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Published on: April 15, 2015
Sedative and Motor Incoordination Effects of Ethanol in Mice Lacking CD14, TLR2, TLR4, or MyD88
Yuri A Blednov1, Mendy Black1, Jillian M Benavidez1
1Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, Texas.
Background:
In our companion article, we examined the role of MyD88-dependent signaling in ethanol (EtOH) consumption in mice lacking key components of this inflammatory pathway and observed differential effects on drinking. Here, we studied the role of these same signaling components in the acute sedative, intoxicating, and physiological effects of EtOH. Toll-like receptor 4 (TLR4) has been reported to strongly reduce the duration of EtOH-induced sedation, although most studies do not support its direct involvement in EtOH consumption. We examined TLR4 and other MyD88 pathway molecules to determine signaling specificity in acute EtOH-related behaviors. We also studied other GABAergic sedatives to gauge the EtOH specificity and potential role for GABA in EtOH's sedative and intoxicating effects in the mutant mice.
Methods:
Loss of righting reflex (LORR) and recovery from motor incoordination were studied following acute injection of EtOH or other sedative drugs in male and female control C57BL/6J mice versus mice lacking CD14, TLR2, TLR4 (C57BL/10ScN), or MyD88. We also examined EtOH-induced hypothermia and blood EtOH clearance in these mice.
Results:
Male and female mice lacking TLR4 or MyD88 showed reduced duration of EtOH-induced LORR and faster recovery from EtOH-induced motor incoordination in the rotarod test. MyD88 knockout mice had slightly faster recovery from EtOH-induced hypothermia compared to control mice. None of the mutants differed from control mice in the rate of blood EtOH clearance. All of the mutants showed similar decreases in the duration of gaboxadol-induced LORR, but only mice lacking TLR4 were less sensitive to the sedative effects of pentobarbital. Faster recovery from diazepam-induced motor impairment was observed in CD14, TLR4, and MyD88 null mice of both sexes.
Conclusions:
TLR4 and MyD88 were key mediators of the sedative and intoxicating effects of EtOH and GABAergic sedatives, indicating a strong influence of TLR4-MyD88 signaling on GABAergic function. Despite the involvement of TLR4 in EtOH's acute behaviors, it did not regulate EtOH consumption in any drinking model as shown in our companion article. Collectively, our studies demonstrate differential effects of TLR-MyD88 components in the acute versus chronic actions of EtOH.
Insights
Toll-like receptor 4 (TLR4) and MyD88 signaling mediate acute sedative and intoxicating effects of alcohol (ethanol). This pathway influences GABAergic function but not alcohol consumption, highlighting distinct roles in acute versus chronic alcohol actions.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- MyD88-dependent signaling pathways influence ethanol (EtOH) consumption.
- Toll-like receptor 4 (TLR4) may reduce EtOH-induced sedation duration but not consumption.
- Investigating TLR4 and MyD88 pathway roles in acute EtOH effects and other sedatives is crucial for understanding signaling specificity.
Purpose of the Study:
- To determine the role of TLR4 and MyD88 signaling in the acute sedative and intoxicating effects of EtOH.
- To assess the specificity of EtOH's effects compared to other GABAergic sedatives.
- To elucidate the influence of TLR4-MyD88 signaling on GABAergic function.
Main Methods:
- Studied loss of righting reflex (LORR) and motor coordination recovery after acute EtOH or sedative drug administration.
- Utilized knockout mice lacking CD14, TLR2, TLR4, or MyD88.
- Assessed EtOH-induced hypothermia and blood EtOH clearance rates.
Main Results:
- Mice lacking TLR4 or MyD88 exhibited reduced EtOH-induced LORR duration and faster motor coordination recovery.
- MyD88 knockout mice showed slightly faster recovery from EtOH-induced hypothermia.
- All mutants displayed similar EtOH blood clearance rates; TLR4 and MyD88 were key mediators of EtOH and GABAergic sedative effects.
Conclusions:
- TLR4 and MyD88 are critical mediators of acute EtOH sedative and intoxicating effects, impacting GABAergic function.
- TLR4's role in acute EtOH behaviors does not extend to regulating EtOH consumption.
- These findings reveal differential roles for TLR-MyD88 components in acute versus chronic EtOH actions.
