Dataset Information

Low ?-Opioid Receptor Status in Alcohol Dependence Identified by Combined Positron Emission Tomography and Post-Mortem Brain Analysis.

ABSTRACT: Blockade of the ?-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 BPND was 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.

SUBMITTER: Hermann D

PROVIDER: S-EPMC5240173 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Low μ-Opioid Receptor Status in Alcohol Dependence Identified by Combined Positron Emission Tomography and Post-Mortem Brain Analysis.

Hermann Derik D Hirth Natalie N Reimold Matthias M Batra Anil A Smolka Michael N MN Hoffmann Sabine S Kiefer Falk F Noori Hamid R HR Sommer Wolfgang H WH Reischl Gerald G la Fougère Christian C Mann Karl K Spanagel Rainer R Hansson Anita C AC

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20160811 3

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 [<sup>11</sup>C]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 cl ...[more]

PMID: 27510425

Similar Datasets

Project description:Positron emission tomography (PET) is an imaging technology that measures the concentration, distribution, and pharmacokinetics of radiotracers-molecules that are labeled with short-lived positron-emitting variants of chemical elements naturally found in the body. These radioisotopes can be attached to compounds involved in normal brain function and then injected into the blood stream. The signals emitted by these radiotracers then are measured using specific detectors. PET is a highly sensitive method; it measures radioisotope concentrations in the nanomolar to picomolar range (10-9 to 10-12 M) . Therefore, the technique can be used to label compounds that are of pharmacological and physiological relevance. These radiotracers then can be used to probe neurochemical and metabolic processes at the relevant physiological concentrations without perturbing the system that is measured. To exert their effects on the brain, alcohol and other drugs (AODs) act on signaling molecules (i.e., neurotransmitters) in the brain as well as on the molecules on the surface of neurons (i.e., receptors) with which the neurotransmitters interact. Specific compounds that selectively bind to such receptors, to the molecules that transport neurotransmitters back into cells, and to the enzymes that are involved in the synthesis or metabolism of neurotransmitters can be labeled for use as PET radiotracers. As a result, PET can be used to assess the metabolic and neurochemical actions of AODs and to evaluate the consequences of chronic AOD use. Since its inception, PET has been used extensively to study the effects of AODs in human and nonhuman primates; however, the recent development of microPET technology has expanded its applications to research in rodents. In addition, increasing numbers of studies are using PET methodology to assess the involvement of genetic variations in individual genes (i.e., polymorphisms) in brain function and neurochemistry. The studies discussed are divided into those that assess the effects of alcohol on brain function (i.e., brain metabolism and cerebral blood flow) and those that assess the effects of alcohol on brain function (i.e., brain metabolism and cerebral blood flow) and those that assess its effects on neurochemistry.

Project description:Fluorine-18-fluoro-2-deoxy-D-glucose (FDG) is widely used as positron-emission-tomography (PET) radiotracer for the detection and staging of human cancer. Tumor uptake of FDG varies substantially between different cancer types and between patients with the same tumor type. The molecular basis for this heterogeneity is unknown. Using cancer cell lines and primary human tumors of distinct histologic origins, we here show that increased FDG uptake is universally associated with coordinate upregulation of genes within the glycolysis, pentose-phosphate, and other related metabolic pathways. In primary human breast cancers, this FDG signature shows significant overlap with established breast cancer signatures for the “basal-like” disease subtype and “poor prognosis”. FDG high breast cancer showed significantly more gene copy number alterations genome wide than FDG low cancers. About 50 % of primary breast cancers with high FDG uptake and FDG gene expression signature show DNA copy gain encompassing the c-myc gene locus and express gene sets regulated by the transcription factor MYC. Our data shows that FDG-PET marks a distinct subset of “basal-like” human breast cancer which is characterized by MYC and prognostically unfavorable gene expression signatures, suggesting that FDG-PET imaging may be useful to risk-stratify patients with locally advanced breast cancer. Our general strategy to identify molecular determinants of FDG-retention through a genome-wide approach consisted of FDG uptake measurements in cancer cell lines and primary human tumors, the selection of samples with particularly high versus low FDG-retention, and subsequent pathway-based analysis of RNA expression data collected from these samples. Cell line RNA was extracted from a 10 cm plate seeded simultaneously and at the same density as the wells for FDG-uptake assays. For primary human tumor samples, RNA was extracted from macrodissected frozen tumor tissue. All cell line RNA samples and the astrocytoma RNA aliquots were hybridized to Affymetrix U133 Plus 2.0 arrays. All primary breast cancer RNA samples were hybridized to Affymetrix U133A arrays.

Dataset Information

Low ?-Opioid Receptor Status in Alcohol Dependence Identified by Combined Positron Emission Tomography and Post-Mortem Brain Analysis.

Publications

Low μ-Opioid Receptor Status in Alcohol Dependence Identified by Combined Positron Emission Tomography and Post-Mortem Brain Analysis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets