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Domi, E., Barchiesi, R. & Barbier, E. (2023). Epigenetic Dysregulation in Alcohol-Associated Behaviors: Preclinical and Clinical Evidence.. In: : . Springer
Open this publication in new window or tab >>Epigenetic Dysregulation in Alcohol-Associated Behaviors: Preclinical and Clinical Evidence.
2023 (English)Chapter in book (Refereed)
Abstract [en]

Alcohol use disorder (AUD) is characterized by loss of control over intake and drinking despite harmful consequences. At a molecular level, AUD is associated with long-term neuroadaptations in key brain regions that are involved in reward processing and decision-making. Over the last decades, a great effort has been made to understand the neurobiological basis underlying AUD. Epigenetic mechanisms have emerged as an important mechanism in the regulation of long-term alcohol-induced gene expression changes. Here, we review the literature supporting a role for epigenetic processes in AUD. We particularly focused on the three most studied epigenetic mechanisms: DNA methylation, Histone modification and non-coding RNAs. Clinical studies indicate an association between AUD and DNA methylation both at the gene and global levels. Using behavioral paradigms that mimic some of the characteristics of AUD, preclinical studies demonstrate that changes in epigenetic mechanisms can functionally impact alcohol-associated behaviors. While many studies support a therapeutic potential for targeting epigenetic enzymes, more research is needed to fully understand their role in AUD. Identification of brain circuits underlying alcohol-associated behaviors has made major advances in recent years. However, there are very few studies that investigate how epigenetic mechanisms can affect these circuits or impact the neuronal ensembles that promote alcohol-associated behaviors. Studies that focus on the role of circuit-specific and cell-specific epigenetic changes for clinically relevant alcohol behaviors may provide new insights on the functional role of epigenetic processes in AUD.

Place, publisher, year, edition, pages
Springer, 2023
Series
Current Topics in Behavioral Neurosciences, ISSN 1866-3370, E-ISSN 1866-3389
Keywords
Alcohol use disorder, DNA methylation, Epigenetic mechanisms, Histone modifications, Non-coding RNAs
National Category
Neurosciences
Identifiers
urn:nbn:se:liu:diva-200748 (URN)10.1007/7854_2022_410 (DOI)36717533 (PubMedID)
Available from: 2024-02-07 Created: 2024-02-07 Last updated: 2024-03-15Bibliographically approved
Domi, A., Lunerti, V., Petrella, M., Domi, E., Borruto, A. M., Ubaldi, M., . . . Ciccocioppo, R. (2022). Genetic deletion or pharmacological blockade of nociceptin/orphanin FQ receptors in the ventral tegmental area attenuates nicotine-motivated behaviour. British Journal of Pharmacology, 179(11), 2647-2658
Open this publication in new window or tab >>Genetic deletion or pharmacological blockade of nociceptin/orphanin FQ receptors in the ventral tegmental area attenuates nicotine-motivated behaviour
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2022 (English)In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 179, no 11, p. 2647-2658Article in journal (Refereed) Published
Abstract [en]

Background and Purpose The nociceptin/orphanin FQ (N/OFQ)-nociceptin opioid-like peptide (NOP) receptor system is widely distributed in the brain and pharmacological activation of this system revealed therapeutic potential in animal models of substance use disorder. Studies also showed that genetic deletion or pharmacological blockade of NOP receptors confer resistance to the development of alcohol abuse. Here, we have used a genetic and pharmacological approach to evaluate the therapeutic potential of NOP antagonism in smoking cessation. Experimental Approach Constitutive NOP receptor knockout rats (NOP-/-) and their wild-type counterparts (NOP+/+) were tested over a range of behaviours to characterize their motivation for nicotine. We next explored the effects of systemic administration of the NOP receptor antagonist LY2817412 (1.0 & 3.0 mg center dot kg(-1)) on nicotine self-administration. NOP receptor blockade was further evaluated at the brain circuitry level, by microinjecting LY2817412 (3.0 & 6.0 mu g center dot mu l(-1)) into the ventral tegmental area (VTA), nucleus accumbens (NAc) and central amygdala (CeA). Key Results Genetic NOP receptor deletion resulted in decreased nicotine intake, decreased motivation to self-administer and attenuation of cue-induced nicotine reinstatement. LY2817412 reduced nicotine intake in NOP+/+ but not in NOP-/- rats, confirming that its effect is mediated by inhibition of NOP transmission. Finally, injection of LY2817412 into the VTA but not into the NAc or CeA decreased nicotine self-administration. Conclusions and Implications These findings indicate that inhibition of NOP transmission attenuates the motivation for nicotine through mechanisms involving the VTA and suggest that NOP receptor antagonism may represent a potential treatment for smoking cessation.

