title: Nalmefene is effective at reducing alcohol seeking, treating alcohol-cocaine interactions and reducing alcohol-induced histone deacetylases gene expression in blood.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Psychobiology, School of Psychology, Campus de Somosaguas, Complutense University of Madrid, Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Calleja-Conde
authors.affiliation: Department of Psychobiology, School of Psychology, Campus de Somosaguas, Complutense University of Madrid, Madrid, Spain.
authors.forename: Victor
authors.initials: V
authors.lastname: Echeverry-Alzate
authors.affiliation: Department of Cellular Biology, School of Medicine, Complutense University of Madrid, Madrid, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Giné
authors.affiliation: Department of Psychobiology, School of Psychology, Campus de Somosaguas, Complutense University of Madrid, Madrid, Spain.
authors.forename: Kora-Mareen
authors.initials: KM
authors.lastname: Bühler
authors.affiliation: Psychobiology Unit, School of Psychology, Institut de Neurociències, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Roser
authors.initials: R
authors.lastname: Nadal
authors.affiliation: Laboratori de Neurofarmacologia, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Maldonado
authors.affiliation: Department of Psychobiology, School of Psychology, Campus de Somosaguas, Complutense University of Madrid, Madrid, Spain.|Instituto IBIMA de Málaga, Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario, Málaga, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Rodríguez de Fonseca
authors.affiliation: Addictions Unit, Department of Psychiatry, Clinical Institute of Neuroscience, Hospital Clínic, Barcelona, Spain.
authors.forename: Antoni
authors.initials: A
authors.lastname: Gual
authors.affiliation: Department of Psychobiology, School of Psychology, Campus de Somosaguas, Complutense University of Madrid, Madrid, Spain.
authors.forename: Jose Antonio
authors.initials: JA
authors.lastname: López-Moreno
mesh_terms: D000428:Alcohol Drinking / Q000097:blood* / Q000517:prevention & control*; D000818:Animals; D003042:Cocaine / Q000008:administration & dosage / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D000431:Ethanol / Q000008:administration & dosage / Q000037:antagonists & inhibitors*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000235:genetics; D006655:Histone Deacetylases / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009271:Naltrexone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
chemical_list: D000431:Ethanol; D009271:Naltrexone; D006655:Histone Deacetylases; D003042:Cocaine; C038981:nalmefene