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

eLife

Andrea Brancale¹  Rainer Spanagel²  Ilaria Maria Morella³  Rick Eugene Bernardi³  Livia Marrone⁴  Riccardo Brambilla⁵  Stefania Fasano⁵  Francesca Marchisella⁶  Alessandro Papale⁷  Marzia Tina Indrigo⁷ 

[1] Central Institute of Mental Health, Heidelberg University, Heidelberg, Germany;Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany;School of Biosciences, Cardiff University, Cardiff, United Kingdom;IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy;Institute of Experimental Neurology, Division of Neuroscience, IRCCS-San Raffaele Scientific Institute, Milan, Italy;Institute of Psychopharmacology, Heidelberg University, Heidelberg, Germany;Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom;

关键词: Ras-ERK signalling;    MEK inhibitor;    cell-penetrating peptide;    cocaine place preference;    cocaine self-administration;   

DOI  :  10.7554/eLife.17111

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown