Ethanol Consumption in Mice Lacking CD14, TLR2, TLR4, or MyD88

Abstract

Background 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. Methods Different ethanol drinking paradigms were studied in male and female control C57BL/6J mice vs. mice lacking CD14, TLR2, TLR4 (C57BL/10ScN), or MyD88. We studied continuous and intermittent access two-bottle choice (2BC) and one-bottle and 2BC drinking-in-the-dark (DID) tests as well as preference for saccharin, quinine, and NaCl. Results In the 2BC continuous access test, ethanol 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, ethanol intake decreased in CD14 KO male and female mice, whereas drinking increased in MyD88 KO male mice. In the 2BC-DID test, ethanol drinking decreased in male and female mice lacking TLR2, whereas drinking increased in MyD88 KO male mice. In the one-bottle DID test, ethanol 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. Conclusions Deletion of key components of the MyD88-dependent pathway produced differential effects on ethanol 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 ethanol-drinking model.

Chronic ethanol consumption: role of TLR3/TRIF‐dependent signaling

“…It is important to note that inhibition of TLR4 signaling does not reduce alcohol consumption emphasizing the importance of the TLR3/TRIF pathway (Harris et al . 2016; Blednov et al . 2017).…”

Glial mechanisms underlying substance use disorders

“…Indeed, alcohol self‐administration increases expression of the TLR4 protein in the VTA of alcohol‐preferring rats (June et al ., ). Mice lacking the TLR4 protein or the TLR4 adaptor protein, MyD88, display lower sensitivity to the sedative and motor‐impairing effects of alcohol compared to wild‐type mice (Wu et al ., ; Harris et al ., ), whereas MYD88 knockout increases ethanol consumption (Blednov et al ., ). TLR4 activation in the VTA and central amygdala, in particular, may be an important signal for binge alcohol consumption, as site‐selective knockdown of TLR4 in these regions using siRNA reduces binge drinking in alcohol‐preferring rats (Liu et al ., ; June et al ., ).…”

“…TLR4 activation in the VTA and central amygdala, in particular, may be an important signal for binge alcohol consumption, as site‐selective knockdown of TLR4 in these regions using siRNA reduces binge drinking in alcohol‐preferring rats (Liu et al ., ; June et al ., ). Furthermore, genetic knockout of TLR2 or CD14, suppresses ethanol intake (Blednov et al ., ). In contrast, some have reported no effect of pharmacological or genetic manipulation of TLR4 on excessive alcohol consumption in the two‐bottle choice, drinking‐in‐the‐dark, or chronic intermittent access paradigms (Blednov et al ., ; Harris et al ., ).…”

“…Furthermore, genetic knockout of TLR2 or CD14, suppresses ethanol intake (Blednov et al ., ). In contrast, some have reported no effect of pharmacological or genetic manipulation of TLR4 on excessive alcohol consumption in the two‐bottle choice, drinking‐in‐the‐dark, or chronic intermittent access paradigms (Blednov et al ., ; Harris et al ., ). Blednov et al .…”

“…Blednov et al . () demonstrated that TLR4 mutant mice have unaltered alcohol consumption behavior. However, Blednov et al .…”