During the previous INIA (Integrated Neurosciences Initiative on Alcoholism)-West project period a genetical genomic/phenomic approach was applied to identify candidate genes in rodents that, through variation in expression levels, contribute to the predisposition to consume varying amounts of alcohol. One such candidate gene is Gnb1 (the G protein beta 1 subunit, Gpi). Brain levels of the Gpi protein are inversely correlated with levels of alcohol consumption in inbred and recombinant inbred strains of mice and in lines of mice selected for differences in alcohol consumption. Treatment of mice with a lentiviral vector expressing a shRNA targeting Gnb1 lowered Gpi levels in nucleus accumbens and increased alcohol consumption by DBA/2 mice. Gpi, as a dimer with Gy proteins, affects numerous intracellular signaling pathways, and has also been reported to interact with, and modify the transcriptional activity of, the Class lla histone deacetylases (HDACs) 4 and 5. HDACs generally repress transcription via modification of histone proteins and class lla HDACs can shuttle between nucleus and cytoplasm, which can regulate their transcriptional activity. In particular, the direct Gpy-HDAC interaction reduces HDAC activity, and therefore has the potential to regulate the transcription of other genes. Given that HDACS activity has previously been found to be crucial for the rewarding effect of cocaine, and that HDAC inhibition reduces alcohol consumption, a role for the Gpy-HDAC interaction in alcohol consumption is postulated. Alcohol consumption will be measured after lowering Gnb1 expression in brains of low alcohol-consuming mice, and after inhibiting or lowering expression of HDACs in brain of high alcohol-consuming mice. To assess the link between Gpi and HDACs, HDAC transcriptional activity (transcript levels and promoter acetylation), as well as HDAC subcellular localization, will be determined after lowering Gpi with RNAi. Overall, this project will investigate molecular mechanisms, focusing on chromatin modification, by which a previously identified candidate gene for alcohol consumption/preference influences transcriptional networks that may underlie this phenotype.
Alcohol consumption is a prerequisite for the development of alcohol dependence, and excessive alcohol consumption may produce changes in the brain that lead to dependence. Genetic characteristics influence both the predisposition to consume alcohol and to become dependent. We have identified a candidate gene that affects the predisposition for alcohol consumption, and we are now exploring its mechanism of action, i.e., this gene may be a crucial regulator of a network of genes and proteins. Understanding this network will provide a new approach to the development of medications to interfere with excessive alcohol consumption.
|Vanderlinden, Lauren A; Saba, Laura M; Bennett, Beth et al. (2015) Influence of sex on genetic regulation of ""drinking in the dark"" alcohol consumption. Mamm Genome 26:43-56|
|Saba, Laura M; Flink, Stephen C; Vanderlinden, Lauren A et al. (2015) The sequenced rat brain transcriptome--its use in identifying networks predisposing alcohol consumption. FEBS J 282:3556-78|
|Vanderlinden, Lauren A; Saba, Laura M; Printz, Morton P et al. (2014) Is the alcohol deprivation effect genetically mediated? Studies with HXB/BXH recombinant inbred rat strains. Alcohol Clin Exp Res 38:2148-57|
|Hoffman, P L; Saba, L M; Flink, S et al. (2014) Genetics of gene expression characterizes response to selective breeding for alcohol preference. Genes Brain Behav 13:743-57|
|Vanderlinden, Lauren A; Saba, Laura M; Kechris, Katerina et al. (2013) Whole brain and brain regional coexpression network interactions associated with predisposition to alcohol consumption. PLoS One 8:e68878|
|Tabakoff, Boris; Hoffman, Paula L (2013) The neurobiology of alcohol consumption and alcoholism: an integrative history. Pharmacol Biochem Behav 113:20-37|
|Hoffman, Paula L; Bennett, Beth; Saba, Laura M et al. (2011) Using the Phenogen website for 'in silico' analysis of morphine-induced analgesia: identifying candidate genes. Addict Biol 16:393-404|
|Desrivières, Sylvane; Pronko, Sergey P; Lourdusamy, Anbarasu et al. (2011) Sex-specific role for adenylyl cyclase type 7 in alcohol dependence. Biol Psychiatry 69:1100-8|
|Saba, Laura M; Bennett, Beth; Hoffman, Paula L et al. (2011) A systems genetic analysis of alcohol drinking by mice, rats and men: influence of brain GABAergic transmission. Neuropharmacology 60:1269-80|
|Bennett, Beth; Saba, Laura M; Hornbaker, Cheryl K et al. (2011) Genetical genomic analysis of complex phenotypes using the PhenoGen website. Behav Genet 41:625-8|
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