Genetic and pharmacologic manipulation of TLR4 has minimal impact on ethanol consumption in rodents

R. Adron Harris*, Michal Bajo, Richard L. Bell, Yuri A. Blednov, Florence P. Varodayan, Jay M. Truitt, Giordano de Guglielmo, Amy W. Lasek, Marian L. Logrip, Leandro F. Vendruscolo, Amanda J. Roberts, Edward Roberts, Olivier George, Jody Mayfield, Timothy R. Billiar, David J. Hackam, R. Dayne Mayfield, George F. Koob, Marisa Roberto, Gregg E. Homanics

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

60 Scopus citations


Toll-like receptor 4 (TLR4) is a critical component of innate immune signaling and has been implicated in alcohol responses in preclinical and clinical models. Members of the Integrative Neuroscience Initiative on Alcoholism (INIA-Neuroimmune) consortium tested the hypothesis that TLR4 mediates excessive ethanol drinking using the following models: (1) Tlr4 knock-out (KO) rats, (2) selective knockdown of Tlr4 mRNA in mouse nucleus accumbens (NAc), and (3) injection of the TLR4 antagonist (+)-naloxone in mice. Lipopolysaccharide (LPS) decreased food/water intake and body weight in ethanol-naive and ethanol-trained wild-type (WT), but not Tlr4 KO rats. There were no consistent genotypic differences in two-bottle choice chronic ethanol intake or operant self-administration in rats before or after dependence. In mice, (+)-naloxone did not decrease drinking-in-the-dark and only modestly inhibited dependence-driven consumption at the highest dose. Tlr4 knockdown in mouse NAc did not decrease drinking in the two-bottle choice continuous or intermittent access tests. However, the latency to ethanol-induced loss of righting reflex increased and the duration decreased in KO versus WT rats. In rat central amygdala neurons, deletion of Tlr4 altered GABAA receptor function, but not GABA release. Although there were no genotype differences in acute ethanol effects before or after chronic intermittent ethanol exposure, genotype differences were observed after LPS exposure. Using different species and sexes, different methods to inhibit TLR4 signaling, and different ethanol consumption tests, our comprehensive studies indicate that TLR4 may play a role in ethanol-induced sedation and GABAA receptor function, but does not regulate excessive drinking directly and would not be an effective therapeutic target.

Original languageEnglish
Pages (from-to)1139-1155
Number of pages17
JournalJournal of Neuroscience
Issue number5
StatePublished - 1 Feb 2017
Externally publishedYes


  • (+)-naloxone
  • Chronic intermittent ethanol vapor
  • Drinking-in-the-dark
  • Lipopolysaccharide
  • Operant self-administration
  • Toll-like receptor 4 knock-out


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