a screening of small therapeutics currently in clinical trials for cancer therapy revealed PD325901 as a brain-penetrating drug that blocks ERK signalling in the nanomolar range. All three compounds have an inhibitory effect on cocaine-induced ERK activation and reward in mice. In particular, PD325901 persistently blocks cocaine-induced place preference and accelerates extinction following cocaine self-administration. Thus, clinically relevant, systemically administered drugs that attenuate Ras-ERK signalling in the brain may be valuable tools for the treatment of cocaine addiction

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy Biosciences
Subjects:	R Medicine > RS Pharmacy and materia medica
Additional Information:	This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Publisher:	eLife Sciences Publications
ISSN:	2050-084X
Date of First Compliant Deposit:	11 September 2016
Date of Acceptance:	4 August 2016
Last Modified:	05 Jan 2024 06:00
URI:	https://orca.cardiff.ac.uk/id/eprint/94429

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