Dataset Information

Chronic Voluntary Ethanol Consumption Induces Favorable Ceramide Profiles in Selectively Bred Alcohol-Preferring (P) Rats.

ABSTRACT: 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.

SUBMITTER: Godfrey J

PROVIDER: S-EPMC4583526 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Chronic Voluntary Ethanol Consumption Induces Favorable Ceramide Profiles in Selectively Bred Alcohol-Preferring (P) Rats.

Godfrey Jessica J Jeanguenin Lisa L Castro Norma N Olney Jeffrey J JJ Dudley Jason J Pipkin Joseph J Walls Stanley M SM Wang Wei W Herr Deron R DR Harris Greg L GL Brasser Susan M SM

PloS one 20150925 9

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 extrace ...[more]

PMID: 26405804

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Project description:Crossed high-alcohol-preferring (cHAP) mice were selectively bred from a cross of the HAP1 × HAP2 replicate lines and demonstrate blood ethanol concentrations (BECs) during free-choice drinking reminiscent of those observed in alcohol-dependent humans. In this report, we investigated the relationship between free-choice drinking, intoxication, tolerance, and sensitization in cHAP mice. We hypothesized that initially mice would become ataxic after drinking alcohol, but that increased drinking over days would be accompanied by increasing tolerance to the ataxic effects of ethanol (EtOH).Male and female cHAP mice had free-choice access to 10% EtOH and water (E), while Water mice (W) had access to water alone. In experiment 1, the first drinking experience was monitored during the dark portion of the cycle. Once E mice reached an average intake rate of ?1.5 g/kg/h, they, along with W mice, were tested for footslips on a balance beam, and BECs were assessed. In experiments 2, 3, and 4, after varying durations of free-choice 10% EtOH access (0, 3, 14, or 21 days), mice were challenged with 20% EtOH and tested for number of footslips on a balance beam or locomotor stimulant response. Blood was sampled for BEC determination.We found that cHAP mice rapidly acquire alcohol intakes that lead to ataxia. Over time, cHAP mice developed behavioral tolerance to the ataxic effects of alcohol, paralleled by escalating alcohol consumption. However, locomotor sensitization did not develop following 14 days of free-choice EtOH access.Overall, we observed increases in free-choice drinking with extended alcohol access paralleled by increases in functional tolerance, but not locomotor sensitization. These data support our hypothesis that escalating free-choice drinking over days in cHAP mice is driven by tolerance to alcohol's behavioral effects. These data are the first to demonstrate that escalating free-choice consumption is accompanied by increasing alcohol tolerance. In addition to buttressing the hypothesized importance of tolerance in drinking, our findings suggest that cHAP mice may be a unique, translational resource for studying tolerance as a contributor to and consequence of chronic, excessive EtOH consumption.

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

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Dataset Information

Chronic Voluntary Ethanol Consumption Induces Favorable Ceramide Profiles in Selectively Bred Alcohol-Preferring (P) Rats.

Publications

Chronic Voluntary Ethanol Consumption Induces Favorable Ceramide Profiles in Selectively Bred Alcohol-Preferring (P) Rats.

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