Emerging evidence implicates a role for toll-like receptor 4 (TLR4) in the central nervous system effects of alcohol. The current study aimed to determine whether TLR4-MyD88-dependent signalling was involved in the acute behavioural actions of alcohol and if alcohol could activate TLR4-downstream MAPK and NFκB pathways.
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 NFκB signalling.
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 (p < 0.05) 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.
These data provide new evidence that TLR4-MyD88 signalling is involved in the acute behavioural actions of alcohol in mice.
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