title: Attenuation of microglial and IL-1 signaling protects mice from acute alcohol-induced sedation and/or motor impairment.
abstract: Alcohol-induced proinflammatory central immune signaling has been implicated in the chronic neurotoxic actions of alcohol, although little work has examined if these non-neuronal actions contribute to the acute behavioral responses elicited by alcohol administration. The present study examined if acute alcohol-induced sedation (loss of righting reflex, sleep time test) and motor impairment (rotarod test) were influenced by acute alcohol-induced microglial-dependent central immune signaling. Inhibition of acute alcohol-induced central immune signaling, through the reduction of proinflammatory microglial activation with minocycline, or by blocking interleukin-1 (IL-1) receptor signaling using IL-1 receptor antagonist (IL-1ra), reduced acute alcohol-induced sedation in mice. Mice treated with IL-1ra recovered faster from acute alcohol-induced motor impairment than control animals. However, minocycline led to greater motor impairment induced by alcohol, implicating different mechanisms in alcohol-induced sedation and motor impairment. At a cellular level, IκBα protein levels in mixed hippocampal cells responded rapidly to alcohol in a time-dependent manner, and both minocycline and IL-1ra attenuated the elevated levels of IκBα protein by alcohol. Collectively these data suggest that alcohol is capable of rapid modification of proinflammatory immune signaling in the brain and this contributes significantly to the pharmacology of alcohol.
authors.affiliation: Discipline of Pharmacology, School of Medical Sciences, University of Adelaide, SA, Australia.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wu
authors.forename: Erin L
authors.initials: EL
authors.lastname: Lousberg
authors.forename: Lachlan M
authors.initials: LM
authors.lastname: Moldenhauer
authors.forename: John D
authors.initials: JD
authors.lastname: Hayball
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Robertson
authors.forename: Janet K
authors.initials: JK
authors.lastname: Coller
authors.forename: Linda R
authors.initials: LR
authors.lastname: Watkins
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Somogyi
authors.forename: Mark R
authors.initials: MR
authors.lastname: Hutchinson
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D008911:Minocycline / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D053573:Receptors, Interleukin-1 Type I / Q000037:antagonists & inhibitors / Q000378:metabolism; D057897:Reflex, Righting / Q000187:drug effects / Q000502:physiology; D045442:Rotarod Performance Test; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D012890:Sleep / Q000187:drug effects / Q000502:physiology
chemical_list: D007375:Interleukin-1; D053573:Receptors, Interleukin-1 Type I; D000431:Ethanol; D008911:Minocycline