title: The endocannabinoid system is altered in the post-mortem prefrontal cortex of alcoholic subjects.
abstract: There is strong biochemical, pharmacological and genetic evidence for the involvement of the endocannabinoid system (ECS) in alcohol dependence. However, the majority of studies have been performed in animal models. The aim of the present study was to assess the state of the CB1 receptor, the enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), and the extracellular signal-regulated kinase (ERK) and cyclic-AMP response element-binding protein (CREB) in the post-mortem prefrontal cortex of alcoholic subjects. Experiments were performed in samples from 44 subjects classified in four experimental groups: (1) non-suicidal alcoholic subjects (n = 11); (2) suicidal alcoholic subjects (n = 11); (3) non-alcoholic suicide victims (n = 11); and (4) control subjects (n = 11). We did not observe statistically significant differences in CB1 mRNA relative expression among the four experimental groups. Conversely, our results showed an increase in CB1 receptor protein expression in the prefrontal cortex of the suicidal alcoholic group (127.2 ± 7.3%), with no changes in functionality with regard to either G protein activation or the inhibition of adenylyl cyclase. In parallel, alcoholic subjects presented lower levels of MAGL activity, regardless of the cause of death. A significant decrease in the active form of ERK and CREB levels was also observed in both alcoholic groups. Taken together, our data are consistent with a role for the ECS in the neurobiological mechanisms underlying alcoholism. Moreover, the alterations reported here should be of great interest for the therapeutic treatment of this chronic psychiatric disease.
authors.affiliation: Department of Pharmacology, University of the Basque Country UPV/EHU, Bizkaia, Spain.|Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain.
authors.forename: Amaia M
authors.initials: AM
authors.lastname: Erdozain
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Medicine, Complutense University, Madrid, Spain.
authors.forename: Marina
authors.initials: M
authors.lastname: Rubio
authors.affiliation: Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain.|Department of Physiology and Pharmacology, Institute of Biomedicine and Biotechnology IBBTEC (Universidad de Cantabria-CSIC-IDICAN) Santander, Cantabria, Spain.
authors.forename: Elsa M
authors.initials: EM
authors.lastname: Valdizan
authors.affiliation: Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain.|Department of Physiology and Pharmacology, Institute of Biomedicine and Biotechnology IBBTEC (Universidad de Cantabria-CSIC-IDICAN) Santander, Cantabria, Spain.
authors.forename: Angel
authors.initials: A
authors.lastname: Pazos
authors.affiliation: Department of Pharmacology, University of the Basque Country UPV/EHU, Bizkaia, Spain.|Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain.|BioCruces Health Research Institute, Bizkaia, Spain.
authors.forename: J Javier
authors.initials: JJ
authors.lastname: Meana
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Medicine, Complutense University, Madrid, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.|Instituto Ramón y Cajal de Investigaciones Sanitarias (IRYCIS), Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Fernández-Ruiz
authors.affiliation: School of Life Sciences, University of Nottingham Medical School, Nottingham, UK.
authors.forename: Stephen P H
authors.initials: SP
authors.lastname: Alexander
authors.affiliation: Department of Pharmacology, University of the Basque Country UPV/EHU, Bizkaia, Spain.|Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain.|BioCruces Health Research Institute, Bizkaia, Spain.
authors.forename: Luis F
authors.initials: LF
authors.lastname: Callado
mesh_terms: D000437:Alcoholism / Q000201:enzymology*; D000581:Amidohydrolases / Q000378:metabolism; D000704:Analysis of Variance; D050882:CREB-Binding Protein / Q000378:metabolism; D002102:Cadaver; D016022:Case-Control Studies; D063388:Endocannabinoids / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008994:Monoacylglycerol Lipases / Q000378:metabolism; D017397:Prefrontal Cortex / Q000201:enzymology*; D012333:RNA, Messenger / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D015398:Signal Transduction; D013405:Suicide; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D050882:CREB-Binding Protein; D063388:Endocannabinoids; D048049:Extracellular Signal-Regulated MAP Kinases; D008994:Monoacylglycerol Lipases; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D000099252:Fatty Acid Amide Hydrolases; C494363:CREBBP protein, human
keywords: Alcoholism; CB1 receptor; CREB; ERK; FAAH; MAGL; human brain