title: Gene expression in brain and liver produced by three different regimens of alcohol consumption in mice: comparison with immune activation.
abstract: Chronically available alcohol escalates drinking in mice and a single injection of the immune activator lipopolysaccharide can mimic this effect and result in a persistent increase in alcohol consumption. We hypothesized that chronic alcohol drinking and lipopolysaccharide injections will produce some similar molecular changes that play a role in regulation of alcohol intake. We investigated the molecular mechanisms of chronic alcohol consumption or lipopolysaccharide insult by gene expression profiling in prefrontal cortex and liver of C57BL/6J mice. We identified similar patterns of transcriptional changes among four groups of animals, three consuming alcohol (vs water) in different consumption tests and one injected with lipopolysaccharide (vs. vehicle). The three tests of alcohol consumption are the continuous chronic two bottle choice (Chronic), two bottle choice available every other day (Chronic Intermittent) and limited access to one bottle of ethanol (Drinking in the Dark). Gene expression changes were more numerous and marked in liver than in prefrontal cortex for the alcohol treatments and similar in the two tissues for lipopolysaccharide. Many of the changes were unique to each treatment, but there was significant overlap in prefrontal cortex for Chronic-Chronic Intermittent and for Chronic Intermittent-lipopolysaccharide and in liver all pairs showed overlap. In silico cell-type analysis indicated that lipopolysaccharide had strongest effects on brain microglia and liver Kupffer cells. Pathway analysis detected a prefrontal cortex-based dopamine-related (PPP1R1B, DRD1, DRD2, FOSB, PDNY) network that was highly over-represented in the Chronic Intermittent group, with several genes from the network being also regulated in the Chronic and lipopolysaccharide (but not Drinking in the Dark) groups. Liver showed a CYP and GST centered metabolic network shared in part by all four treatments. We demonstrate common consequences of chronic alcohol consumption and immune activation in both liver and brain and show distinct genomic consequences of different types of alcohol consumption.
authors.affiliation: Waggoner Center for Alcohol and Addiction Research, Colleges of Natural Science and Pharmacy, University of Texas at Austin, Austin, Texas, United States of America.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Osterndorff-Kahanek
authors.forename: Igor
authors.initials: I
authors.lastname: Ponomarev
authors.forename: Yuri A
authors.initials: YA
authors.lastname: Blednov
authors.forename: R Adron
authors.initials: RA
authors.lastname: Harris
mesh_terms: D000428:Alcohol Drinking; D000818:Animals; D001921:Brain / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002755:Choice Behavior; D004327:Drinking Behavior; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D008070:Lipopolysaccharides / Q000378:metabolism; D008099:Liver / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D017397:Prefrontal Cortex / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D008070:Lipopolysaccharides; D000431:Ethanol
references.citation: World J Gastroenterol. 2006 Oct 28;12(40):6473-99
references.pmid: 17072980
references.citation: Brain Behav Immun. 2011 Jun;25 Suppl 1:S4-S12
references.pmid: 21402143
references.citation: Neuropsychopharmacology. 2010 May;35(6):1402-11
references.pmid: 20147889
references.citation: Arch Gen Psychiatry. 1998 Oct;55(10):905-12
references.pmid: 9783561
references.citation: Physiol Behav. 2005 Jan 31;84(1):53-63
references.pmid: 15642607
references.citation: Alcohol. 1999 Apr;17(3):175-83
references.pmid: 10231165
references.citation: Proc Natl Acad Sci U S A. 2011 Apr 19;108(16):6626-31
references.pmid: 21464311
references.citation: Nat Rev Neurosci. 2007 Nov;8(11):844-58
references.pmid: 17948030
references.citation: Alcohol Clin Exp Res. 2011 May;35(5):782-6
references.pmid: 21284666
references.citation: Addict Biol. 2011 Jul;16(3):499-509
references.pmid: 21521424
references.citation: Addict Biol. 2013 Jan;18(1):161-9
references.pmid: 21955155
references.citation: Biol Psychiatry. 2013 Apr 1;73(7):602-12
references.pmid: 23206318
references.citation: Alcohol Clin Exp Res. 2005 May;29(5):730-8
references.pmid: 15897716
references.citation: Addict Biol. 2012 Sep;17(5):920-33
references.pmid: 22741603
