Nalmefene is effective at reducing alcohol seeking, treating alcohol-cocaine interactions and reducing alcohol-induced histone deacetylases gene expression in blood

Javier Calleja-Conde, Victor Echeverry-Alzate, Elena Giné, Kora Mareen Bühler, Roser Nadal, Rafael Maldonado, Fernando Rodríguez de Fonseca, Antoni Gual, Jose Antonio López-Moreno

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Abstract

© 2016 The British Pharmacological Society Background and Purpose: The opioid antagonist nalmefene (selincro®) was approved for alcohol-related disorders by the European Medicines Agency in 2013. However, there have been no studies regarding the effectiveness of nalmefene when alcohol is used in combination with cocaine. Experimental Approach: Using operant alcohol self-administration in Wistar rats and qRT-PCR, we evaluated (i) the dose–response curve for s.c. and p.o. nalmefene; (ii) the effects of nalmefene with increasing concentrations of alcohol; (iii) the efficacy of nalmefene on cocaine-potentiated alcohol responding; and (iv) the gene expression profiles of histone deacetylases (Hdac1–11) in peripheral blood in vivo and in the prefrontal cortex, heart, liver and kidney post mortem. Key Results: S.c. (0.01, 0.05, 0.1 mg·kg−1) and p.o. (10, 20, 40 mg·kg−1) nalmefene dose-dependently reduced alcohol-reinforced responding by up to 50.3%. This effect of nalmefene was not dependent on alcohol concentration (10, 15, 20%). Cocaine potentiated alcohol responding by approximately 40% and nalmefene (0.05 mg·kg−1) reversed this effect of cocaine. Alcohol increased Hdac gene expression in blood and nalmefene prevented the increases in Hdacs 3, 8, 5, 7, 9, 6 and 10. In the other tissues, alcohol and nalmefene either did not alter the gene expression of Hdacs, as in the prefrontal cortex, or a tissue-Hdac-specific effect was observed. Conclusions and Implications: Nalmefene might be effective as a treatment for alcohol-dependent patients who also use cocaine. Also, the expression of Hdacs in peripheral blood might be useful as a biomarker of alcohol use and drug response.
Original languageEnglish
Pages (from-to)2490-2505
JournalBritish Journal of Pharmacology
DOIs
Publication statusPublished - 1 Jan 2016

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    Calleja-Conde, J., Echeverry-Alzate, V., Giné, E., Bühler, K. M., Nadal, R., Maldonado, R., Rodríguez de Fonseca, F., Gual, A., & López-Moreno, J. A. (2016). Nalmefene is effective at reducing alcohol seeking, treating alcohol-cocaine interactions and reducing alcohol-induced histone deacetylases gene expression in blood. British Journal of Pharmacology, 2490-2505. https://doi.org/10.1111/bph.13526