Inhibiting the TLR4-MyD88 signalling cascade by genetic or pharmacological strategies reduces acute alcohol-induced sedation and motor impairment in mice

Authors

  • Yue Wu,

    1. Discipline of Pharmacology, School of Medical Sciences, University of Adelaide, South Australia, Australia
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  • Erin L Lousberg,

    1. Hanson Institute, SA Pathology, South Australia, Australia
    2. Sansom Institute, School of Pharmacy and Medical Science, University of South Australia, South Australia, Australia
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  • Lachlan M Moldenhauer,

    1. Research Centre for Reproductive Health, School of Paediatric and Reproductive Health, University of Adelaide, South Australia, Australia
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  • John D Hayball,

    1. Hanson Institute, SA Pathology, South Australia, Australia
    2. Sansom Institute, School of Pharmacy and Medical Science, University of South Australia, South Australia, Australia
    3. School of Medicine, University of Adelaide, South Australia, Australia
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  • Janet K Coller,

    1. Discipline of Pharmacology, School of Medical Sciences, University of Adelaide, South Australia, Australia
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  • Kenner C Rice,

    1. Chemical Biology Research Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism National Institutes of Health, Rockville, Maryland, USA
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  • Linda R Watkins,

    1. Department of Psychology and Neuroscience and The Center for Neuroscience, University of Colorado at Boulder, Boulder, Colorado, USA
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  • Andrew A Somogyi,

    1. Discipline of Pharmacology, School of Medical Sciences, University of Adelaide, South Australia, Australia
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  • Mark R Hutchinson

    Corresponding author
    1. Discipline of Pharmacology, School of Medical Sciences, University of Adelaide, South Australia, Australia
    2. Discipline of Physiology, School of Medical Sciences, University of Adelaide, South Australia, Australia
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Mark R Hutchinson, Discipline of Physiology, School of Medical Sciences, University of Adelaide, Adelaide, Australia. E-mail: mark.hutchinson@adelaide.edu.au

Abstract

BACKGROUND AND PURPOSE 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.

EXPERIMENTAL APPROACH 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.

KEY 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 AND IMPLICATIONS These data provide new evidence that TLR4–MyD88 signalling is involved in the acute behavioural actions of alcohol in mice.

LINKED ARTICLE This article is commented on by Pandey, pp. 1316–1318 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2011.01695.x

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