title: Role of interleukin-1 receptor signaling in the behavioral effects of ethanol and benzodiazepines.
abstract: Gene expression studies identified the interleukin-1 receptor type I (IL-1R1) as part of a pathway associated with a genetic predisposition to high alcohol consumption, and lack of the endogenous IL-1 receptor antagonist (IL-1ra) strongly reduced ethanol intake in mice. Here, we compared ethanol-mediated behaviors in mice lacking Il1rn or Il1r1. Deletion of Il1rn (the gene encoding IL-1ra) increases sensitivity to the sedative/hypnotic effects of ethanol and flurazepam and reduces severity of acute ethanol withdrawal. Conversely, deletion of Il1r1 (the gene encoding the IL-1 receptor type I, IL-1R1) reduces sensitivity to the sedative effects of ethanol and flurazepam and increases the severity of acute ethanol withdrawal. The sedative effects of ketamine and pentobarbital were not altered in the knockout (KO) strains. Ethanol intake and preference were not changed in mice lacking Il1r1 in three different tests of ethanol consumption. Recovery from ethanol-induced motor incoordination was only altered in female mice lacking Il1r1. Mice lacking Il1rn (but not Il1r1) showed increased ethanol clearance and decreased ethanol-induced conditioned taste aversion. The increased ethanol- and flurazepam-induced sedation in Il1rn KO mice was decreased by administration of IL-1ra (Kineret), and pre-treatment with Kineret also restored the severity of acute ethanol withdrawal. Ethanol-induced sedation and withdrawal severity were changed in opposite directions in the null mutants, indicating that these responses are likely regulated by IL-1R1 signaling, whereas ethanol intake and preference do not appear to be solely regulated by this pathway.
authors.affiliation: Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, TX 78712, USA.
authors.forename: Yuri A
authors.initials: YA
authors.lastname: Blednov
authors.affiliation: Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, TX 78712, USA.
authors.forename: Jillian M
authors.initials: JM
authors.lastname: Benavidez
authors.affiliation: Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, TX 78712, USA.
authors.forename: Mendy
authors.initials: M
authors.lastname: Black
authors.affiliation: Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, TX 78712, USA.
authors.forename: Jody
authors.initials: J
authors.lastname: Mayfield
authors.affiliation: Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, TX 78712, USA. Electronic address: harris@austin.utexas.edu.
authors.forename: R Adron
authors.initials: RA
authors.lastname: Harris
mesh_terms: D000428:Alcohol Drinking / Q000378:metabolism; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D001569:Benzodiazepines / Q000494:pharmacology*; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D005479:Flurazepam / Q000494:pharmacology; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D007649:Ketamine / Q000494:pharmacology; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D010424:Pentobarbital / Q000494:pharmacology; D053573:Receptors, Interleukin-1 Type I / Q000235:genetics / Q000378:metabolism*; D012720:Severity of Illness Index; D013375:Substance Withdrawal Syndrome / Q000378:metabolism; D055697:Taste Perception / Q000187:drug effects / Q000502:physiology
chemical_list: D006993:Hypnotics and Sedatives; C583355:IL1R1 protein, mouse; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D053573:Receptors, Interleukin-1 Type I; D001569:Benzodiazepines; D000431:Ethanol; D007649:Ketamine; D010424:Pentobarbital; D005479:Flurazepam
keywords: Alcohol withdrawal; Anakinra; Conditioned taste aversion; Drinking in the dark; Flurazepam; IL-1R1; IL-1ra; Il1r1; Il1rn; Kineret; Knockout mice; Loss of righting reflex; Two-bottle choice
references.citation: Brain Behav Immun. 2013 Jul;31:31-47
references.pmid: 22580182
references.citation: Physiol Behav. 2001 Sep 1-15;74(1-2):109-17
references.pmid: 11564458
