title: Low μ-Opioid Receptor Status in Alcohol Dependence Identified by Combined Positron Emission Tomography and Post-Mortem Brain Analysis.
abstract: Blockade of the μ-opioid receptor (MOR) by naltrexone reduces relapse risk in a subpopulation of alcohol-dependent patients. Previous positron-emission-tomography (PET) studies using the MOR ligand [11C]carfentanil have found increased MOR availability in abstinent alcoholics, which may reflect either increased MOR expression or lower endogenous ligand concentration. To differentiate between both effects, we investigated two cohorts of alcoholic subjects using either post-mortem or clinical PET analysis. Post-mortem brain tissue of alcohol-dependent subjects and controls (N=43/group) was quantitatively analyzed for MOR ([3H]DAMGO)-binding sites and OPRM1 mRNA in striatal regions. [11C]carfentanil PET was performed in detoxified, medication free alcohol-dependent patients (N=38), followed by a randomized controlled study of naltrexone versus placebo and follow-up for 1 year (clinical trial number: NCT00317031). Because the functional OPRM1 variant rs1799971:A>G affects the ligand binding, allele carrier status was considered in the analyses. MOR-binding sites were reduced by 23-51% in post-mortem striatal tissue of alcoholics. In the PET study, a significant interaction of OPRM1 genotype, binding potential (BPND) for [11C]carfentanil in the ventral striatum, and relapse risk was found. Particularly in G-allele carriers, lower striatal BPNDwas associated with a higher relapse risk. Interestingly, this effect was more pronounced in the naltrexone treatment group. Reduced MOR is interpreted as a neuroadaptation to an alcohol-induced release of endogenous ligands in patients with severe alcoholism. Low MOR availability may explain the ineffectiveness of naltrexone treatment in this subpopulation. Finally, low MOR-binding sites are proposed as a molecular marker for a negative disease course.
authors: Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors: Derik
authors: D
authors: Hermann
authors: Institute of Psychopharmacology, Central Institute of Mental Health Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors: Natalie
authors: N
authors: Hirth
authors: Department of Nuclear Medicine, University of Tübingen, Tübingen, Germany.
authors: Matthias
authors: M
authors: Reimold
authors: Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany.
authors: Anil
authors: A
authors: Batra
authors: Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.|Department of Psychiatry and Psychotherapy, Technische Universität Dresden, Dresden, Germany.
authors: Michael N
authors: MN
authors: Smolka
authors: Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors: Sabine
authors: S
authors: Hoffmann
authors: Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors: Falk
authors: F
authors: Kiefer
authors: Institute of Psychopharmacology, Central Institute of Mental Health Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors: Hamid R
authors: HR
authors: Noori
authors: Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.|Institute of Psychopharmacology, Central Institute of Mental Health Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors: Wolfgang H
authors: 0000-0002-5903-6521
authors: WH
authors: Sommer
authors: Department of Preclinical Imaging and Radiopharmacy, University of Tübingen, Tübingen, Germany.
authors: Gerald
authors: G
authors: Reischl
authors: Department of Nuclear Medicine, University of Tübingen, Tübingen, Germany.
authors: Christian
authors: C
authors: la Fougère
authors: Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors: Karl
authors: K
authors: Mann
authors: Institute of Psychopharmacology, Central Institute of Mental Health Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors: Rainer
authors: R
authors: Spanagel
authors: Institute of Psychopharmacology, Central Institute of Mental Health Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors: Anita C
authors: AC
authors: Hansson
mesh_terms: D000328:Adult; D000368:Aged; D000437:Alcoholism / Q000000981:diagnostic imaging / Q000378:metabolism*; D000701:Analgesics, Opioid / Q000378:metabolism*; D005283:Fentanyl / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009271:Naltrexone / Q000008:administration & dosage / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D049268:Positron-Emission Tomography; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000378:metabolism*; D014015:Tissue Banks; D066328:Ventral Striatum / Q000000981:diagnostic imaging / Q000378:metabolism*
chemical_list: D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; C485764:OPRM1 protein, human; D017450:Receptors, Opioid, mu; D009271:Naltrexone; C017114:carfentanil; D005283:Fentanyl