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Gene expression changes in the nucleus accumbens of alcohol-preferring rats following chronic ethanol consumption.

ABSTRACT: The objective of this study was to determine the effects of binge-like alcohol drinking on gene expression changes in the nucleus accumbens (ACB) of alcohol-preferring (P) rats. Adult male P rats were given ethanol under multiple scheduled access (MSA; three 1-h dark cycle sessions/day) conditions for 8 weeks. For comparison purposes, a second ethanol drinking group was given continuous/daily alcohol access (CA; 24h/day). A third group was ethanol-naïve (W group). Average ethanol intakes for the CA and MSA groups were approximately 9.5 and 6.5 g/kg/day, respectively. Fifteen hours after the last drinking episode, rats were euthanized, the brains extracted, and the ACB dissected. RNA was extracted and purified for microarray analysis. The only significant differences were between the CA and W groups (p<0.01; Storey false discovery rate=0.15); there were 374 differences in named genes between these 2 groups. There were 20 significant Gene Ontology (GO) categories, which included negative regulation of protein kinase activity, anti-apoptosis, and regulation of G-protein coupled receptor signaling. Ingenuity analysis indicated a network of transcription factors, involving oncogenes (Fos, Jun, Junb had higher expression in the ACB of the CA group), suggesting increased neuronal activity. There were 43 genes located within rat QTLs for alcohol consumption and preference; 4 of these genes (Tgfa, Hspa5, Mtus1 and Creb3l2) are involved in anti-apoptosis and increased transcription, suggesting that they may be contributing to cellular protection and maintaining high alcohol intakes. Overall, these findings suggest that chronic CA drinking results in genomic changes that can be observed during the early acute phase of ethanol withdrawal. Conversely, chronic MSA drinking, with its associated protracted withdrawal periods, results in genomic changes that may be masked by tight regulation of these genes following repeated experiences of ethanol withdrawal.

SUBMITTER: Bell RL

PROVIDER: S-EPMC2771758 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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Gene expression changes in the nucleus accumbens of alcohol-preferring rats following chronic ethanol consumption.

Bell Richard L RL Kimpel Mark W MW McClintick Jeanette N JN Strother Wendy N WN Carr Lucinda G LG Liang Tiebing T Rodd Zachary A ZA Mayfield R Dayne RD Edenberg Howard J HJ McBride William J WJ

Pharmacology, biochemistry, and behavior 20090808 1

The objective of this study was to determine the effects of binge-like alcohol drinking on gene expression changes in the nucleus accumbens (ACB) of alcohol-preferring (P) rats. Adult male P rats were given ethanol under multiple scheduled access (MSA; three 1-h dark cycle sessions/day) conditions for 8 weeks. For comparison purposes, a second ethanol drinking group was given continuous/daily alcohol access (CA; 24h/day). A third group was ethanol-naïve (W group). Average ethanol intakes for the ...[more]

PMID: 19666046

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Project description:This study investigated changes in gene expression associated with ethanol drinking in adult male P rats under the following conditions for 8 weeks: continuous access (24 hr/day, 7 days/week), multiple scheduled access (three 1-hr sessions during the dark cycle/day, 5 days/week) and ethanol-naive (water). The objective of this study was to investigate changes in gene expression associated with ethanol drinking. Adult male alcohol-preferring (P) rats were given Ethanol in their home-cages under continuous access (CA; 24 hr/day, 7 days/week) or multiple scheduled access (MSA; three 1-hr sessions during the dark cycle/day, 5 days/week) conditions for 8 weeks. A third group was ethanol-naïve (W group). Average ethanol intakes, across the 8 weeks, for the CA and MSA groups were approximately 9.5 and 6.5 g/kg/day, respectively. Fifteen hr after the last ethanol drinking episode, rats were euthanized, the brains rapidly extracted, and the nucleus accumbens (ACB) dissected. RNA was extracted and purified for microarray analysis. The only significant differences, overall, were between the CA and W groups (p < 0.01; Storey false discovery rate = 0.15); there were 374 significant differences in unique named genes between these 2 groups. There were 20 significant Gene Ontology (GO) biological processes categories, which included ‘negative regulation of protein kinase activity’, ‘anti-apoptosis’, and ‘regulation of G-protein-coupled receptor protein signaling pathway’. Ingenuity® analysis indicated a network of transcription factors, involving oncogenes (Fos, Jun, Junb had higher expression levels in the ACB of the CA than W group), suggesting increased neuronal activity in the CA group. There were 13 genes (Hspa5, Stom, Lcn7, Tceb3, Cdc42, Rap1ga1, Ece1, Dhrs3, Plod1, Kif1b, Nmnat1, Srpr, Esam) significantly different between the CA and W groups located within both mouse and rat ethanol QTLs, suggesting that these genes may contribute to ethanol drinking behavior. In conclusion, the robust differences in gene expression found between the CA and W groups, but not observed between the MSA and W groups, may be a result of the higher daily ethanol intakes of the CA group, and/or its initial ethanol withdrawal. Keywords: comparison of gene expression profiles for treated vs. control

