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

• Main Authors: Alessandro Papale, Ilaria Maria Morella, Marzia Tina Indrigo, Rick Eugene Bernardi, Livia Marrone, Francesca Marchisella, Andrea Brancale, Rainer Spanagel, Riccardo Brambilla, Stefania Fasano
• Format: Article
• Language: English
• Published: eLife Sciences Publications Ltd 2016-08-01
• Series: eLife
• Subjects: Ras-ERK signalling; MEK inhibitor; cell-penetrating peptide; cocaine place preference; cocaine self-administration
• Online Access: https://elifesciences.org/articles/17111

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.