Alcohol‐responsive genes in the frontal cortex and nucleus accumbens of human alcoholics

Abstract

The molecular processes underlying alcohol dependence are not fully understood. Many characteristic behaviours result from neuroadaptations in the mesocorticolimbic system. In addition, alcoholism is associated with a distinct neuropathology. To elucidate the molecular basis of these features, we compared the RNA expression profile of the nucleus accumbens and prefrontal cortex of human brain from matched individual alcoholic and control cases using cDNA microarrays. Approximately 6% of genes with a marked alcohol response were common to the two brain regions. Alcohol-responsive genes were grouped into 11 functional categories. Predominant alcohol-responsive genes in the prefrontal cortex were those encoding DNA-binding proteins including transcription factors and repair proteins. There was also a down-regulation of genes encoding mitochondrial proteins, which could result in disrupted mitochondrial function and energy production leading to oxidative stress. Other alcohol-responsive genes in the prefrontal cortex were associated with neuroprotection/apoptosis. In contrast, in the nucleus accumbens, alcohol-responsive genes were associated with vesicle formation and regulation of cell architecture, which suggests a neuroadaptation to chronic alcohol exposure at the level of synaptic structure and function. Our data are in keeping with the previously reported alcoholism-related pathology characteristic of the prefrontal cortex, but suggest a persistent decrease in neurotransmission and changes in plasticity in the nucleus accumbens of the alcoholic.

Microarray Analysis of the Effects of a γ-protein Kinase C Null Mutation on Gene Expression in Striatum: A Role for Transthyretin in Mutant Phenotypes

“…Thus, it is not unreasonable to propose that an ethanol-induced decrease in transthyretin expression in the mutants may be associated with increased ethanol toxicity and decreased viability of the mutants during chronic ethanol treatment. Microarray studies have been performed to elucidate genes that regulate acute responses to ethanol (Kerns et al 2005;Kwon et al 2004) that underlie genetic differences in inbred and selected lines of rodents (Edenberg et al 2004;Saito et al 2004, Spence et al 2005Thibault et al 2000), the effects of chronic ethanol treatment or withdrawal in rodents and worms (Daniels and Buck 2002;Kwon et al 2004;Rimondini et al 2002Saito et al 2002, and the effects of long-term alcohol use in humans (Flatscher-Bader et al 2005;Lewohl et al 2000;Mayfield et al 2002). These studies varied in experimental design (for review see Rahman and Miles 2001;Worst and Vrana 2005).…”

Candidate genes, pathways and mechanisms for alcoholism: an expanded convergent functional genomics approach

“…111,45 Moreover, MAPK14 has been shown to be upregulated in the PFC and NAC in post-mortem human brains from alcoholics. 27 Heat-shock 27 kDa protein 1 (HSPB1) is downstream of MAPK14 in the MAPK pathway, and is involved in stress resistance and actin organization. Mutations in HSPB1 are the cause of Charcot-Marie-Tooth disease type 2 and of distal hereditary motor neuropathy.…”

“…Animal studies, human imaging and post-mortem analyses have previously provided evidence that these regions are implicated in alcoholism. [26][27][28] Data for the analysis came from studies of three experimental paradigms. Paradigm 1 29 examined basal level of gene expression in the brains of the alcohol-naïve iP and iNP lines of rats.…”

Effects of exercise and antioxidant supplementation on endothelial gene expression

“…Amplified RNA was reverse transcribed to cDNA with incorporation of Alexa-Fluor dyes using a SuperScript Plus Direct Labeling System according to the manufacturer's instructions. Microarray slides were scanned using a high resolution Agilent scanner, and spot detection was carried out using the ImaGene 6.0 software and median spot and background intensities were used for further analysis using GeneSpring 6.1 software following the procedure described elsewhere [17]. Microarray data is accessible at GEO database (http://www.ncbi.nlm.nih.gov/geo/, accession number GSE14044).…”