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Expression of pronociceptin and its receptor is downregulated in the brain of human alcoholics
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Molecular neuropsychopharmacology)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Molecular neuropsychopharmacology)
The Discipline of Pathology, University of Sydney, Sydney, NSF, Australia.
The Discipline of Pathology, University of Sydney, Sydney, NSF, Australia.
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2009 (English)In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1305, no Suppl. 1, S80-85 p.Article in journal (Refereed) Published
Abstract [en]

Animal studies demonstrated a role of neuropeptide nociceptin (NC) and its receptor (opiate receptor like-1, OPRL1) in ethanol-induced reward; activation of the OPRL1 by natural or synthetic ligands reduced ethanol self-administration and prevented relapse to ethanol drinking. The endogenous NC may function in neuronal circuits involved in reinforcing or conditioning effects of ethanol as a "brake" to limit ethanol intake (Roberto, M., Siggins, G.R. 2006. Nociceptin/orphanin FQ presynaptically decreases GABAergic transmission and blocks the ethanol-induced increase of GABA release in central amygdala. Proc. Natl. Acad. Sci. USA 103. 9715-9720), whereas repeated ethanol intake may downregulate the endogenous NC/OPRL1 system resulting in activation of ethanol consumption. To address this hypothesis, we evaluated whether expression of the pronociceptin (PNOC) and OPRL1 genes is altered in human alcoholics. mRNAs transcribed from these genes were analyzed by quantitative RT-PCR in the prefrontal and orbitofrontal cortices, central amygdala and hippocampal dentate gyrus, structures controlling alcohol consumption. Reduction in PNOC mRNA (1.7-fold) was found in the hippocampus of alcoholics, whereas OPRL1 mRNA levels were decreased (1.4-fold) in the central amygdala. No changes in expression of these genes in other brain areas analyzed were evident. We hypothesise that chronic ethanol intake downregulates PNOC and OPRL1 gene expression in the hippocampus and amygdala, respectively. The findings may be also interpreted as inherited molecular differences between alcoholics and controls. The PNOC/OPRL1 downregulation may underlie impairment of cognitive control over alcohol seeking in alcoholics. Stimulation of the OPRL1 receptors with synthetic agonists may increase threshold for activation of ethanol-related behaviour by environmental cues, and thus may reduce cue- or stress-primed relapse to ethanol consumption.

Place, publisher, year, edition, pages
2009. Vol. 1305, no Suppl. 1, S80-85 p.
Keyword [en]
Alcoholism, nociceptin, OPRL1, amygdala, hippocampus
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-119998DOI: 10.1016/j.brainres.2009.05.067ISI: 000273202100010PubMedID: 19501074OAI: oai:DiVA.org:uu-119998DiVA: diva2:302480
Available from: 2010-03-08 Created: 2010-03-04 Last updated: 2017-12-12Bibliographically approved
In thesis
1. Epigenetic Dysregulations in the Brain of Human Alcoholics: Analysis of Opioid Genes
Open this publication in new window or tab >>Epigenetic Dysregulations in the Brain of Human Alcoholics: Analysis of Opioid Genes
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Neuropeptides are special in their expression profiles restricted to neuronal subpopulations and low tissue mRNA levels. Genetic, epigenetic and transcriptional mechanisms that define spatiotemporal expression of the neuropeptide genes have utmost importance for the formation and functions of neural circuits in normal and pathological human brain. This thesis focuses on regulation of transcription of the opioid/nociceptin genes, the largest neuropeptide family, and on identification of adaptive changes in these mechanisms associated with alcoholism as model human pathology. Two epigenetic mechanisms, the common for most cells in the dorsolateral prefrontal cortex (dlPFC) and the neuron-subpopulation specific that may orchestrate prodynorphin (PDYN) transcription in the human dlPFC have been uncovered. The first, repressive mechanism may operate through control of DNA methylation/demethylation in a short, nucleosome size promoter CpG island (CGI). The second mechanism may involve USF2, the sequence–specific methylation–sensitive transcription factor which interaction with its target element in the CpG island results in USF2 and PDYN co-expression in the same neurons. The short PDYN promoter CGI may function as a chromatin element that integrates cellular and environmental signals through changes in methylation and transcription factor binding. Alterations in USF2–dependent PDYN transcription are affected by the promoter SNP (rs1997794: T>C) under transition to pathological state, i.e. in the alcoholic brain. This and two other PDYN SNPs that are most significantly associated with alcoholism represent CpG-SNPs, which are differentially methylated in the human dlPFC. The T, low risk allele of the promoter SNP forms a noncanonical AP-1–binding element. JUND and FOSB proteins, which may form homo- or heterodimers have been identified as dominant constituents of AP-1 complex. The C, non-risk variant of the PDYN 3′ UTR SNP (rs2235749 SNP: C>T) demonstrated significantly higher methylation in alcoholics compared to controls. PDYN mRNA and dynorphin levels significantly and positively correlated with methylation of the PDYN 3′ UTR CpG-SNP suggesting its involvement in PDYN regulation. A DNA–binding factor with differential binding affinity for the T allele and methylated and unmethylated C alleles of the PDYN 3′ UTR SNP (the T allele specific binding factor, Ta-BF) has been discovered, which may function as a regulator of PDYN transcription. These findings emphasize the complexity of PDYN regulation that determines its expression in specific neuronal subpopulations and suggest previously unknown integration of epigenetic, transcriptional and genetic mechanisms that orchestrate alcohol–induced molecular adaptations in the human brain. Given the important role of PDYN in addictive behavior, the findings provide a new insight into fundamental molecular mechanisms of human brain disorder. In addition to PDYN in the dlPFC, the PNOC gene in the hippocampus and OPRL1 gene in central amygdala that were downregulated in alcoholics may contribute to impairment of cognitive control over alcohol seeking and taking behaviour.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 84 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 209
Keyword
neuropeptides, dynorphin, human brain, alcohol dependence, epigenetics, gene transcription
National Category
Natural Sciences Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-270321 (URN)978-91-554-9445-2 (ISBN)
Public defence
2016-02-26, B/B7:113a, Husargatan 3, Uppsala, 10:15 (English)
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Supervisors
Available from: 2016-02-04 Created: 2015-12-27 Last updated: 2016-02-12

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Kuzmin, AlexanderBazov, IgorBakalkin, Georgy

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