Project description:This study investigated changes in gene expression associated with ethanol drinking in adult male P rats under the following conditions for 8 weeks: continuous access (24 hr/day, 7 days/week), multiple scheduled access (three 1-hr sessions during the dark cycle/day, 5 days/week) and ethanol-naive (water). The objective of this study was to investigate changes in gene expression associated with ethanol drinking. Adult male alcohol-preferring (P) rats were given Ethanol in their home-cages under continuous access (CA; 24 hr/day, 7 days/week) or multiple scheduled access (MSA; three 1-hr sessions during the dark cycle/day, 5 days/week) conditions for 8 weeks. A third group was ethanol-naÃÂ¯ve (W group). Average ethanol intakes, across the 8 weeks, for the CA and MSA groups were approximately 9.5 and 6.5 g/kg/day, respectively. Fifteen hr after the last ethanol drinking episode, rats were euthanized, the brains rapidly extracted, and the nucleus accumbens (ACB) dissected. RNA was extracted and purified for microarray analysis. The only significant differences, overall, were between the CA and W groups (p < 0.01; Storey false discovery rate = 0.15); there were 374 significant differences in unique named genes between these 2 groups. There were 20 significant Gene Ontology (GO) biological processes categories, which included Ã¢ÂÂnegative regulation of protein kinase activityÃ¢ÂÂ, Ã¢ÂÂanti-apoptosisÃ¢ÂÂ, and Ã¢ÂÂregulation of G-protein-coupled receptor protein signaling pathwayÃ¢ÂÂ. IngenuityÃÂ® analysis indicated a network of transcription factors, involving oncogenes (Fos, Jun, Junb had higher expression levels in the ACB of the CA than W group), suggesting increased neuronal activity in the CA group. There were 13 genes (Hspa5, Stom, Lcn7, Tceb3, Cdc42, Rap1ga1, Ece1, Dhrs3, Plod1, Kif1b, Nmnat1, Srpr, Esam) significantly different between the CA and W groups located within both mouse and rat ethanol QTLs, suggesting that these genes may contribute to ethanol drinking behavior. In conclusion, the robust differences in gene expression found between the CA and W groups, but not observed between the MSA and W groups, may be a result of the higher daily ethanol intakes of the CA group, and/or its initial ethanol withdrawal. Experiment Overall Design: 10 samples each of control, continuous ethanol and limited access ethanol

Project description:Heavy alcohol consumption has detrimental neurologic effects, inducing widespread neuronal loss in both fetuses and adults. One proposed mechanism of ethanol-induced cell loss with sufficient exposure is an elevation in concentrations of bioactive lipids that mediate apoptosis, including the membrane sphingolipid metabolites ceramide and sphingosine. While these naturally-occurring lipids serve as important modulators of normal neuronal development, elevated levels resulting from various extracellular insults have been implicated in pathological apoptosis of neurons and oligodendrocytes in several neuroinflammatory and neurodegenerative disorders. Prior work has shown that acute administration of ethanol to developing mice increases levels of ceramide in multiple brain regions, hypothesized to be a mediator of fetal alcohol-induced neuronal loss. Elevated ceramide levels have also been implicated in ethanol-mediated neurodegeneration in adult animals and humans. Here, we determined the effect of chronic voluntary ethanol consumption on lipid profiles in brain and peripheral tissues from adult alcohol-preferring (P) rats to further examine alterations in lipid composition as a potential contributor to ethanol-induced cellular damage. P rats were exposed for 13 weeks to a 20% ethanol intermittent-access drinking paradigm (45 ethanol sessions total) or were given access only to water (control). Following the final session, tissues were collected for subsequent chromatographic analysis of lipid content and enzymatic gene expression. Contrary to expectations, ethanol-exposed rats displayed substantial reductions in concentrations of ceramides in forebrain and heart relative to non-exposed controls, and modest but significant decreases in liver cholesterol. qRT-PCR analysis showed a reduction in the expression of sphingolipid delta(4)-desaturase (Degs2), an enzyme involved in de novo ceramide synthesis. These findings indicate that ethanol intake levels achieved by alcohol-preferring P rats as a result of chronic voluntary exposure may have favorable vs. detrimental effects on lipid profiles in this genetic line, consistent with data supporting beneficial cardioprotective and neuroprotective effects of moderate ethanol consumption.

