Ethanol Consumption in Mice Lacking CD14, TLR2, TLR4, or MyD88.
Molecular and behavioral studies support a role for innate immune proinflammatory pathways in mediating the effects of alcohol. Increased levels of Toll-like receptors (TLRs) have been observed in animal models of alcohol consumption and in human alcoholics, and many of these TLRs signal via the MyD88-dependent pathway. We hypothesized that this pathway is involved in alcohol drinking and examined some of its key signaling components.



Different ethanol (EtOH)-drinking paradigms were studied in male and female control C57BL/6J mice versus mice lacking CD14, TLR2, TLR4 (C57BL/10ScN), or MyD88. We studied continuous and intermittent access 2-bottle choice (2BC) and 1-bottle and 2BC drinking-in-the-dark (DID) tests as well as preference for saccharin, quinine, and NaCl.



In the 2BC continuous access test, EtOH intake decreased in male TLR2 knockout (KO) mice, and we previously reported reduced 2BC drinking in male and female CD14 KO mice. In the intermittent access 2BC test, EtOH intake decreased in CD14 KO male and female mice, whereas drinking increased in MyD88 KO male mice. In the 2BC-DID test, EtOH drinking decreased in male and female mice lacking TLR2, whereas drinking increased in MyD88 KO male mice. In the 1-bottle DID test, EtOH intake decreased in female TLR2 KO mice. TLR2 KO and CD14 KO mice did not differ in saccharin preference but showed reduced preference for NaCl. MyD88 KO mice showed a slight reduction in preference for saccharin.



Deletion of key components of the MyD88-dependent pathway produced differential effects on EtOH intake by decreasing (TLR2 KO and CD14 KO) or increasing (MyD88 KO) drinking, while deletion of TLR4 had no effect. Some of the drinking effects depended on the sex of the mice and/or the EtOH-drinking model.
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.
Julia
J
Chernis
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
D000428:Alcohol Drinking / Q000378:metabolism*; D000818:Animals; D002755:Choice Behavior / Q000187:drug effects / Q000502:physiology; D000431:Ethanol / Q000008:administration & dosage*; D005260:Female; D018950:Lipopolysaccharide Receptors / Q000172:deficiency*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency*; D012737:Sex Factors; D051195:Toll-Like Receptor 2 / Q000172:deficiency*; D051197:Toll-Like Receptor 4 / Q000172:deficiency*
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
2-Bottle Choice and Drinking-in-the-Dark; CD14 KO; MyD88 KO; TLR2 KO; TLR4-Deficient (C57BL/10ScN) Mice