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

Papale, Alessandro, Morella, Ilaria, Indrigo, Marzia Tina, Bernardi, Rick Eugene, Marrone, Livia, Marchisella, Francesca, Brancale, Andrea, Spanagel, Rainer, Brambilla, Riccardo and Fasano, Stefania 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: Published Online
Status: Published
Schools: Biosciences
Pharmacy
Subjects: R Medicine > RS Pharmacy and materia medica
Publisher: eLife Science Publications
ISSN: 2050-084X
Date of First Compliant Deposit: 11 September 2016
Date of Acceptance: 4 August 2016
Last Modified: 23 Feb 2019 23:53
URI: http://orca.cf.ac.uk/id/eprint/94429

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Cited 11 times in Scopus. View in Scopus. Powered By Scopus® Data

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