Gene Expression Under the Influence: Transcriptional Profiling of Ethanol in the Brain

Abstract

Sensitivity to ethanol intoxication, propensity to drink ethanol and vulnerability to develop alcoholism are all influenced by genetic factors. Conversely, exposure to ethanol or subsequent withdrawal produce gene expression changes, which, in combination with environmental variables, may participate in the emergence of compulsive drinking and relapse. The present review offers an integrated perspective on brain gene expression profiling in rodent models of predisposition to differential ethanol sensitivity or consumption, in rats and mice subjected to acute or chronic ethanol exposure, as well as in human alcoholics. The functional categories over-represented among differentially expressed genes suggest that the transcriptional effects of chronic ethanol consumption contribute to the neuroplasticity and neurotoxicity characteristic of alcoholism. Importantly, ethanol produces distinct transcriptional changes within the different brain regions involved in intoxication, reinforcement and addiction. Special emphasis is put on recent profiling studies that have provided some insights into the molecular mechanisms potentially mediating genome-wide regulation of gene expression by ethanol. In particular, current evidence for a role of transcription factors, chromatin remodeling and microRNAs in coordinating the expression of large sets of genes in animals predisposed to excessive ethanol drinking or exposed to protracted abstinence, as well as in human alcoholics, is presented. Finally, studies that have compared ethanol with other drugs of abuse have highlighted common gene expression patterns that may play a central role in drug addiction. The availability of novel technologies and a focus on mechanistic approaches are shaping the future of ethanol transcriptomics.

Expression of specific ionotropic glutamate and GABA-A receptor subunits is decreased in central amygdala of alcoholics

“…We have recently shown up-regulation of several subunit mRNAs of ionotropic glutamate (GluA2 and GluA3, GluK2, GluK3 and GluK5, GluN1, GluN2A, GluN2C, GluN2D and GluN3A) and GABA-A receptors (α1, α5, β1, and γ1) in the hippocampal dentate gyrus, up-regulation of GluN3A but down-regulation of GABA-A β2 and δ in the orbitofrontal cortex, and no difference in subunit expression in the dorsolateral prefrontal cortex of human alcoholics as compared to control subjects (Jin et al, 2012, 2014). Importantly, our studies and other gene expression studies on human post-mortem brain (Flatscher-Bader et al, 2006; Contet, 2012; Ponomarev et al, 2012), show that changes in gene expression pattern of the ionotropic glutamate and GABA-A receptors subunits induced by chronic alcohol intake greatly vary between brain regions.…”

Regional Differences and Similarities in the Brain Transcriptome for Mice Selected for Ethanol Preference From HS-CC Founders

“…Dlg2 encodes for post-synaptic density protein 93 (PSD-93), Gatad2b encodes for transcriptional repressor p66-beta, Pcdhac2 encodes for protocadherin αc2, Tnks encodes for Tankyrase-1, Usp29 encodes for ubiquitin specific protease 29 and Usp9x encodes for ubiquitin specific protease 9, X-linked. That two ubiquitin-related genes are in this group cannot be unexpected, given the long standing observations that ubiquitination is associated with chronic ethanol exposure in both animals and humans (see Sokolov et al, 2003; Liu et al, 2006; Contet, 2012; Melendez et al, 2012; Widagdo et al, 2017). Our data link ubiquitination to risk for excessive consumption.…”

“…Contet (2012) surveyed the existing literature and noted that multiple functional categories were associated with a “predisposition” to excessive ethanol consumption and in most cases each of the categories have been supported by multiple publications (see Table 2 in Contet, 2012). Some regional specificity for each of the functional categories was also noted; however, the regional differences in gene expression were generally larger than those associated with selection for preference or binge drinking (Kimpel et al, 2007; Mulligan et al, 2011).…”

“…Contet (2012) reviewed the existing literature and noted that the genes associated with the risk of excessive consumption and/or the effects of excessive consumption had regionally specific effects on gene expression. Subsequent studies have confirmed and extended the “region" effect (e.g., Melendez et al, 2012; Osterndorff-Kahanek et al, 2015; Smith et al, 2016; Mulligan et al, 2017).…”

Multiparameter rodent chronic model for complex evaluation of alcoholism-mediated metabolic violations

“…As for alcohol effects on nucleic acids structure, functions and metabolisms, it was shown that ethanol induced a complex pattern of hormonal responses in individual rats causing multiple changes in genes transcription processes [9]. Exposure to ethanol or subsequent withdrawal produced gene expression changes [10].…”