Although much has been learned about molecular sites of action for ethanol, there remains few effective treatments for alcoholism. Naltrexone (NTX) reduces recidivism and ethanol consumption in alcoholics. NTX, an un-selective opioid antagonist, has also been shown to decrease ethanol drinking behavior in animal models, including blocking increased ethanol drinking in a model of relapse drinking, the ethanol deprivation effect (EDE). The molecular mechanism(s) for these responses are not entirely understood. We hypothesize that by studying genome-wide gene expression patterns associated with naltrexone action, EDE and naltrexone effects on EDE, we might gain novel insight into mechanisms relevant to relapse drinking behavior. In this project high-density oligonucleotide arrays will first be used to characterize gene expression patterns evoked by NTX in naive C57BL/6 mice. Ventral tegmental area, nucleus accumbens and medial prefrontal cortex brain regions in C57BL/6 mice will be studied. Expression profiles of NTX will also be compared to those from two other agents that decrease ethanol drinking or the EDE, acamproste and MPEP, an inhibitor of the mGluR5 glutamate receptor.
Aim two will then use arrays to study action of NTX on gene expression patterns evoked by ethanol-deprivation in a 2-bottle choice model of ethanol self administration. Through data mining the combined expression patterns related to NTX action in aims 1-2, we will then characterize particular candidate genes in regard to cellular patterns of their expression changes.
In Aim 3, candidate genes will be evaluated for their role in ethanol drinking or the EDE in a 2-bottle choice model. Pharmacological or genetic (viral vectors, antisense oligonucleotides) means will be used to alter the expression of candidate genes prior to behavioral testing. These studies should provide novel insight into the mechanisms of the EDE and mechanisms of NTX action in altering ethanol drinking behavior. Together, these findings may identify novel targets for therapeutic intervention in alcoholism.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA014717-04
Application #
7277862
Study Section
Special Emphasis Panel (ZRG1-IFCN-D (03))
Program Officer
Guo, Qingbin
Project Start
2004-09-27
Project End
2009-08-31
Budget Start
2007-09-01
Budget End
2008-08-31
Support Year
4
Fiscal Year
2007
Total Cost
$320,012
Indirect Cost
Name
Virginia Commonwealth University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
Putman, A H; Wolen, A R; Harenza, J L et al. (2016) Identification of quantitative trait loci and candidate genes for an anxiolytic-like response to ethanol in BXD recombinant inbred strains. Genes Brain Behav 15:367-81
Farris, Sean P; Miles, Michael F (2013) Fyn-dependent gene networks in acute ethanol sensitivity. PLoS One 8:e82435
Costin, Blair N; Wolen, Aaron R; Fitting, Sylvia et al. (2013) Role of adrenal glucocorticoid signaling in prefrontal cortex gene expression and acute behavioral responses to ethanol. Alcohol Clin Exp Res 37:57-66
O'Brien, M A; Costin, B N; Miles, M F (2012) Using genome-wide expression profiling to define gene networks relevant to the study of complex traits: from RNA integrity to network topology. Int Rev Neurobiol 104:91-133
Farris, Sean P; Miles, Michael F (2012) Ethanol modulation of gene networks: implications for alcoholism. Neurobiol Dis 45:115-21
Jackson, Kia J; Chen, Xiangning; Miles, Michael F et al. (2011) The neuropeptide galanin and variants in the GalR1 gene are associated with nicotine dependence. Neuropsychopharmacology 36:2339-48
Wolstenholme, Jennifer T; Warner, Jon A; Capparuccini, Maria I et al. (2011) Genomic analysis of individual differences in ethanol drinking: evidence for non-genetic factors in C57BL/6 mice. PLoS One 6:e21100
Farris, Sean P; Wolen, Aaron R; Miles, Michael F (2010) Using expression genetics to study the neurobiology of ethanol and alcoholism. Int Rev Neurobiol 91:95-128
Guo, An-Yuan; Webb, Bradley T; Miles, Michael F et al. (2009) ERGR: An ethanol-related gene resource. Nucleic Acids Res 37:D840-5
Kerns, Robnet T; Miles, Michael F (2008) Microarray analysis of ethanol-induced changes in gene expression. Methods Mol Biol 447:395-410

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