Stress‐Related Alcohol Consumption in Heavy Drinkers Correlates with Expression of miR‐10a, miR‐21, and Components of the TAR‐RNA‐Binding Protein‐Associated Complex

Abstract

Background Alterations in stress-related gene-expression may play a role in stress-related drinking and the risk for alcohol dependence. Methods Microarrays were used to measure changes in gene-expression in peripheral blood in non-smoking, social drinking subjects exposed to three types of personalized imagery: neutral, stressful (but not alcohol-related), and alcohol-related cues. Gene-expression was measured at baseline, immediately after, and 1 hour after stimulus presentation. Subjects were allowed to drink up to 750cc of beer in a “taste-test” following stimulus presentation in each imagery condition, and the amount of beer consumed was recorded. Gene-expression levels were compared in 2 groups of non-smoking subjects (n=11/group): heavy drinkers (HD, defined as regular alcohol use over the past year of at least 8 standard drinks/week for women and at least 15 standard drinks/week for men), and moderate drinkers (MD, defined as up to 7 standard drinks/week for women and 14 standard drinks/week for men). Expression of microRNA10 (miR-10a) and microRNA 21 (miR-21) was assessed by quantitative real-time PCR (qRT-PCR). Results After correction for multiple testing (FDR<0.05), 79 genes were identified that changed by > 1.3 fold in the HD group, but not the MD group, following exposure to stress. No changes were observed for any of these genes in either group following exposure to neutral or alcohol-related imagery. Pathway analysis suggested that many of these genes, form part of the TAR-RNA binding protein (TRBP)-associated complex and are positively regulated by miR-10a and MiR-21. Expression of both miR-10a and miR-21 was up-regulated following psychological stress in HD, but not MD subjects, however the differences between groups were not statistically significant. Expression levels of both microRNAs was correlated (miR-10a, R2= 0.59, miR-21 R2= 0.57) with amount drunk in HD, but not MD subjects. Conclusions Expression of miR-10a, miR-21 and several of their target genes is regulated by acute psychological stress, and is correlated with stress-induced drinking in a laboratory setting. Alterations in miRNA expression may be one mechanism linking psychological stress with changes in gene-expression and increased alcohol intake in binge/heavy drinkers.

Analyses of differentially expressed genes after exposure to acute stress, acute ethanol, or a combination of both in mice

“…Other studies examining differences in alcohol preference and alcohol consumption in animal models identified Cacnalg , Kcnh7 , Fgf12 , Gad1 , Luc7l2 , Smpd3 , and Ttn (Carr et al, 2007; Fehr, Rademacher, & Buck, 2003; McClintick et al, 2013; Mulligan et al, 2008; Wang et al, 2014, p. P12). Additionally, seven genes from the RSE vs. NOE or NOE group ( Ankib1 , Astn1 , Ccdc88a , Cpne3 , Tnn , Tns1 , and Synpo2 ) have been shown to be either differentially expressed in human alcoholics versus controls, or identified in a human genome-wide association study on alcoholism (Beech et al, 2014; Gelernter et al, 2014; Kryger & Wilce, 2010; Zuo et al, 2012). Finally, six differentially expressed genes ( Adcy8 , Myef2 , Per3 , S ynpo2 , Tbc1d9b , and Tsc22d3 ) have been linked to both stress and ethanol responses, although separately.…”

Molecular mechanisms underlying alcohol-drinking behaviours

“…Overexpression of miR-382 in the NAc of mice attenuated excessive alcohol consumption and preference (20%IA2BC paradigm) 155 ; however, more studies are necessary to establish a direct link between endogenous miR-382 and alcohol intake. Furthermore, the levels of miR-10a and miR-21 were elevated in the blood of humans who consumed excessive amounts of alcohol and were exposed to a stressful cue 156 ; it would be of interest to test the role of these specific miRNAs in animal studies.…”

MicroRNAs in Psychological Stress Reactions and Their Use as Stress-Associated Biomarkers, Especially in Human Saliva

“…Furthermore, the authors suggested changes in specific gene expressions, which might be related to the upregulation of these miRNAs. As a conclusion of these results, it can be suggested that miR-10a and miR-21 expression in whole blood is regulated by acute psychological stress in this context [22]. …”

“…Two of these studies used experimental stress elicitation tasks - analyzing acute, not chronic stress reactions [21,22]. Three of these studies used stressors of everyday life, such as academic exams or tests as events to be expected and therefore functioning as chronic psychological stressors [13,23,24].…”

“…Beech et al [22] investigated miRNA expression in an acute stress response in humans. They used an imaginary script development procedure to induce a condition of acute psychological stress.…”