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Downregulation of the neuronal opioid gene expression concomitantly with neuronal decline in dorsolateral prefrontal cortex of human alcoholics
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.ORCID iD: 0000-0003-4388-1656
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.ORCID iD: 0000-0002-2451-4386
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.ORCID iD: 0000-0002-1332-7067
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
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2018 (English)In: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 8, article id 122Article in journal (Refereed) Published
Abstract [en]

Molecular changes in cortical areas of addicted brain may underlie cognitive impairment and loss of control over intake of addictive substances and alcohol. Prodynorphin (PDYN) gives rise to dynorphin (DYNs) opioid peptides which target kappa-opioid receptor (KOR). DYNs mediate alcohol-induced impairment of learning and memory, while KOR antagonists block excessive, compulsive-like drug and alcohol self-administration in animal models. In human brain, the DYN/KOR system may undergo adaptive changes, which along with neuronal loss, may contribute to alcohol-associated cognitive deficit. We addressed this hypothesis by comparing the expression levels and co-expression (transcriptionally coordinated) patterns of PDYN and KOR (OPRK1) genes in dorsolateral prefrontal cortex (dlPFC) between human alcoholics and controls. Postmortem brain specimens of 53 alcoholics and 55 controls were analyzed. PDYN was found to be downregulated in dlPFC of alcoholics, while OPRK1 transcription was not altered. PDYN downregulation was confined to subgroup of subjects carrying C, a high-risk allele of PDYN promoter SNP rs1997794 associated with alcoholism. Changes in PDYN expression did not depend on the decline in neuronal proportion in alcoholics, and thereby may be attributed to transcriptional adaptations in alcoholic brain. Absolute expression levels of PDYN were lower compared to those of OPRK1, suggesting that PDYN expression is a limiting factor in the DYN/KOR signaling, and that the PDYN downregulation diminishes efficacy of DYN/KOR signaling in dlPFC of human alcoholics. The overall outcome of the DYN/KOR downregulation may be disinhibition of neurotransmission, which when overactivated could contribute to formation of alcohol-related behavior.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2018. Vol. 8, article id 122
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Neurosciences Biochemistry and Molecular Biology
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URN: urn:nbn:se:uu:diva-358683DOI: 10.1038/s41398-017-0075-5ISI: 000437025300001PubMedID: 29925858OAI: oai:DiVA.org:uu-358683DiVA, id: diva2:1245707
Funder
Forte, Swedish Research Council for Health, Working Life and Welfare, 2009-1709Forte, Swedish Research Council for Health, Working Life and Welfare, 259-2012-23Swedish Research Council, K2014-62X-12190-19-5Available from: 2018-09-05 Created: 2018-09-05 Last updated: 2018-09-17Bibliographically approved

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Bazov, IgorSarkisyan, DaniilKononenko, OlgaWatanabe, HiroyukiYakovleva, TatianaBakalkin, Georgy

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