Sedative and Motor Incoordination Effects of Ethanol in Mice Lacking CD14, TLR2, TLR4, or MyD88.
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.



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.



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.



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.
Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, Texas.
Yuri A
YA
Blednov
Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, Texas.
Mendy
M
Black
Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, Texas.
Jillian M
JM
Benavidez
Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, Texas.
Adriana
A
Da Costa
Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, Texas.
Jody
J
Mayfield
Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, Texas.
R Adron
RA
Harris
D000818:Animals; D000431:Ethanol / Q000008:administration & dosage*; D005260:Female; D018757:GABA Modulators / Q000008:administration & dosage; D006993:Hypnotics and Sedatives / Q000008:administration & dosage; D018950:Lipopolysaccharide Receptors / Q000172:deficiency*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency*; D057897:Reflex, Righting / Q000187:drug effects* / Q000502:physiology; D045442:Rotarod Performance Test / Q000379:methods; D051195:Toll-Like Receptor 2 / Q000172:deficiency*; D051197:Toll-Like Receptor 4 / Q000172:deficiency*
D018757:GABA Modulators; D006993:Hypnotics and Sedatives; D018950:Lipopolysaccharide Receptors; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D000431:Ethanol
CD14 KO; Loss of Righting Reflex and Motor Incoordination; MyD88 KO; TLR2 KO; TLR4-Deficient (C57BL/10ScN) Mice