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.