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...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2016-08-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/17111 |
| _version_ | 1811227858795757568 |
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| author | Alessandro Papale Ilaria Maria Morella Marzia Tina Indrigo Rick Eugene Bernardi Livia Marrone Francesca Marchisella Andrea Brancale Rainer Spanagel Riccardo Brambilla Stefania Fasano |
| author_facet | Alessandro Papale Ilaria Maria Morella Marzia Tina Indrigo Rick Eugene Bernardi Livia Marrone Francesca Marchisella Andrea Brancale Rainer Spanagel Riccardo Brambilla Stefania Fasano |
| author_sort | Alessandro Papale |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T09:49:05Z |
| format | Article |
| id | doaj.art-a7b49f64c639469c84fc4766a8920a03 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T09:49:05Z |
| publishDate | 2016-08-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-a7b49f64c639469c84fc4766a8920a032022-12-22T03:37:53ZengeLife Sciences Publications LtdeLife2050-084X2016-08-01510.7554/eLife.17111Impairment of cocaine-mediated behaviours in mice by clinically relevant Ras-ERK inhibitorsAlessandro Papale0https://orcid.org/0000-0002-8794-0171Ilaria Maria Morella1Marzia Tina Indrigo2Rick Eugene Bernardi3Livia Marrone4Francesca Marchisella5Andrea Brancale6Rainer Spanagel7https://orcid.org/0000-0003-2151-4521Riccardo Brambilla8https://orcid.org/0000-0003-3569-5706Stefania Fasano9https://orcid.org/0000-0002-3696-7139Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom; School of Biosciences, Cardiff University, Cardiff, United KingdomNeuroscience and Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom; School of Biosciences, Cardiff University, Cardiff, United KingdomIRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, ItalyInstitute of Psychopharmacology, Heidelberg University, Heidelberg, Germany; Central Institute of Mental Health, Heidelberg University, Heidelberg, Germany; Medical Faculty Mannheim, Heidelberg University, Heidelberg, GermanyInstitute of Experimental Neurology, Division of Neuroscience, IRCCS-San Raffaele Scientific Institute, Milan, ItalyInstitute of Experimental Neurology, Division of Neuroscience, IRCCS-San Raffaele Scientific Institute, Milan, ItalySchool of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, United KingdomInstitute of Psychopharmacology, Heidelberg University, Heidelberg, Germany; Central Institute of Mental Health, Heidelberg University, Heidelberg, Germany; Medical Faculty Mannheim, Heidelberg University, Heidelberg, GermanyNeuroscience and Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom; School of Biosciences, Cardiff University, Cardiff, United KingdomNeuroscience and Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom; School of Biosciences, Cardiff University, Cardiff, United KingdomRas-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.https://elifesciences.org/articles/17111Ras-ERK signallingMEK inhibitorcell-penetrating peptidecocaine place preferencecocaine self-administration |
| spellingShingle | Alessandro Papale Ilaria Maria Morella Marzia Tina Indrigo Rick Eugene Bernardi Livia Marrone Francesca Marchisella Andrea Brancale Rainer Spanagel Riccardo Brambilla Stefania Fasano Impairment of cocaine-mediated behaviours in mice by clinically relevant Ras-ERK inhibitors eLife Ras-ERK signalling MEK inhibitor cell-penetrating peptide cocaine place preference cocaine self-administration |
| title | Impairment of cocaine-mediated behaviours in mice by clinically relevant Ras-ERK inhibitors |
| title_full | Impairment of cocaine-mediated behaviours in mice by clinically relevant Ras-ERK inhibitors |
| title_fullStr | Impairment of cocaine-mediated behaviours in mice by clinically relevant Ras-ERK inhibitors |
| title_full_unstemmed | Impairment of cocaine-mediated behaviours in mice by clinically relevant Ras-ERK inhibitors |
| title_short | Impairment of cocaine-mediated behaviours in mice by clinically relevant Ras-ERK inhibitors |
| title_sort | impairment of cocaine mediated behaviours in mice by clinically relevant ras erk inhibitors |
| topic | Ras-ERK signalling MEK inhibitor cell-penetrating peptide cocaine place preference cocaine self-administration |
| url | https://elifesciences.org/articles/17111 |
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