Impairment of cocaine-mediated behaviours in mice by clinically relevant ras-ERK inhibitors
Articolo
Data di Pubblicazione:
2016
Citazione:
Impairment of cocaine-mediated behaviours in mice by clinically relevant ras-ERK inhibitors / A. Papale, I.M. Morella, M.T. Indrigo, R.E. Bernardi, L. Marrone, F. Marchisella, A. Brancale, R. Spanagel, R. Brambilla, S. Fasano. - In: ELIFE. - ISSN 2050-084X. - 5(2016), pp. e17111.1-e17111.25. [10.7554/eLife.17111]
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.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
signal-regulated kinase; nucleus-accumbens core; dopa-induced dyskinesia; recognition memory; peptide inhibitor; prefrontal cortex; place preference; protein-kinases; activator son; mek inhibitor
Elenco autori:
A. Papale, I.M. Morella, M.T. Indrigo, R.E. Bernardi, L. Marrone, F. Marchisella, A. Brancale, R. Spanagel, R. Brambilla, S. Fasano
Link alla scheda completa:
Link al Full Text: