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 [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 clinical PET analysis. Post-mortem brain tissue of alcohol-dependent subjects and controls (N=43/group) was quantitatively analyzed for MOR ([H]DAMGO)-binding sites and OPRM1 mRNA in striatal regions. [C]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 (BP) for [C]carfentanil in the ventral striatum, and relapse risk was found. Particularly in G-allele carriers, lower striatal BP 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.

Dynorphin and κ-Opioid Receptor Dysregulation in the Dopaminergic Reward System of Human Alcoholics

“…These transcriptional changes may have functional consequences contributing to the dysregulation of the D1-/D2-MSN circuits in addicted brain. Importantly, observed downregulation of DRD1 expression but unaltered KOR and DRD2 mRNA in alcoholics corroborates our previously demonstrated decline in D1-receptor as well as unchanged D2- and KOR receptor-binding potential in NAc of human alcoholics and in rat model of alcohol dependence [ 15 , 75 ]. Detailed information on the concentration of dynorphins in the vicinity of the receptor molecules is missing; at the present, it is challenging and virtually impossible to obtain such information for the human brain.…”

Analysis of whole genome-transcriptomic organization in brain to identify genes associated with alcoholism

“…The transcriptional effects of long-term alcohol consumption are associated with pathways involved in the neuro-immune system, neurotoxicity, and changes in neuroplasticity 6,7,9 . Transcriptomes from complex tissues, such as human brain, may be organized into networks of co-expressed genes that better reflect the biological functions and organization of the tissue 7–14 . Application of bioinformatics techniques, such as weighted gene co-expression network analysis (WGCNA) 15 , has uncovered networks associated with alcohol dependence 8,9 .…”

Analysis of whole genome-transcriptomic organization in brain to identify genes associated with alcoholism

“…The transcriptional effects of long-term alcohol consumption are associated with pathways involved in the neuro-immune system, neurotoxicity, and changes in neuroplasticity 6,7,9 . Transcriptomes from complex tissues, such as human brain, may be organized into networks of co-expressed genes that better reflect the biological functions and organization of the tissue [7][8][9][10][11][12][13][14] . Application of bioinformatics techniques, such as weighted gene co-expression network analysis (WGCNA) 15 , has uncovered networks associated with alcohol dependence 8,9 .…”