Neuronal nicotinic acetylcholine receptors are important targets for alcohol reward and dependence

Wu, Jie; Gao, Ming; Taylor, Devin H.

doi:10.1038/aps.2013.181

Cited by 32 publications

(22 citation statements)

References 47 publications

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“…It is possible that the effect varenicline has on the nicotinic receptors is the same basic mechanism that reduces both drinking and smoking. For example, it has been hypothesized that varenicline works through the nicotinic receptors to increase dopamine release in the nucleus accumbens, altering the rewarding effect of the addictive substance, be it alcohol or nicotine (Feduccia et al, 2012; Wu et al, 2014). Thus, individuals who experienced no effect in reducing smoking also may experience no effect on drinking, whereas the opposite occurs for those who experience a reduction in cigarettes per day.…”

Section: Discussionmentioning

confidence: 99%

Moderators of Varenicline Treatment Effects in a Double-Blind, Placebo-Controlled Trial for Alcohol Dependence

Falk

Castle²,

Ryan³

et al. 2015

Journal of Addiction Medicine

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Objectives To explore if varenicline (Chantix®) showed more efficacy in treating certain subgroups of patients. In a recent multi-site trial, varenicline was shown to be effective in reducing drinking in alcohol dependent patients, both smokers and nonsmokers. Given the heterogeneity among alcohol dependent patients, secondary analyses were conducted to determine if certain subgroups responded more favorably than others to treatment with varenicline. Methods Data were drawn from a Phase 2 randomized, double-blind, placebo-controlled multi-site 13-week trial of varenicline in alcohol dependent patients (Litten et al., 2013). Seventeen moderator variables were selected for exploratory testing on the basis of theoretical and scientific interest. Results Of the 17 moderator variables assessed, four were statistically significant, including cigarettes per day reduction, treatment drinking goal, years drinking regularly, and age of patient. Two other variables—the type of adverse events experienced by patients and the severity of alcohol-related consequences—appeared to moderate the varenicline treatment effect at borderline statistical significance. Individuals who reduced the number of cigarettes per day experienced a significant effect from varenicline in reducing drinking, whereas those who did not change or who increased their number of cigarettes observed no beneficial effect. Reviewing the moderators related to severity, varenicline appeared to have greater efficacy than placebo among less severely-dependent patients. Conclusions Varenicline appears to be more efficacious in certain subgroups, particularly in those who reduced their smoking and in the “less severe” patient. Additional studies are warranted to confirm the results of these exploratory analyses.

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Section: Discussionmentioning

confidence: 99%

Moderators of Varenicline Treatment Effects in a Double-Blind, Placebo-Controlled Trial for Alcohol Dependence

Falk

Castle²,

Ryan³

et al. 2015

Journal of Addiction Medicine

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“…Chrna4, a nicotinic acetylcholine receptor, is regulated by Spi1, and A/J-specific SNP rs27680347 is located in a motif-binding site of Spi1. Neuronal nicotinic acetylcholine receptors are important targets for alcohol reward and dependence (25). Oprl1, an opioid-related nociceptin receptor, is regulated by Sox4, Fli1, and Esrrg, and A/J-specific SNPs rs27688371, rs29586730, and rs27702497 are located in the motif-binding site of these three TFs, respectively.…”

