Genome-wide gene expression analysis identifies K-ras as a regulator of alcohol intake

Repunte‐Canonigo, Vez; Stap, Lena D. van der; Chen, Jihuan; Sabino, Valentina; Wagner, Ulrich; Zorrilla, Eric P.; Schumann, Gunter; Roberts, Amanda J.; Sanna, Pietro Paolo

doi:10.1016/j.brainres.2010.03.063

Cited by 25 publications

(28 citation statements)

References 70 publications

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“…Heterozygous Nf1 (+/−) and homozygous K-Ras (−/−) mice do not escalate ethanol consumption after CIE (Repunte-Canonigo et al, 2015; Repunte-Canonigo et al, 2010), similar to what we observed in Alk −/− mice. Neurofibromin is a Ras GTPase activating protein and a negative regulator of Ras/ERK signaling.…”

Section: Discussionsupporting

confidence: 88%

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Dependence-induced ethanol drinking and GABA neurotransmission are altered in Alk deficient mice

et al. 2016

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Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that is expressed in the brain and implicated in alcohol abuse in humans and behavioral responses to ethanol in mice. Previous studies have shown an association of human ALK with acute responses to alcohol and alcohol dependence. In addition, Alk knockout (Alk −/−) mice consume more ethanol in a binge-drinking test and show increased sensitivity to ethanol sedation. However, the function of ALK in excessive drinking following the establishment of ethanol dependence has not been examined. In this study, we tested Alk −/− mice for dependence-induced drinking using the chronic intermittent ethanol-two bottle choice drinking (CIE-2BC) protocol. We found that Alk −/− mice initially consume more ethanol prior to CIE exposure, but do not escalate ethanol consumption after exposure, suggesting that ALK may promote the escalation of drinking after ethanol dependence. To determine the mechanism(s) responsible for this behavioral phenotype we used an electrophysiological approach to examine GABA neurotransmission in the central nucleus of the amygdala (CeA), a brain region that regulates alcohol consumption and shows increased GABA signaling after chronic ethanol exposure. GABA transmission in ethanol-naïve Alk −/− mice was enhanced at baseline and potentiated in response to acute ethanol application when compared to wild-type (Alk +/+) mice. Moreover, basal GABA transmission was not elevated by CIE exposure in Alk −/− mice as it was in Alk +/+ mice. These data suggest that ALK plays a role in dependence-induced drinking and the regulation of presynaptic GABA release in the CeA.

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Section: Discussionsupporting

confidence: 88%

“…CIE has been shown to increase GABA neurotransmission in rats and mice (Repunte-Canonigo et al, 2015; Repunte-Canonigo et al, 2010; Roberto et al, 2004). Although ethanol-naïve Alk −/− mice display increased GABA release, GABA neurotransmission after CIE is not augmented in Alk −/− mice as it is in Alk +/+ mice.…”

Section: Discussionmentioning

confidence: 99%

Dependence-induced ethanol drinking and GABA neurotransmission are altered in Alk deficient mice

et al. 2016

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“…Rats with a history of excessive alcohol intake and abstinence show activation of HRAS in the NAc 25 , and downregulation of HRAS expression or inhibition of its activity in the NAc attenuates the self-administration of alcohol in models of excessive alcohol intake in mice (20%IA2BC paradigm) and rats (20%IA2BC and 20%LA models)25. In line with these findings, escalation of alcohol drinking (20%LA procedure) is not detected in mice with heterozygous knockout of the gene encoding another member of the RAS GTPases, KRAS 43 .…”

Section: Go Pathways Promote Excessive Drinkingsupporting

confidence: 61%

Molecular mechanisms underlying alcohol-drinking behaviours

2016

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The main characteristic of alcohol use disorder is the consumption of large quantities of alcohol despite the negative consequences. The transition from the moderate use of alcohol to excessive, uncontrolled alcohol consumption results from neuroadaptations that cause aberrant motivational learning and memory processes. Here, we examine studies that have combined molecular and behavioural approaches in rodents to elucidate the molecular mechanisms that keep the social intake of alcohol in check, which we term ‘stop pathways’, and the neuroadaptations that underlie the transition from moderate to uncontrolled, excessive alcohol intake, which we term ‘go pathways’. We also discuss post-transcriptional, genetic and epigenetic alterations that underlie both types of pathways.

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“…1 and Table 3). The GTPase H-ras encoded by HRAS in the nucleus accumbens plays a key role in neuroadaptations that underlie excessive alcohol-drinking behaviors in mice (Ben Hamida et al, 2012), while the GTPase K-ras encoded by KRAS is differentially expressed after repeated alcohol in the anterior cingulate cortex and alcohol differentially affected various pathways in a K-ras dependent manner suggesting that K-ras-regulatory pathways play a key role in excessive alcohol drinking after a history of dependence (Repunte-Canonigo et al, 2010). Thus genetic variation affecting the regulation of RASL11A could likely play a role in behaviors associated with protracted abstinence from alcohol and thus represents a novel and compelling candidate gene based on human GWAS and molecular biology studies in rodents.…”

Section: Genome-wide Association Studies Of Alcohol Dependencementioning

confidence: 99%

Genetic studies of alcohol dependence in the context of the addiction cycle

et al. 2017

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Family, twin and adoption studies demonstrate clearly that alcohol dependence and alcohol use disorders are phenotypically complex and heritable. The heritability of alcohol use disorders is estimated at approximately 50–60% of the total phenotypic variability. Vulnerability to alcohol use disorders can be due to multiple genetic or environmental factors or their interaction which gives rise to extensive and daunting heterogeneity. This heterogeneity makes it a significant challenge in mapping and identifying the specific genes that influence alcohol use disorders. Genetic linkage and (candidate gene) association studies have been used now for decades to map and characterize genomic loci and genes that underlie the genetic vulnerability to alcohol use disorders. These approaches have been moderately successful in identifying several genes that contribute to the complexity of alcohol use disorders. Recently, genome-wide association studies have become one of the major tools for identifying genes for alcohol use disorders by examining correlations between millions of common single-nucleotide polymorphisms with diagnosis status. Genome-wide association studies are just beginning to uncover novel biology; however, the functional significance of results remains a matter of extensive debate and uncertainty. In this review, we present a select group of genome-wide association studies of alcohol dependence, as one example of a way to generate functional hypotheses, within the addiction cycle framework. This analysis may provide novel directions for validating the functional significance of alcohol dependence candidate genes. This article is part of the Special Issue entitled “Alcoholism”.

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Genome-wide gene expression analysis identifies K-ras as a regulator of alcohol intake

Cited by 25 publications

References 70 publications

Dependence-induced ethanol drinking and GABA neurotransmission are altered in Alk deficient mice

Dependence-induced ethanol drinking and GABA neurotransmission are altered in Alk deficient mice

Molecular mechanisms underlying alcohol-drinking behaviours

Genetic studies of alcohol dependence in the context of the addiction cycle

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