Calleja Conde, JavierEcheverry Alzate, VíctorGiné, ElenaBühler, Kora MareenNadal, RoserMaldonado, Rafael, 1961-Rodríguez de Fonseca, FernandoGual, AntoniLópez Moreno, José A.2017-04-262016Calleja-Conde J, Echeverry-Alzate V, Giné E, Bühler KM, Nadal R, Maldonado R et al. Nalmefene is effective at reducing alcohol seeking, treating alcohol-cocaine interactions and reducing alcohol-induced histone deacetylases gene expression in blood. Br J Pharmacol. 2016 Aug;173(16):2490-505. DOI: 10.1111/bph.135260007-1188http://hdl.handle.net/10230/30903BACKGROUND 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.application/pdfengThis is the pre-peer reviewed version of the following article: Calleja-Conde J, Echeverry-Alzate V, Giné E, Bühler KM, Nadal R, Maldonado R et al. Nalmefene is effective at reducing alcohol seeking, treating alcohol-cocaine interactions and reducing alcohol-induced histone deacetylases gene expression in blood. Br J Pharmacol. 2016 Aug; 173(16): 2490-505, which has been published in final form at http://dx.doi.org/10.1111/bph.13526. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-ArchivingOpiacis -- ReceptorsAlcoholismeCocaïnainfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1111/bph.13526info:eu-repo/semantics/openAccess