title: Neuroimmune regulation of alcohol consumption: behavioral validation of genes obtained from genomic studies.
abstract: Analysis of mouse brain gene expression, using strains that differ in alcohol consumption, provided a number of novel candidate genes that potentially regulate alcohol consumption. We selected six genes [beta-2-microglobulin (B2m), cathepsin S (Ctss), cathepsin F (Ctsf), interleukin 1 receptor antagonist (Il1rn), CD14 molecule (Cd14) and interleukin 6 (Il6)] for behavioral validation using null mutant mice. These genes are known to be important for immune responses but were not specifically linked to alcohol consumption by previous research. Null mutant mice were tested for ethanol intake in three tests: 24-hour two-bottle choice, limited access two-bottle choice and limited access to one bottle of ethanol. Ethanol consumption and preference were reduced in all the null mutant mice in the 24-hour two-bottle choice test, the test that was the basis for selection of these genes. No major differences were observed in consumption of saccharin or quinine in the null mutant mice. Deletion of B2m, Ctss, Il1rn, Cd14 and Il6 also reduced ethanol consumption in the limited access two bottle choice test for ethanol intake; with the Il1rn and Ctss null mutants showing reduced intake in all three tests (with some variation between males and females). These results provide the most compelling evidence to date that global gene expression analysis can identify novel genetic determinants of complex behavioral traits. Specifically, they suggest a novel role for neuroimmune signaling in regulation of alcohol consumption.
authors.affiliation: Waggoner Center for Alcohol and Addiction Research, Section of Neurobiology and Department Pharmacology/Toxicology, University of Texas, Austin, USA. yablednov@mail.utexas.edu
authors.forename: Yuri A
authors.initials: YA
authors.lastname: Blednov
authors.forename: Igor
authors.initials: I
authors.lastname: Ponomarev
authors.forename: Chelsea
authors.initials: C
authors.lastname: Geil
authors.forename: Susan
authors.initials: S
authors.lastname: Bergeson
authors.forename: George F
authors.initials: GF
authors.lastname: Koob
authors.forename: R Adron
authors.initials: RA
authors.lastname: Harris
mesh_terms: D000428:Alcohol Drinking / Q000276:immunology*; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D056646:Cathepsin F / Q000235:genetics / Q000276:immunology; D002403:Cathepsins / Q000235:genetics* / Q000276:immunology; D002492:Central Nervous System Depressants / Q000008:administration & dosage / Q000276:immunology; D002755:Choice Behavior; D000431:Ethanol / Q000008:administration & dosage / Q000276:immunology; D005260:Female; D023281:Genomics / Q000379:methods; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics* / Q000276:immunology; D018950:Lipopolysaccharide Receptors / Q000235:genetics* / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015213:Neuroimmunomodulation / Q000235:genetics* / Q000276:immunology; D011803:Quinine / Q000008:administration & dosage; D012439:Saccharin / Q000008:administration & dosage; D001613:beta 2-Microglobulin / Q000235:genetics* / Q000276:immunology
chemical_list: D002492:Central Nervous System Depressants; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D018950:Lipopolysaccharide Receptors; D001613:beta 2-Microglobulin; D000431:Ethanol; D011803:Quinine; D002403:Cathepsins; C028217:cathepsin S; D056646:Cathepsin F; C534092:Ctsf protein, mouse; D012439:Saccharin