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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.
AuthorsYuri A Blednov, Jillian M Benavidez, Mendy Black, Jody Mayfield, R Adron Harris
JournalNeuropharmacology (Neuropharmacology) Vol. 95 Pg. 309-20 (Aug 2015) ISSN: 1873-7064 [Electronic] England
PMID25839897 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
CopyrightCopyright © 2015 Elsevier Ltd. All rights reserved.
Chemical References
  • Hypnotics and Sedatives
  • IL1R1 protein, mouse
  • Il1rn protein, mouse
  • Interleukin 1 Receptor Antagonist Protein
  • Receptors, Interleukin-1 Type I
  • Benzodiazepines
  • Ethanol
  • Ketamine
  • Pentobarbital
  • Flurazepam
Topics
  • Alcohol Drinking (metabolism)
  • Animals
  • Avoidance Learning (drug effects, physiology)
  • Behavior, Animal (drug effects, physiology)
  • Benzodiazepines (pharmacology)
  • Ethanol (pharmacology)
  • Female
  • Flurazepam (pharmacology)
  • Hypnotics and Sedatives (pharmacology)
  • Interleukin 1 Receptor Antagonist Protein (genetics, metabolism, pharmacology)
  • Ketamine (pharmacology)
  • Male
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Motor Activity (drug effects, physiology)
  • Pentobarbital (pharmacology)
  • Receptors, Interleukin-1 Type I (genetics, metabolism)
  • Severity of Illness Index
  • Substance Withdrawal Syndrome (metabolism)
  • Taste Perception (drug effects, physiology)

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