references.citation: J Pharmacol Exp Ther. 1991 May;257(2):663-7
references.pmid: 2033513
references.citation: Neuropharmacology. 2013 Apr;67:46-56
references.pmid: 23147414
references.citation: Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):11008-13
references.pmid: 8855299
references.citation: J Periodontal Res. 2013 Dec;48(6):748-56
references.pmid: 23586622
references.citation: J Pharmacol Exp Ther. 2003 Jun;305(3):854-63
references.pmid: 12626647
references.citation: J Neurochem. 2004 Sep;90(5):1050-8
references.pmid: 15312160
references.citation: Pharmacogenet Genomics. 2009 Nov;19(11):869-76
references.pmid: 19801958
references.citation: Brain Behav Immun. 2011 Jun;25 Suppl 1:S155-64
references.pmid: 21276848
references.citation: Proc Natl Acad Sci U S A. 2014 Jun 3;111(22):8263-8
references.pmid: 24830427
references.citation: Alcohol Alcohol. 2005 May-Jun;40(3):181-6
references.pmid: 15797878
references.citation: Adv Pharmacol. 2006;54:171-203
references.pmid: 17175815
references.citation: J Biol Chem. 2012 Nov 23;287(48):40224-31
references.pmid: 23038269
references.citation: Neurosci Biobehav Rev. 1987 Spring;11(1):107-30
references.pmid: 3554039
references.citation: Mamm Genome. 1998 Dec;9(12):983-90
references.pmid: 9880664
references.citation: J Exp Med. 1998 May 4;187(9):1463-75
references.pmid: 9565638
references.citation: J Neurosci. 1997 Jul 1;17(13):5129-35
references.pmid: 9185550
references.citation: Nature. 1999 Oct 21;401(6755):796-800
references.pmid: 10548105
references.citation: Nat Methods. 2014 Jun;11(6):629-32
references.pmid: 24776635
references.citation: J Biol Chem. 2006 May 26;281(21):14632-43
references.pmid: 16567807
references.citation: Biochem Pharmacol. 2004 Oct 15;68(8):1581-602
references.pmid: 15451402
references.citation: Proc Natl Acad Sci U S A. 2006 Apr 18;103(16):6368-73
references.pmid: 16618939
references.citation: Behav Neurosci. 1997 Feb;111(1):129-36
references.pmid: 9109631
references.citation: Psychopharmacology (Berl). 1998 Sep;139(1-2):145-53
references.pmid: 9768552
references.citation: J Clin Invest. 2012 Oct;122(10):3476-89
references.pmid: 22945633
references.citation: Addict Biol. 2012 Jan;17(1):108-20
references.pmid: 21309947
references.citation: Cell Rep. 2012 Sep 27;2(3):488-96
references.pmid: 22999935
references.citation: Psychopharmacology (Berl). 2009 Sep;205(4):529-64
references.pmid: 19455309
references.citation: J Neurosci. 2014 Feb 12;34(7):2618-31
references.pmid: 24523551
references.citation: Physiol Behav. 2005 Jan 31;84(1):53-63
references.pmid: 15642607
references.citation: Mol Pharmacol. 2007 Mar;71(3):852-9
references.pmid: 17164405
references.citation: Brain Behav Immun. 2011 Jun;25 Suppl 1:S4-S12
references.pmid: 21402143
references.citation: Genes Brain Behav. 2010 Oct;9(7):768-76
references.pmid: 20608999
references.citation: Brain Behav Immun. 2008 Aug;22(6):797-803
references.pmid: 18495419
references.citation: J Immunol. 1997 Oct 1;159(7):3364-71
references.pmid: 9317135
references.citation: Addict Biol. 2006 Sep;11(3-4):195-269
references.pmid: 16961758
references.citation: Curr Opin Neurobiol. 2013 Aug;23(4):513-20
references.pmid: 23434064
references.citation: Science. 1974 Sep 6;185(4154):824-31
references.pmid: 11785521
references.citation: Eur J Neurosci. 2007 Oct;26(7):1862-9
references.pmid: 17868373
references.citation: Behav Brain Res. 2014 Oct 1;272:46-54
references.pmid: 24933191
references.citation: Alcohol. 2008 Feb;42(1):1-11
references.pmid: 18164576
references.citation: J Neurosci. 2006 May 24;26(21):5673-83
references.pmid: 16723524
references.citation: Brain Behav Immun. 2011 Jun;25 Suppl 1:S92-S105
references.pmid: 21266194
references.citation: J Immunol. 1997 Sep 1;159(5):2452-61
references.pmid: 9278338
references.citation: Brain Behav Immun. 2015 Mar;45:189-97
references.pmid: 25479427
references.citation: PLoS One. 2013;8(8):e70945
references.pmid: 23951048
references.citation: Ann Rheum Dis. 2000 Nov;59 Suppl 1:i60-4
references.pmid: 11053091