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

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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.

DOI: http://dx.doi.org/10.7554/eLife.17111.001

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Identification of a novel inhibitor of mitogen-activated protein kinase kinase.

M Favata, K Y Horiuchi, E. J. Manos … (1998)

The compound U0126 (1,4-diamino-2,3-dicyano-1, 4-bis[2-aminophenylthio]butadiene) was identified as an inhibitor of AP-1 transactivation in a cell-based reporter assay. U0126 was also shown to inhibit endogenous promoters containing AP-1 response elements but did not affect genes lacking an AP-1 response element in their promoters. These effects of U0126 result from direct inhibition of the mitogen-activated protein kinase kinase family members, MEK-1 and MEK-2. Inhibition is selective for MEK-1 and -2, as U0126 shows little, if any, effect on the kinase activities of protein kinase C, Abl, Raf, MEKK, ERK, JNK, MKK-3, MKK-4/SEK, MKK-6, Cdk2, or Cdk4. Comparative kinetic analysis of U0126 and the MEK inhibitor PD098059 (Dudley, D. T., Pang, L., Decker, S. J., Bridges, A. J., and Saltiel, A. R. (1995) Proc. Natl. Acad. Sci U. S. A. 92, 7686-7689) demonstrates that U0126 and PD098059 are noncompetitive inhibitors with respect to both MEK substrates, ATP and ERK. We further demonstrate that the two compounds bind to deltaN3-S218E/S222D MEK in a mutually exclusive fashion, suggesting that they may share a common or overlapping binding site(s). Quantitative evaluation of the steady state kinetics of MEK inhibition by these compounds reveals that U0126 has approximately 100-fold higher affinity for deltaN3-S218E/S222D MEK than does PD098059. We further tested the effects of these compounds on the activity of wild type MEK isolated after activation from stimulated cells. Surprisingly, we observe a significant diminution in affinity of both compounds for wild type MEK as compared with the deltaN3-S218E/S222D mutant enzyme. These results suggest that the affinity of both compounds is mediated by subtle conformational differences between the two activated MEK forms. The MEK affinity of U0126, its selectivity for MEK over other kinases, and its cellular efficacy suggest that this compound will serve as a powerful tool for in vitro and cellular investigations of mitogen-activated protein kinase-mediated signal transduction.

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Thomas M Tzschentke (2007)

Conditioned place preference (CPP) continues to be one of the most popular models to study the motivational effects of drugs and non-drug treatments in experimental animals. This is obvious from a steady year-to-year increase in the number of publications reporting the use this model. Since the compilation of the preceding review in 1998, more than 1000 new studies using place conditioning have been published, and the aim of the present review is to provide an overview of these recent publications. There are a number of trends and developments that are obvious in the literature of the last decade. First, as more and more knockout and transgenic animals become available, place conditioning is increasingly used to assess the motivational effects of drugs or non-drug rewards in genetically modified animals. Second, there is a still small but growing literature on the use of place conditioning to study the motivational aspects of pain, a field of pre-clinical research that has so far received little attention, because of the lack of appropriate animal models. Third, place conditioning continues to be widely used to study tolerance and sensitization to the rewarding effects of drugs induced by pre-treatment regimens. Fourth, extinction/reinstatement procedures in place conditioning are becoming increasingly popular. This interesting approach is thought to model certain aspects of relapse to addictive behavior and has previously almost exclusively been studied in drug self-administration paradigms. It has now also become established in the place conditioning literature and provides an additional and technically easy approach to this important phenomenon. The enormous number of studies to be covered in this review prevented in-depth discussion of many methodological, pharmacological or neurobiological aspects; to a large extent, the presentation of data had to be limited to a short and condensed summary of the most relevant findings.

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The MAPK cascade is required for mammalian associative learning.

J Petraitis, J. Sweatt, Joel Selcher … (1998)

Mitogen-activated protein kinase (MAPK) is an integral component of cellular signaling during mitogenesis and differentiation of mitotic cells. Recently MAPK activation in post-mitotic cells has been implicated in hippocampal long-term potentiation (LTP), a potential cellular mechanism of learning and memory. Here we investigate the involvement of MAPK in learning and memory in behaving animals. MAPK activation increased in the rat hippocampus after an associative learning task, contextual fear conditioning. Two other protein kinases known to be activated during hippocampal LTP, protein kinase C and alpha-calcium/calmodulin protein kinase II, also were activated in the hippocampus after learning. Inhibition of the specific upstream activator of MAPK, MAPK kinase (MEK), blocked fear conditioning. Thus, classical conditioning in mammals activates MAPK, which is necessary for consolidation of the resultant learning.

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Author and article information

Contributors

Anne West: Role: Reviewing editor

Journal

Journal ID (nlm-ta): eLife

Journal ID (iso-abbrev): Elife

Journal ID (hwp): eLife

Journal ID (publisher-id): eLife

Title: eLife

Publisher: eLife Sciences Publications, Ltd

ISSN (Electronic): 2050-084X

Publication date (Electronic, pub): 24 August 2016

Publication date Collection: 2016

Volume: 5

Electronic Location Identifier: e17111

Affiliations

[1 ]deptNeuroscience and Mental Health Research Institute , Cardiff University , Cardiff, United Kingdom

[2 ]deptSchool of Biosciences , Cardiff University , Cardiff, United Kingdom

[3 ]IRCCS-Istituto di Ricerche Farmacologiche Mario Negri , Milan, Italy

[4 ]deptInstitute of Psychopharmacology , Heidelberg University , Heidelberg, Germany

[5 ]deptCentral Institute of Mental Health , Heidelberg University , Heidelberg, Germany

[6 ]deptMedical Faculty Mannheim , Heidelberg University , Heidelberg, Germany

[7 ]deptInstitute of Experimental Neurology, Division of Neuroscience , IRCCS-San Raffaele Scientific Institute , Milan, Italy

[8 ]deptSchool of Pharmacy and Pharmaceutical Sciences , Cardiff University , Cardiff, United Kingdom

[9]Duke University School of Medicine , United States

[10]Duke University School of Medicine , United States

Author notes

brambillar@ 123456cardiff.ac.uk (RB);

fasanos@ 123456cardiff.ac.uk (SF)

[†]

These authors contributed equally to this work.

Author information

Alessandro Papale http://orcid.org/0000-0002-8794-0171

Rainer Spanagel http://orcid.org/0000-0003-2151-4521

Riccardo Brambilla http://orcid.org/0000-0003-3569-5706

Stefania Fasano http://orcid.org/0000-0002-3696-7139

Article

Publisher ID: 17111

DOI: 10.7554/eLife.17111

PMC ID: 4996650

PubMed ID: 27557444

SO-VID: 4129e674-6d20-4cf4-b78f-d662ff74caad

License:

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

History

Date received : 20 April 2016

Date accepted : 04 August 2016

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;

Award ID: 383/5-1

Award Recipient : Rainer Spanagel

Funded by: ERANET;

Award ID: COCADDICT

Award Recipient : Rainer Spanagel

Funded by: Fondazione Cariplo;