title: Altered CB1 receptor coupling to G-proteins in the post-mortem caudate nucleus and cerebellum of alcoholic subjects.
abstract: Biochemical, pharmacological and genetic evidence suggests the involvement of the endocannabinoid system in alcohol dependence. The aim of the present study was to evaluate the state of CB1 receptors in post-mortem caudate nucleus, hippocampus and cerebellum of alcoholic subjects.CB1 protein levels were measured by Western blot, CB1 receptor density and affinity by [(3)H]WIN55,212-2 saturation assays and CB1 functionality by [(35)S]GTPγS binding assays. Experiments were performed in samples from 24 subjects classified as non-suicidal alcoholics (n = 6), suicidal alcoholics (n = 6), non-alcoholic suicide victims (n = 6) and control subjects (n = 6).Alcoholic subjects presented hyperfunctional CB1 receptors in the caudate nucleus resulting in a higher maximal effect in both alcoholic groups compared to the non-alcoholic groups (p < 0.001). Conversely, in the cerebellum the non-suicidal alcoholic subjects showed hypofunctional receptors with lower maximal effect and potency (p < 0.001). No changes were found in the CB1 protein expression in either region. In the hippocampus of alcoholic subjects, no changes were observed either in the functionality, density or protein levels.Our data support an association between endocannabinoid system activity and alcoholism. The modifications reported here could be either a consequence of high lifetime ethanol consumption or a vulnerability factor to develop alcohol addiction.
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 Current address: Neuroscience Paris Seine, CNRS UMR 8246, INSERM U1130, Université Pierre et Marie Curie, Paris, France.
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: 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: 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 lf.callado@ehu.eus.
authors.forename: Luis F
authors.initials: LF
authors.lastname: Callado
mesh_terms: D000328:Adult; D000368:Aged; D000437:Alcoholism / Q000378:metabolism*; D048588:Benzoxazines / Q000378:metabolism; D016022:Case-Control Studies; D002421:Caudate Nucleus / Q000000981:diagnostic imaging / Q000378:metabolism*; D002531:Cerebellum / Q000000981:diagnostic imaging / Q000378:metabolism*; D005260:Female; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D006624:Hippocampus / Q000000981:diagnostic imaging / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000378:metabolism; D009281:Naphthalenes / Q000378:metabolism; D011180:Postmortem Changes; D011869:Radioligand Assay; D011877:Radionuclide Imaging; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D013405:Suicide; D013462:Sulfur Radioisotopes / Q000378:metabolism; D014316:Tritium / Q000378:metabolism
chemical_list: D048588:Benzoxazines; D009025:Morpholines; D009281:Naphthalenes; D043884:Receptor, Cannabinoid, CB1; D013462:Sulfur Radioisotopes; D014316:Tritium; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D020962:Heterotrimeric GTP-Binding Proteins
keywords: CB1 receptors; G-proteins; alcoholism; caudate; cerebellum; human brain