Project description:Growing evidence suggests that epigenetic mechanisms, such as DNA methylation and demethylation, and histone modifications, are involved in the development of alcohol and drug addiction. However, studies of alcohol use disorder (AUD) that are focused on epigenetic DNA modifications and gene expression changes remain conflicting. Our aim was to study the effect of repeated ethanol consumption on epigenetic regulatory enzymes such as DNA methyltransferase and demethylase enzymes and whether those changes affected dynorphin/kappa-opioid receptor system in the Nucleus Accumbens (NAc). Two groups of male alcohol-preferring Alko Alcohol (AA) rats, rats which are selectively bred for high voluntary alcohol consumption and one group of male Wistar rats were used. The first group of AA rats had access to alcohol (10% ethanol solution) for 90 min on Mondays, Wednesdays and Fridays over a period of 3 weeks to establish a stable baseline of ethanol intake (AA-ethanol). The second group of AA rats (AA-water) and the Wistar rats (Wistar-water) were provided with water. Using qPCR, we found that voluntary alcohol drinking increased Dnmt1, -3a, and -3b mRNA levels and did not affect Tet family transcripts in the AA-ethanol group when compared with AA- and Wistar-water rats. DNMT and TET enzymatic activity measurements showed similar results to qPCR, where DNMT activity was increased in AA-ethanol group compared with AA-water and Wistar-water groups, with no statistically significant difference between groups in TET enzyme activity. In line with previous data, we found an increased percentage of global DNA methylation and hydroxymethylation in the AA-ethanol group compared with control rats. Finally, we investigated changes of selected candidate genes from dynorphin/kappa-opioid receptor system (Pdyn, Kor) and Dnmt3a genes that might be important in AUD-related behaviour. Our gene expression and promoter methylation analysis revealed a significant increase in the mRNA levels of Pdyn, Kor, and Dnmt3a in the AA-ethanol group, however, these changes can only be partially associate with the aberrant DNA methylation in promoter areas of the selected candidate genes. Thus, our findings suggest that the aberrant DNA methylation is rather one of the several mechanisms involved in gene expression regulation in AA rat model.

Project description:The objective of this study was to determine changes in gene expression within the extended amygdala following binge-like alcohol drinking by adolescent alcohol-preferring (P) rats. Starting at 28 days of age, P rats were given concurrent access to 15 and 30 % ethanol for 3 one-h sessions for 5 consecutive days each week until they were 49 days old. Rats were killed by decapitation 3 h after the first ethanol access session on the 15th day of drinking. RNA was prepared from micropunch samples of the nucleus accumbens shell (Acb-sh) and central nucleus of the amygdala (CeA). Ethanol intakes were 2.5 ‚Äì 3.0 g/kg/session. There were 154 and 182 unique named genes that significantly differed (FDR = 0.2) between the water and ethanol group in the Acb-sh and CeA, respectively. Gene Ontology (GO) analyses indicated that adolescent binge drinking produced changes in the in biological processes involved in cell proliferation and regulation of cellular structure in the Acb-sh, and in neuron projection and positive regulation of cellular organization in the CeA. Ingenuity Pathway Analysis indicated that, in the Acb-sh, there were several major intracellular signaling pathways (e.g., cAMP-mediated and protein kinase A signaling pathways) altered by adolescent drinking, with 3-fold more genes up-regulated than down-regulated in the alcohol group. The cAMP-mediated signaling system was also up-regulated in the CeA of the alcohol group. Weighted gene co-expression network analysis (WGCNA) indicated significant G-protein coupled receptor signaling and transmembrane receptor protein kinase signaling categories in the Acb-sh and CeA, respectively. Overall, the results of this study indicated that binge-like alcohol drinking by adolescent P rats is differentially altering the expression of genes in the Acb-sh and CeA, some of which are involved in intracellular signaling pathways and may produce long-term changes in neuronal function. Differences in gene expression in brain nucleus accumbens shell (Acb-sh) were compared in two groups of alcohol-preferring (P) rats, one given water only and the other given access to 15 & 30% ethanol during adolescence.

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Gene expression changes in the nucleus accumbens of alcohol-preferring rats following chronic ethanol consumption.

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Gene expression changes in the nucleus accumbens of alcohol-preferring rats following chronic ethanol consumption.

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