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Elife. 2016 Aug 24;5. pii: e17111. doi: 10.7554/eLife.17111.

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

Author information

1
Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom.
2
School of Biosciences, Cardiff University, Cardiff, United Kingdom.
3
IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
4
Institute of Psychopharmacology, Heidelberg University, Heidelberg, Germany.
5
Central Institute of Mental Health, Heidelberg University, Heidelberg, Germany.
6
Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
7
Institute of Experimental Neurology, Division of Neuroscience, IRCCS-San Raffaele Scientific Institute, Milan, Italy.
8
School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, United Kingdom.

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.

KEYWORDS:

MEK inhibitor; Ras-ERK signalling; cell-penetrating peptide; cocaine place preference; cocaine self-administration; mouse; neuroscience

PMID:
27557444
PMCID:
PMC4996650
DOI:
10.7554/eLife.17111
[Indexed for MEDLINE]
Free PMC Article

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