Place, publisher, year, edition, pages
WILEY, 2022
Keywords
nicotine; NOP; reinforcement; relapse; reward; VTA
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:liu:diva-183228 (URN)10.1111/bph.15762 (DOI)000753476300001 ()34854073 (PubMedID)
Note

Funding Agencies|National Institute on Alcohol Abuse and AlcoholismUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Alcohol Abuse & Alcoholism (NIAAA) [AA014351, PRIN 2017SXEXT5]; National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA

Available from: 2022-03-01 Created: 2022-03-01 Last updated: 2023-02-16Bibliographically approved
Johnstone, A. L., Andrade, N. S., Barbier, E., Khomtchouk, B. B., Rienas, C. A., Lowe, K., . . . Wahlestedt, C. (2021). Dysregulation of the histone demethylase KDM6B in alcohol dependence is associated with epigenetic regulation of inflammatory signaling pathways. Addiction Biology, 26(1), Article ID e12816.
Open this publication in new window or tab >>Dysregulation of the histone demethylase KDM6B in alcohol dependence is associated with epigenetic regulation of inflammatory signaling pathways
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2021 (English)In: Addiction Biology, ISSN 1355-6215, E-ISSN 1369-1600, Vol. 26, no 1, article id e12816Article in journal (Refereed) Published
Abstract [en]

Epigenetic enzymes oversee long-term changes in gene expression by integrating genetic and environmental cues. While there are hundreds of enzymes that control histone and DNA modifications, their potential roles in substance abuse and alcohol dependence remain underexplored. A few recent studies have suggested that epigenetic processes could underlie transcriptomic and behavioral hallmarks of alcohol addiction. In the present study, we sought to identify epigenetic enzymes in the brain that are dysregulated during protracted abstinence as a consequence of chronic and intermittent alcohol exposure. Through quantitative mRNA expression analysis of over 100 epigenetic enzymes, we identified 11 that are significantly altered in alcohol-dependent rats compared with controls. Follow-up studies of one of these enzymes, the histone demethylase KDM6B, showed that this enzyme exhibits region-specific dysregulation in the prefrontal cortex and nucleus accumbens of alcohol-dependent rats. KDM6B was also upregulated in the human alcoholic brain. Upregulation of KDM6B protein in alcohol-dependent rats was accompanied by a decrease of trimethylation levels at histone H3, lysine 27 (H3K27me3), consistent with the known demethylase specificity of KDM6B. Subsequent epigenetic (chromatin immunoprecipitation [ChIP]-sequencing) analysis showed that alcohol-induced changes in H3K27me3 were significantly enriched at genes in the IL-6 signaling pathway, consistent with the well-characterized role of KDM6B in modulation of inflammatory responses. Knockdown of KDM6B in cultured microglial cells diminished IL-6 induction in response to an inflammatory stimulus. Our findings implicate a novel KDM6B-mediated epigenetic signaling pathway integrated with inflammatory signaling pathways that are known to underlie the development of alcohol addiction.

Place, publisher, year, edition, pages
WILEY, 2021
Keywords
alcoholism; epigenetics; inflammation; JMJD3; KDM6B; nucleus accumbens; prefrontal cortex
National Category
Neurosciences
Identifiers
urn:nbn:se:liu:diva-159869 (URN)10.1111/adb.12816 (DOI)000480180400001 ()31373129 (PubMedID)
Note

Funding Agencies|National Institute of Mental Health [MH084880]; National Institute on Alcohol Abuse and Alcoholism [R01AA023781]; National Institutes of Health [DA035592, NS071674]; National Institute of Alcohol Abuse and Alcoholism of the National Institutes of Health [R28AA012725]; NIAAA division of Intramural Research; Swedish Research Council; US National Institute of Health [MH084880, DA035592, NS071674]; United States Department of Defense (DoD); NIAAA [1R01AA023781-01A1]; European Union [668863]

Available from: 2019-08-27 Created: 2019-08-27 Last updated: 2022-05-26
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-5726-4814

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