Inhibiting the TLR4-MyD88 signalling cascade by genetic or pharmacological strategies reduces acute alcohol-induced sedation and motor impairment in mice
Version of Record online: 10 FEB 2012
© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society
British Journal of Pharmacology
Volume 165, Issue 5, pages 1319–1329, March 2012
How to Cite
Wu, Y., Lousberg, E. L., Moldenhauer, L. M., Hayball, J. D., Coller, J. K., Rice, K. C., Watkins, L. R., Somogyi, A. A. and Hutchinson, M. R. (2012), Inhibiting the TLR4-MyD88 signalling cascade by genetic or pharmacological strategies reduces acute alcohol-induced sedation and motor impairment in mice. British Journal of Pharmacology, 165: 1319–1329. doi: 10.1111/j.1476-5381.2011.01572.x
- Issue online: 10 FEB 2012
- Version of Record online: 10 FEB 2012
- Accepted manuscript online: 28 SEP 2011 09:26PM EST
- Received; 1 April 2011; Revised; 7 June 2011; Accepted; 9 June 2011
- loss of righting reflex;
- motor impairment;
- mice studies
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