title: Inhibiting the TLR4-MyD88 signalling cascade by genetic or pharmacological strategies reduces acute alcohol-induced sedation and motor impairment in mice.
abstract: OBJECTIVE
  Emerging evidence implicates a role for toll-like receptor 4 (TLR4) in the CNS effects of alcohol. The aim of the current study was to determine whether TLR4-MyD88-dependent signalling is involved in the acute behavioural actions of alcohol and if alcohol can activate TLR4-downstream MAPK and NF-κB pathways.
  
  
  METHODS
  The TLR4 pathway was evaluated using the TLR4 antagonist (+)-naloxone (µ-opioid receptor-inactive isomer) and mice with null mutations in the TLR4 and MyD88 genes. Sedation and motor impairment induced by a single dose of alcohol were assessed by loss of righting reflex (LORR) and rotarod tests, separately. The phosphorylation of JNK, ERK and p38, and levels of IκBα were measured to determine the effects of acute alcohol exposure on MAPK and NF-κB signalling.
  
  
  RESULTS
  After a single dose of alcohol, both pharmacological inhibition of TLR4 signalling with (+)-naloxone and genetic deficiency of TLR4 or MyD88 significantly (P < 0.0001) reduced the duration of LORR by 45-78% and significantly decreased motor impairment recovery time to 62-88% of controls. These behavioural actions were not due to changes in the peripheral or central alcohol pharmacokinetics. IκBα levels responded to alcohol by 30 min in mixed hippocampal cell samples, from wild-type mice, but not in cells from TLR4- or MyD88-deficient mice.
  
  
  CONCLUSIONS
  These data provide new evidence that TLR4-MyD88 signalling is involved in the acute behavioural actions of alcohol in mice.
authors.affiliation: Discipline of Pharmacology, School of Medical Sciences, University of Adelaide, South Australia, 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: Janet K
authors.initials: JK
authors.lastname: Coller
authors.forename: Kenner C
authors.initials: KC
authors.lastname: Rice
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: D000818:Animals; D000431:Ethanol / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D020672:I-kappa B Proteins / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009046:Motor Neurons / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D009154:Mutation; D053594:Myeloid Differentiation Factor 88 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D009270:Naloxone / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D006993:Hypnotics and Sedatives; D020672:I-kappa B Proteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D000072000:NF-KappaB Inhibitor alpha; D009270:Naloxone; D000431:Ethanol; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases