Deletion of Tlr3 reduces acute tolerance to alcohol and alcohol consumption in the intermittent access procedure in male mice

Abstract

Pharmacological studies implicate toll‐like receptor 3 (TLR3) signaling in alcohol drinking. We examined the role of TLR3 in behavioral responses to alcohol and GABAergic drugs by studying Tlr3 −/− mice. Because of opposing signaling between TLR3 and MyD88 pathways, we also evaluated Myd88 −/− mice. Ethanol consumption and preference decreased in male but not in female Tlr3 −/− mice during two‐bottle choice every‐other‐day (2BC‐EOD) drinking. There were no genotype differences in either sex during continuous or limited‐access drinking. Null mutations in Tlr3 or Myd88 did not alter conditioned taste aversion to alcohol and had small or no effects on conditioned place preference. The Tlr3 null mutation did not alter acute alcohol withdrawal. Male, but not female, Tlr3 −/− mice took longer than wild‐type littermates to recover from ataxia by ethanol or diazepam and longer to recover from sedative‐hypnotic effects of ethanol or gaboxadol, indicating regulation of GABAergic signaling by TLR3. Acute functional tolerance (AFT) to alcohol‐induced ataxia was decreased in Tlr3 −/− mice but was increased in Myd88 −/− mice. Thus, MyD88 and TLR3 pathways coordinately regulate alcohol consumption and tolerance to intoxicating doses of alcohol and GABAergic drugs. Despite similar alcohol metabolism and similar amounts of total alcohol consumed during 2BC and 2BC‐EOD procedures in C57BL/6J mice, only 2BC‐EOD drinking induced tolerance to alcohol‐induced ataxia. Ataxia recovery was inversely correlated with level of drinking in wild‐type and Tlr3 −/− littermates. Thus, deleting Tlr3 reduces alcohol consumption by reducing AFT to alcohol and not by altering tolerance induced by 2BC‐EOD drinking.

Toll-like receptor-mediated neuroinflammation: relevance for cognitive dysfunctions

“…Following ethanol intake, TLR2, TLR3, TLR4, and TLR7 expression increases in the mouse prefrontal cortex, another important area involved in cognitive function [69]. Ethanol-induced TLR3 activation increases the expression of inflammatory IL-1β, IL-6, and TNF in the hippocampus [70], as well as voluntary alcohol intake [71,72]. TLR2 and TLR4 knockout rodents are protected from ethanol-induced neuroinflammation [73],…”

Possible Mechanisms Underlying the Effects of Glucagon-Like Peptide-1 Receptor Agonist on Cocaine Use Disorder

“…Congruent with these findings, studies in animals demonstrated that TLR4 may have an essential and underappreciated role in reward-related behaviors induced by alcohol ( June et al, 2015 ), morphine ( Hutchinson et al, 2012 ), and cocaine ( Kashima and Grueter, 2017 ). In addition, the TLR3 and TLR2 signaling pathways were shown to increase cocaine consumption ( Blednov et al, 2017 ; Zhu et al, 2018 ; Blednov et al, 2020 ). Furthermore, cocaine alone is sufficient to upregulate the expression of other cytokines including NF-κβ ( Zhu et al, 2021 ), TNF-α ( Lewitus et al, 2016 ; Brown et al, 2018 ), IL-1β ( Northcutt et al, 2015 ), and IL-8 ( Meckel and Kiraly, 2019 ), which in turn enhances dopamine release and finally exaggerates the drugs-mediated behavioral response.…”

Increased alcohol self-administration following repeated Toll-like receptor 3 agonist treatment in male and female rats

“…Expression of TLR3 receptors is increased following alcohol intake (Warden et al, 2019a)and treatment with the TLR3 agonist polyinosinic:polycytadylic acid (poly(I:C)) increases alcohol intake in mice and rats (Qin and Crews, 2012;Randall et al, 2019;Warden et al, 2019a, b). Furthermore, genetic knockout of TLR3 not only decreases alcohol intake but also decreases acute tolerance to alcohol in male mice further suggesting an important role of TLR3 in both alcohol intake and physiological response to alcohol (Blednov et al, 2021).…”