Section: Interpretation Of Genetic Variants Relevant To Traits and DImentioning

confidence: 99%

Modeling gene regulation from paired expression and chromatin accessibility data

Duren

Chen

Jiang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

181

198

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The rapid increase of genome-wide datasets on gene expression, chromatin states, and transcription factor (TF) binding locations offers an exciting opportunity to interpret the information encoded in genomes and epigenomes. This task can be challenging as it requires joint modeling of context-specific activation of cis-regulatory elements (REs) and the effects on transcription of associated regulatory factors. To meet this challenge, we propose a statistical approach based on paired expression and chromatin accessibility (PECA) data across diverse cellular contexts. In our approach, we model (i) the localization to REs of chromatin regulators (CRs) based on their interaction with sequence-specific TFs, (ii) the activation of REs due to CRs that are localized to them, and (iii) the effect of TFs bound to activated REs on the transcription of target genes (TGs). The transcriptional regulatory network inferred by PECA provides a detailed view of how trans-and cis-regulatory elements work together to affect gene expression in a context-specific manner. We illustrate the feasibility of this approach by analyzing paired expression and accessibility data from the mouse Encyclopedia of DNA Elements (ENCODE) and explore various applications of the resulting model. gene regulation | transcription factor | regulatory element | chromatin regulator | chromatin activity E ver since the emergence of high-throughput gene expression experiments (1), computational biologists have been interested in the inference of gene regulatory relationships from gene expression data across diverse cellular contexts corresponding to diverse cell types and experimental conditions ( Fig. 1, red boxes). However, progress has been hindered by the fact that gene expression measurements provide little information on underlying regulatory mechanisms such as transcription factor binding and chromatin modification. To fill this gap, chromatin immunoprecipitationbased methods (2, 3) have been developed for the genome-wide mapping of transcriptional regulator binding locations and the detection of epigenetic marks characteristic of specific chromatin states. For example, by performing thousands of ChIP-seq experiments, the Encyclopedia of DNA Elements (ENCODE) consortium has generated such data for many chromatin marks and transcriptional regulators on a small number of cell lines (Fig. 1, green boxes). However, because a large number of transcriptional regulators and chromatin marks have to be analyzed one by one, it is unlikely that such comprehensive data will become available for many other cell lines. For most cellular contexts, the desired data will remain missing in the foreseeable future (Fig. 1, gray boxes).On the other hand, it is known that many of the protein-DNA interactions important for gene regulation occur in regulatory elements (REs) such as enhancers and insulators, which compose only a small portion of the noncoding sequences in a genome. The REs active in gene regulation in a given cellular state tend to have an open chromatin struc...

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“…The neuronal nAChR probably plays a significant role in the development of alcoholism when considering indirect evidence. Alcohol is frequently coabused with nicotine accepted via smoking and the role of ethanol in the mesolimbic pathway is also discussed 84 . Abuse of alcohol can be reduced by the application of another nAChR modulator, as proven with varenicline 85 .…”

Section: Interaction With Receptors and Regulatory Pathwaysmentioning

confidence: 99%

Toxicology and the biological role of methanol and ethanol: Current view

Pohanka¹

2016

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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Background. Alcohol variants such as ethanol and methanol are simple organic compounds widely used in foods, pharmaceuticals, chemical synthesis, etc. Both are becoming an emerging health problem; abuse of ethanol containing beverages can lead to disparate health problems and methanol is highly toxic and unfit for consumption. Methods and Results. This review summarizes the basic knowledge about ethanol and methanol toxicity, the effect mechanism on the body, the current care of poisoned individuals and the implication of alcohols in the development of diseases. Alcohol related dementia, stroke, metabolic syndrome and hepatitis are discussed as well. Besides ethanol, methanol toxicity and its biodegradation pathways are addressed. Conclusions. The impact of ethanol and methanol on the body is shown as case reports, along with a discussion on the possible implication of alcohol in Alzheimer's disease and antidotal therapy for methanol poisoning. The role of ethanol in cancer and degenerative disorders seems to be underestimated given the current knowledge. Treatment in case of poisoning is another issue that remains unresolved even though effective protocols and drugs exist.

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Neuronal nicotinic acetylcholine receptors are important targets for alcohol reward and dependence

Cited by 32 publications

References 47 publications

Moderators of Varenicline Treatment Effects in a Double-Blind, Placebo-Controlled Trial for Alcohol Dependence

Moderators of Varenicline Treatment Effects in a Double-Blind, Placebo-Controlled Trial for Alcohol Dependence

Modeling gene regulation from paired expression and chromatin accessibility data

Toxicology and the biological role of methanol and ethanol: Current view

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