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Identifying candidate drivers of alcohol dependence-induced excessive drinking by assembly and interrogation of brain-specific regulatory networks.

ABSTRACT: A systems biology approach based on the assembly and interrogation of gene regulatory networks, or interactomes, was used to study neuroadaptation processes associated with the transition to alcohol dependence at the molecular level.Using a rat model of dependent and non-dependent alcohol self-administration, we reverse engineered a global transcriptional regulatory network during protracted abstinence, a period when relapse rates are highest. We then interrogated the network to identify master regulator genes that mechanistically regulate brain region-specific signatures associated with dependent and non-dependent alcohol self-administration. Among these, the gene coding for the glucocorticoid receptor was independently identified as a master regulator in multiple brain regions, including the medial prefrontal cortex, nucleus accumbens, central nucleus of the amygdala, and ventral tegmental area, consistent with the view that brain reward and stress systems are dysregulated during protracted abstinence. Administration of the glucocorticoid antagonist mifepristone in either the nucleus accumbens or ventral tegmental area selectively decreased dependent, excessive, alcohol self-administration in rats but had no effect on non-dependent, moderate, alcohol self-administration.Our study suggests that assembly and analysis of regulatory networks is an effective strategy for the identification of key regulators of long-term neuroplastic changes within specific brain regions that play a functional role in alcohol dependence. More specifically, our results support a key role for regulatory networks downstream of the glucocorticoid receptor in excessive alcohol drinking during protracted alcohol abstinence.

SUBMITTER: Repunte-Canonigo V

PROVIDER: S-EPMC4410476 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Identifying candidate drivers of alcohol dependence-induced excessive drinking by assembly and interrogation of brain-specific regulatory networks.

Repunte-Canonigo Vez V Shin William W Vendruscolo Leandro F LF Lefebvre Celine C van der Stap Lena L Kawamura Tomoya T Schlosburg Joel E JE Alvarez Mariano M Koob George F GF Califano Andrea A Sanna Pietro Paolo PP

Genome biology 20150202

<h4>Background</h4>A systems biology approach based on the assembly and interrogation of gene regulatory networks, or interactomes, was used to study neuroadaptation processes associated with the transition to alcohol dependence at the molecular level.<h4>Results</h4>Using a rat model of dependent and non-dependent alcohol self-administration, we reverse engineered a global transcriptional regulatory network during protracted abstinence, a period when relapse rates are highest. We then interroga ...[more]

PMID: 25886852

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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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Identifying candidate drivers of alcohol dependence-induced excessive drinking by assembly and interrogation of brain-specific regulatory networks.

Publications

Identifying candidate drivers of alcohol dependence-induced excessive drinking by assembly and interrogation of brain-specific regulatory networks.

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