Impairment of cocaine-mediated behaviours in mice by clinically relevant Ras-ERK inhibitors
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...
Gespeichert in:
| Hauptverfasser: | , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
24 August 2016
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| In: |
eLife
Year: 2016, Jahrgang: 5 |
| ISSN: | 2050-084X |
| DOI: | 10.7554/eLife.17111 |
| Online-Zugang: | Verlag, Volltext: https://doi.org/10.7554/eLife.17111
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| Verfasserangaben: | Alessandro Papale, Ilaria Maria Morella, Marzia Tina Indrigo, Rick Eugene Bernardi, Livia Marrone, Francesca Marchisella, Andrea Brancale, Rainer Spanagel, Riccardo Brambilla, Stefania Fasano |
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| 520 | |a 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. | ||
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