Dataset Information

Identification and validation of midbrain Kcnq4 regulation of heavy alcohol consumption in rodents.

ABSTRACT: Currently available pharmacotherapies for treating alcohol use disorder (AUD) suffer from deleterious side effects and are not efficacious in diverse populations. Clinical and preclinical studies provide evidence that the Kcnq family of genes that encode KV7 channels influence alcohol intake and dependence. KV7 channels are a class of slowly activating voltage-dependent K+ channels that regulate neuronal excitability. Studies indicate that the KV7 channel positive modulator retigabine can decrease dopaminergic neuron firing, alter dopamine (DA) release, and reduce alcohol intake in heavy drinking rodents. Given the critical nature of ventral tegmental area (VTA) DA to the addiction process and predominant expression of Kcnq4 in DA neurons, we investigated the role of midbrain Kcnq genes and KV7 channels in the VTA of genetically diverse mice and long-term heavy drinking rats, respectively. Integrative bioinformatics analysis identified negative correlations between midbrain Kcnq4 expression and alcohol intake and seeking behaviors. Kcnq4 expression levels were also correlated with dopaminergic-related phenotypes in BXD strains, and Kcnq4 was present in support intervals for alcohol sensitivity and alcohol withdrawal severity QTLs in rodents. Pharmacological validation studies revealed that VTA KV7 channels regulate excessive alcohol intake in rats with a high-drinking phenotype. Administration of a novel and selective KV7.2/4 channel positive modulator also reduced alcohol drinking in rats. Together, these findings indicate that midbrain Kcnq4 expression regulates alcohol-related behaviors in genetically diverse mice and provide evidence that KV7.4 channels are a critical mediator of excessive alcohol drinking.

SUBMITTER: McGuier NS

PROVIDER: S-EPMC6054890 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Identification and validation of midbrain Kcnq4 regulation of heavy alcohol consumption in rodents.

McGuier Natalie S NS Rinker Jennifer A JA Cannady Reginald R Fulmer Diana B DB Jones Sara R SR Hoffman Michaela M Mulholland Patrick J PJ

Neuropharmacology 20180525

Currently available pharmacotherapies for treating alcohol use disorder (AUD) suffer from deleterious side effects and are not efficacious in diverse populations. Clinical and preclinical studies provide evidence that the Kcnq family of genes that encode KV7 channels influence alcohol intake and dependence. KV7 channels are a class of slowly activating voltage-dependent K+ channels that regulate neuronal excitability. Studies indicate that the KV7 chan ...[more]

PMID: 29775679

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Project description:High average daily consumption of alcohol has been associated with elevated mortality risk, but more moderate consumption, relative to abstinence, has been associated with reduced mortality risk. However, average daily consumption can be complicated to assess, limiting its usefulness in both research and clinical practice. There are also concerns that average consumption fails to capture the risk associated with certain drinking patterns, such as heavy episodic drinking. This study assessed mortality associated with drinking pattern, operationalized as the frequency of both heavy and nonheavy drinking occasions.Data from the 1997 to 2001 administrations of the National Health Interview Survey (NHIS; n = 111,511) were paired with the current release of the NHIS Linked Mortality Files, which provided mortality follow-up data through the end of 2006. We estimated the impact of drinking pattern on all-cause mortality, operationalized as the frequency of heavy (5+ drinks) and nonheavy (<5 drinks) drinking occasions. Other covariates in the model included survey wave, sex, age, race/ethnicity, ratio of family income to poverty threshold, educational attainment, body mass index, and smoking status.Over a third of past-year drinkers reported heavy drinking. Mortality risk increased steadily as heavy drinking frequency increased; daily heavy drinkers exhibited an almost 2-fold risk of death compared with abstainers (p < 0.001). Regular nonheavy drinking was associated with decreased mortality, similar to the "J-shaped curve" highlighted in past research on alcohol mortality; this potential protective effect peaked around 2 nonheavy occasions per week.Any heavy drinking likely elevates mortality risk, and substantial health benefits could be realized by reducing heavy drinking occasions or limiting overall drinking. Heavy and nonheavy drinking frequencies are valid targets for clinical screening and could be helpful in assessing risk and promoting less harmful drinking behavior.

Project description:AbstractPresenteeism refers to the practice of going to work despite poor health, resulting in subpar performance. This study aimed to explore the impacts of smoking and alcohol consumption on workplace presenteeism based on demographic, health-related, and employment variables.The study adopted a cross sectional design with 60,051 wage workers from the database of the second and third Korean Working Conditions Surveys in 2010 and 2011, respectively. A total of 41,404 workers aged 19 years and older, who had worked for at least 1 hour in the previous week, answered the survey questions. Chi-square test as well as univariate and multiple logistic regression analyses were conducted using SPSS, version 18.0, to determine the impacts of smoking and alcohol consumption on workplace presenteeism.Of the 41,404 Korean workers, 8512 (20.6%) had experienced presenteeism in the past 12 months. There were significant differences among gender, age, educational status, income, health problems, absenteeism, shift work, night shift, weekly working hours, exposure to secondhand smoke at work, and satisfaction with the workplace environment. Based on the results of multiple regression analysis, heavy smoking (adjusted odds ratio = 1.38, 95% confidence intervals [1.11, 1.72]) and high-risk drinking (adjusted odds ratio = 1.19, 95% confidence intervals [1.08, 1.31]) were significantly related to presenteeism among workers.The results of our study confirmed that smoking and alcohol drinking were related to presenteeism even after controlling other variables (demographic, health-related, and employment variables) that affect presenteeism. Smoking and alcohol drinking are associated with and potentially influence presenteeism; in particular, heavy smoking and high-risk drinking contributed to presenteeism. Companies that encourage employees to receive treatments for reduction of smoking or alcohol consumption may benefit from greater productivity. Hence, we should consider the impact of smoking and alcohol consumption in the workplace and build appropriate strategies and programs to help reduce these behaviors.

Dataset Information

Identification and validation of midbrain Kcnq4 regulation of heavy alcohol consumption in rodents.

Publications

Identification and validation of midbrain Kcnq4 regulation of heavy alcohol consumption in rodents.

Similar Datasets

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