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Chromatin remodeling--a novel strategy to control excessive alcohol drinking.

ABSTRACT: Harmful excessive use of alcohol has a severe impact on society and it remains one of the major causes of morbidity and mortality in the population. However, mechanisms that underlie excessive alcohol consumption are still poorly understood, and thus available medications for alcohol use disorders are limited. Here, we report that changing the level of chromatin condensation by affecting DNA methylation or histone acetylation limits excessive alcohol drinking and seeking behaviors in rodents. Specifically, we show that decreasing DNA methylation by inhibiting the activity of DNA methyltransferase (DNMT) with systemic administration of the FDA-approved drug, 5-azacitidine (5-AzaC) prevents excessive alcohol use in mice. Similarly, we find that increasing histone acetylation via systemic treatment with several histone deacetylase (HDAC) inhibitors reduces mice binge-like alcohol drinking. We further report that systemic administration of the FDA-approved HDAC inhibitor, SAHA, inhibits the motivation of rats to seek alcohol. Importantly, the actions of both DNMT and HDAC inhibitors are specific for alcohol, as no changes in saccharin or sucrose intake were observed. In line with these behavioral findings, we demonstrate that excessive alcohol drinking increases DNMT1 levels and reduces histone H4 acetylation in the nucleus accumbens (NAc) of rodents. Together, our findings illustrate that DNA methylation and histone acetylation control the level of excessive alcohol drinking and seeking behaviors in preclinical rodent models. Our study therefore highlights the possibility that DNMT and HDAC inhibitors can be used to treat harmful alcohol abuse.

SUBMITTER: Warnault V

PROVIDER: S-EPMC3591000 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Chromatin remodeling--a novel strategy to control excessive alcohol drinking.

Warnault V V Darcq E E Levine A A Barak S S Ron D D

Translational psychiatry 20130219

Harmful excessive use of alcohol has a severe impact on society and it remains one of the major causes of morbidity and mortality in the population. However, mechanisms that underlie excessive alcohol consumption are still poorly understood, and thus available medications for alcohol use disorders are limited. Here, we report that changing the level of chromatin condensation by affecting DNA methylation or histone acetylation limits excessive alcohol drinking and seeking behaviors in rodents. Sp ...[more]

PMID: 23423140

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Project description:BackgroundBinge drinking (BD) refers to a pattern of alcohol consumption characterized by the consumption of large amounts of alcohol in a short period of time followed by periods of abstinence. This drinking pattern is prevalent worldwide, mainly among young people. Excessive alcohol consumption is the spectrum of consumption patterns that may have or have had health consequences, and includes the concepts of risky alcohol use, harmful alcohol use and alcohol dependence according to Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), the latter two are currently grouped into alcohol use disorder (AUD) according to the fifth edition of the DSM (DSM-5). Due to the high prevalence of BD among young people, especially university students, as well as the important consequences of its practice, a study was conducted to evaluate excessive alcohol consumption and its relationship with the practice of BD in university students.MethodsA cross-sectional study was conducted among students (aged 18-30 years) enrolled in the academic year 2018-2019 at the Faculty of Nursing at a university in northern Spain. Data collection included sociodemographic information, and alcohol use information, collected using a semi-structured questionnaire. To measure the excessive alcohol consumption, this study used the Alcohol Use Disorders Identification Test (AUDIT).ResultsA total of 142 participants were included, of which 88.03% were women. Up to 38.03% were classified as BD. Up to 14.77% of non-BD participants and 66.67% of BD participants were classified as risky drinkers (AUDIT Total geq 8 in men or geq 6 in women) (p < 0.001). Up to 3.41% of the non-BD and 24.07% of the BD were drinkers with harmful alcohol use and probable alcohol dependence (AUDIT Total geq 13) (p < 0.001). A total of 5.68% of non-BD and 42.59% of BD were AUD drinkers (AUDIT Total geq 9 in males or geq 8 in females) (p < 0.001). In addition, statistically significant differences were found between the BD and non-BD groups in the responses to each of the AUDIT items, as well as in the total score and also in the scores of the three domains of the questionnaire.ConclusionsExcessive alcohol consumption is frequent among university students, especially among those who practice BD.

Project description:BACKGROUND:Liver damage is a serious and sometimes fatal consequence of long-term alcohol intake, which progresses from early-stage fatty liver (steatosis) to later-stage steatohepatitis with inflammation and fibrosis/necrosis. However, very little is known about earlier stages of liver disruption that may occur in problem drinkers, those who drink excessively but are not dependent on alcohol. METHODS:We examined how repeated binge-like alcohol drinking in C57BL/6 mice altered liver function, as compared with a single binge-intake session and with repeated moderate alcohol consumption. We measured a number of markers associated with early- and later-stage liver disruption, including liver steatosis, measures of liver cytochrome P4502E1 (CYP2E1) and alcohol dehydrogenase (ADH), alcohol metabolism, expression of cytokine mRNA, accumulation of 4-hydroxynonenal (4-HNE) as an indicator of oxidative stress, and alanine transaminase/aspartate transaminase as a measure of hepatocyte injury. RESULTS:Importantly, repeated binge-like alcohol drinking increased triglyceride levels in the liver and plasma, and increased lipid droplets in the liver, indicators of steatosis. In contrast, a single binge-intake session or repeated moderate alcohol consumption did not alter triglyceride levels. In addition, alcohol exposure can increase rates of alcohol metabolism through CYP2E1 and ADH, which can potentially increase oxidative stress and liver dysfunction. Intermittent, excessive alcohol intake increased liver CYP2E1 mRNA, protein, and activity, as well as ADH mRNA and activity. Furthermore, repeated, binge-like drinking, but not a single binge or moderate drinking, increased alcohol metabolism. Finally, repeated, excessive intake transiently elevated mRNA for the proinflammatory cytokine IL-1B and 4-HNE levels, but did not alter markers of later-stage liver hepatocyte injury. CONCLUSIONS:Together, we provide data suggesting that even relatively limited binge-like alcohol drinking can lead to disruptions in liver function, which might facilitate the transition to more severe forms of liver damage.

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Chromatin remodeling--a novel strategy to control excessive alcohol drinking.

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Chromatin remodeling--a novel strategy to control excessive alcohol drinking.

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