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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.<\/jats:p>","DOI":"10.7554\/elife.17111","type":"journal-article","created":{"date-parts":[[2016,8,23]],"date-time":"2016-08-23T04:58:58Z","timestamp":1471928338000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.17111","source":"Crossref","is-referenced-by-count":42,"title":["Impairment of cocaine-mediated behaviours in mice by clinically relevant Ras-ERK inhibitors"],"prefix":"10.7554","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8794-0171","authenticated-orcid":true,"given":"Alessandro","family":"Papale","sequence":"first","affiliation":[{"name":"Neuroscience and Mental Health Research Institute, Cardiff University","place":["Cardiff, United Kingdom"]},{"name":"School of Biosciences, Cardiff University","place":["Cardiff, United 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