title: Impairment of cocaine-mediated behaviours in mice by clinically relevant Ras-ERK inhibitors.
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.
authors.affiliation: Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom.|School of Biosciences, Cardiff University, Cardiff, United Kingdom.
authors.forename: Alessandro
authors.identifier: http://orcid.org/0000-0002-8794-0171
authors.initials: A
authors.lastname: Papale
authors.affiliation: Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom.|School of Biosciences, Cardiff University, Cardiff, United Kingdom.
authors.forename: Ilaria Maria
authors.initials: IM
authors.lastname: Morella
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors.forename: Marzia Tina
authors.initials: MT
authors.lastname: Indrigo
authors.affiliation: Institute of Psychopharmacology, Heidelberg University, Heidelberg, Germany.|Central Institute of Mental Health, Heidelberg University, Heidelberg, Germany.|Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
authors.forename: Rick Eugene
authors.initials: RE
authors.lastname: Bernardi
authors.affiliation: Institute of Experimental Neurology, Division of Neuroscience, IRCCS-San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Livia
authors.initials: L
authors.lastname: Marrone
authors.affiliation: Institute of Experimental Neurology, Division of Neuroscience, IRCCS-San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Marchisella
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, United Kingdom.
authors.forename: Andrea
authors.initials: A
authors.lastname: Brancale
authors.affiliation: Institute of Psychopharmacology, Heidelberg University, Heidelberg, Germany.|Central Institute of Mental Health, Heidelberg University, Heidelberg, Germany.|Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
authors.forename: Rainer
authors.identifier: http://orcid.org/0000-0003-2151-4521
authors.initials: R
authors.lastname: Spanagel
authors.affiliation: Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom.|School of Biosciences, Cardiff University, Cardiff, United Kingdom.
authors.forename: Riccardo
authors.identifier: http://orcid.org/0000-0003-3569-5706
authors.initials: R
authors.lastname: Brambilla
authors.affiliation: Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom.|School of Biosciences, Cardiff University, Cardiff, United Kingdom.
authors.forename: Stefania
authors.identifier: http://orcid.org/0000-0002-3696-7139
authors.initials: S
authors.lastname: Fasano
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001549:Benzamides / Q000378:metabolism; D057846:Cell-Penetrating Peptides / Q000378:metabolism; D003042:Cocaine / Q000008:administration & dosage*; D003342:Corpus Striatum / Q000187:drug effects; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D019966:Substance-Related Disorders / Q000188:drug therapy*; D018631:ras Proteins / Q000037:antagonists & inhibitors*
chemical_list: D001549:Benzamides; D057846:Cell-Penetrating Peptides; C506614:mirdametinib; D004159:Diphenylamine; D018631:ras Proteins; D003042:Cocaine
keywords: MEK inhibitor; Ras-ERK signalling; cell-penetrating peptide; cocaine place preference; cocaine self-administration; mouse; neuroscience