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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AA016649-08
Application #
8527622
Study Section
Special Emphasis Panel (ZAA1-DD (50))
Program Officer
Reilly, Matthew
Project Start
2006-09-30
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
8
Fiscal Year
2013
Total Cost
$325,196
Indirect Cost
$110,373
Name
University of Colorado Denver
Department
Pharmacology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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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
Desrivieres, 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
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
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
Pronko, Sergey P; Saba, Laura M; Hoffman, Paula L et al. (2010) Type 7 adenylyl cyclase-mediated hypothalamic-pituitary-adrenal axis responsiveness: influence of ethanol and sex. J Pharmacol Exp Ther 334:44-52
Tabakoff, Boris; Saba, Laura; Printz, Morton et al. (2009) Genetical genomic determinants of alcohol consumption in rats and humans. BMC Biol 7:70

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