references.citation: Proc Natl Acad Sci U S A. 2006 Oct 31;103(44):16364-9
references.pmid: 17053075
references.citation: Alcohol Clin Exp Res. 1999 Apr;23(4):683-92
references.pmid: 10235304
references.citation: J Neurosci. 2010 Jun 16;30(24):8285-95
references.pmid: 20554880
references.citation: Genes Brain Behav. 2012 Jun;11(4):415-23
references.pmid: 22443215
references.citation: Nat Protoc. 2009;4(1):44-57
references.pmid: 19131956
references.citation: Alcohol. 2010 Mar;44(2):171-83
references.pmid: 20116196
references.citation: Biol Psychiatry. 2011 Apr 1;69(7):618-24
references.pmid: 21195386
references.citation: Nat Neurosci. 2008 Nov;11(11):1271-82
references.pmid: 18849986
references.citation: Pharmacol Biochem Behav. 2009 Sep;93(3):237-47
references.pmid: 19410598
references.citation: Neurosci Lett. 2011 Sep 26;503(1):31-6
references.pmid: 21843598
references.citation: Alcohol Clin Exp Res. 2008 Oct;32(10):1816-23
references.pmid: 18671810
references.citation: J Neurosci. 2012 May 2;32(18):6391-410
references.pmid: 22553043
references.citation: J Neurosci. 2008 Jan 2;28(1):264-78
references.pmid: 18171944
references.citation: Pharmacol Biochem Behav. 2009 Nov;94(1):131-47
references.pmid: 19666046
references.citation: Addict Biol. 2011 Oct;16(4):615-9
references.pmid: 21392173
references.citation: Neuropharmacology. 2004;47 Suppl 1:14-23
references.pmid: 15464122
references.citation: PLoS One. 2011;6(6):e21100
references.pmid: 21698166
references.citation: Addict Biol. 2013 May;18(3):496-507
references.pmid: 22862671
references.citation: Int Rev Neurobiol. 2010;91:95-128
references.pmid: 20813241
references.citation: Alcohol. 2006 Oct;40(2):73-86
references.pmid: 17307643
references.citation: Proc Natl Acad Sci U S A. 2006 Apr 18;103(16):6368-73
references.pmid: 16618939
references.citation: Br J Pharmacol. 2008 May;154(2):275-87
references.pmid: 18362899
references.citation: Front Biosci. 2007 Jan 01;12:2616-30
references.pmid: 17127267
references.citation: Alcohol Clin Exp Res. 2004 Dec;28(12):1829-38
references.pmid: 15608599
references.citation: Nat Neurosci. 2002 Jul;5(7):641-8
references.pmid: 12068305
references.citation: Toxicol Appl Pharmacol. 2009 Mar 15;235(3):312-20
references.pmid: 19167417
references.citation: Neurosci Lett. 2011 Jan 13;488(1):31-5
references.pmid: 21056629
references.citation: Alcohol Clin Exp Res. 2011 Apr;35(4):659-70
references.pmid: 21223303
references.citation: J Hepatol. 2004 Feb;40(2):219-27
references.pmid: 14739091
references.citation: Brain Behav Immun. 2001 Mar;15(1):7-24
references.pmid: 11259077
references.citation: Nucleic Acids Res. 2009 Jan;37(1):1-13
references.pmid: 19033363
references.citation: Pharmacol Biochem Behav. 1995 Apr;50(4):619-26
references.pmid: 7617710
references.citation: Nat Rev Neurosci. 2011 Oct 12;12(11):623-37
references.pmid: 21989194
references.citation: Alcohol Clin Exp Res. 2010 May;34(5):777-89
references.pmid: 20201932
references.citation: Brain Behav Immun. 2011 Jun;25 Suppl 1:S92-S105
references.pmid: 21266194
references.citation: J Neurosci. 2012 Aug 22;32(34):11706-15
references.pmid: 22915113
references.citation: Annu Rev Nutr. 2012 Aug 21;32:343-68
references.pmid: 22524187
references.citation: Addict Biol. 2012 Mar;17(2):322-37
references.pmid: 21966993
references.citation: Addict Biol. 2010 Apr;15(2):109-24
references.pmid: 20148775
references.citation: Pharmacol Biochem Behav. 2008 Jun;89(4):481-98
references.pmid: 18405950
references.citation: Ann N Y Acad Sci. 2011 Jan;1216:24-40
references.pmid: 21272009
references.citation: Stat Appl Genet Mol Biol. 2004;3:Article3
references.pmid: 16646809
references.citation: Addict Biol. 2012 Mar;17(2):351-64
references.pmid: 21812870
references.citation: Neuropsychopharmacology. 2006 Jul;31(7):1574-82
references.pmid: 16292326
references.citation: Bioinformatics. 2003 Jan 22;19(2):185-93
references.pmid: 12538238
references.citation: Bioinformatics. 2008 Jul 1;24(13):1547-8
references.pmid: 18467348
references.citation: Pharmacol Biochem Behav. 1997 May-Jun;57(1-2):179-83
references.pmid: 9164570
references.citation: Brain Behav Immun. 2010 Jan;24(1):102-9
references.pmid: 19735725
references.citation: J Neurosci. 2008 Oct 15;28(42):10460-71
references.pmid: 18923023
references.citation: Addict Biol. 2012 Jan;17(1):108-20
references.pmid: 21309947
references.citation: Nucleic Acids Res. 2008 Feb;36(2):e11
references.pmid: 18178591
references.citation: J Neurosci. 2012 Feb 1;32(5):1884-97
references.pmid: 22302827