Genes and Alcohol Consumption

Mayfield, Jody; Arends, Michael A.; Harris, R. Adron; Blednov, Yuri A.

doi:10.1016/bs.irn.2016.02.014

Cited by 50 publications

(20 citation statements)

References 264 publications

(180 reference statements)

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“…Our results are consistent with other studies showing that null mutant mice lacking genes associated with proinflammatory pathways had reduced levels of chemokines and cytokines, and reduced voluntary ethanol consumption (Blednov et al, 2005, 2012). However, not all inflammatory-related genes studied to date have been shown to regulate ethanol drinking in mouse knock-out models (Mayfield et al, 2016), suggesting that indiscriminant inhibition of inflammatory pathways is not a viable strategy to limit excessive drinking and further highlighting the relevance of the current study in targeting treatment strategies.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of IKKβ Reduces Ethanol Consumption in C57BL/6J Mice

Truitt

Blednov

Benavidez

et al. 2016

eNeuro

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Proinflammatory pathways in neuronal and non-neuronal cells are implicated in the acute and chronic effects of alcohol exposure in animal models and humans. The nuclear factor-κB (NF-κB) family of DNA transcription factors plays important roles in inflammatory diseases. The kinase IKKβ mediates the phosphorylation and subsequent proteasomal degradation of cytosolic protein inhibitors of NF-κB, leading to activation of NF-κB. The role of IKKβ as a potential regulator of excessive alcohol drinking had not previously been investigated. Based on previous findings that the overactivation of innate immune/inflammatory signaling promotes ethanol consumption, we hypothesized that inhibiting IKKβ would limit/decrease drinking by preventing the activation of NF-κB. We studied the systemic effects of two pharmacological inhibitors of IKKβ, TPCA-1 and sulfasalazine, on ethanol intake using continuous- and limited-access, two-bottle choice drinking tests in C57BL/6J mice. In both tests, TPCA-1 and sulfasalazine reduced ethanol intake and preference without changing total fluid intake or sweet taste preference. A virus expressing Cre recombinase was injected into the nucleus accumbens and central amygdala to selectively knock down IKKβ in mice genetically engineered with a conditional Ikkb deletion (IkkbF/F). Although IKKβ was inhibited to some extent in astrocytes and microglia, neurons were a primary cellular target. Deletion of IKKβ in either brain region reduced ethanol intake and preference in the continuous access two-bottle choice test without altering the preference for sucrose. Pharmacological and genetic inhibition of IKKβ decreased voluntary ethanol consumption, providing initial support for IKKβ as a potential therapeutic target for alcohol abuse.

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Section: Discussionmentioning

confidence: 99%

Inhibition of IKKβ Reduces Ethanol Consumption in C57BL/6J Mice

Truitt

Blednov

Benavidez

et al. 2016

eNeuro

View full text Add to dashboard Cite

show abstract

“…The genomic studies provided the initial evidence that immune/inflammatory genes may be important in excessive alcohol consumption. Behavioral evidence subsequently validated the role of some of these genes in ethanol drinking in mouse models (Mayfield et al, 2016). Ethanol treatment in vivo has been shown to increase the expression of TLRs, resulting in NF-κB activation and cytokine induction (Crews et al, 2013; Lippai et al, 2013).…”

Section: Functional Systems Associated With Alcohol Dependencementioning

confidence: 94%

Gene expression profiling in the human alcoholic brain

Warden

Mayfield

2017

Neuropharmacology

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Long-term alcohol use causes widespread changes in gene expression in the human brain. Aberrant gene expression changes likely contribute to the progression from occasional alcohol use to alcohol use disorder (including alcohol dependence). Transcriptome studies have identified individual gene candidates that are linked to alcohol-dependence phenotypes. The use of bioinformatics techniques to examine expression datasets has provided novel systems-level approaches to transcriptome profiling in human postmortem brain. These analytical advances, along with recent developments in next-generation sequencing technology, have been instrumental in detecting both known and novel coding and non-coding RNAs, alternative splicing events, and cell-type specific changes that may contribute to alcohol-related pathologies. This review offers an integrated perspective on alcohol-responsive transcriptional changes in the human brain underlying the regulatory gene networks that contribute to alcohol dependence.

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“…Similar to the first caveat, especially since most of the transgenic work has involved mice, this was done due to space limitations. For excellent discussions on both of these subjects see Barkley-Levenson and Crabbe (2014), Bilbao (2013), Crabbe et al (2006), Fisch and Flint (2006), Greenberg and Crabbe (2016), Kalueff and Bergner (2010), Mayfield et al (2016), as well as Oberlin et al (2011). Third, models of withdrawal, and to some degree dependence, as well as stress and its associated medications screening received limited review.…”

Section: Caveats Challenges and Conclusionmentioning

confidence: 99%

Rat animal models for screening medications to treat alcohol use disorders

et al. 2017

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The purpose of this review is to present animal research models that can be used to screen and/or repurpose medications for the treatment of alcohol abuse and dependence. The focus will be on rats and in particular selectively bred rats. Brief introductions discuss various aspects of the clinical picture, which provide characteristics of individuals with alcohol use disorders (AUDs) to model in animals. Following this, multiple selectively bred rat lines will be described and evaluated in the context of animal models used to screen medications to treat AUDs. Next, common behavioral tests for drug efficacy will be discussed particularly as they relate to stages in the addiction cycle. Tables highlighting studies that have tested the effects of compounds using the respective techniques are included. Wherever possible the Tables are organized chronologically in ascending order to describe changes in the focus of research on AUDs over time. In general, high ethanol-consuming selectively bred rats have been used to test a wide range of compounds. Older studies usually followed neurobiological findings in the selected lines that supported an association with a propensity for high ethanol intake. Most of these tests evaluated the compound's effects on the maintenance of ethanol drinking. Very few compounds have been tested during ethanol-seeking and/or relapse and fewer still have assessed their effects during the acquisition of AUDs. Overall, while a substantial number of neurotransmitter and neuromodulatory system targets have been assessed; the roles of sex- and age-of-animal, as well as the acquisition of AUDs, ethanol-seeking and relapse continue to be factors and behaviors needing further study.

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Genes and Alcohol Consumption

Cited by 50 publications

References 264 publications

Inhibition of IKKβ Reduces Ethanol Consumption in C57BL/6J Mice

Inhibition of IKKβ Reduces Ethanol Consumption in C57BL/6J Mice

Gene expression profiling in the human alcoholic brain

Rat animal models for screening medications to treat alcohol use disorders

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