Toll-like receptor 3 activation increases voluntary alcohol intake in C57BL/6J male mice

Anna S. Warden, Moatasem Azzam, Adriana DaCosta, Sonia Mason, Yuri A. Blednov, Robert O Messing, R. Dayne Mayfield, R A Harris

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Many genes differentially expressed in brain tissue from human alcoholics and animals that have consumed large amounts of alcohol are components of the innate immune toll-like receptor (TLR) pathway. TLRs initiate inflammatory responses via two branches: (1) MyD88-dependent or (2) TRIF-dependent. All TLRs signal through MyD88 except TLR3. Prior work demonstrated a direct role for MyD88-dependent signaling in regulation of alcohol consumption. However, the role of TLR3 as a potential regulator of excessive alcohol drinking has not previously been investigated. To test the possibility TLR3 activation regulates alcohol consumption, we injected mice with the TLR3 agonist polyinosinic:polycytidylic acid (poly(I:C)) and tested alcohol consumption in an every-other-day two-bottle choice test. Poly(I:C) produced a persistent increase in alcohol intake that developed over several days. Repeated poly(I:C) and ethanol exposure altered innate immune transcript abundance; increased levels of TRIF-dependent pathway components correlated with increased alcohol consumption. Administration of poly(I:C) before exposure to alcohol did not alter alcohol intake, suggesting that poly(I:C) and ethanol must be present together to change drinking behavior. To determine which branch of TLR signaling mediates poly(I:C)-induced changes in drinking behavior, we tested either mice lacking MyD88 or mice administered a TLR3/dsRNA complex inhibitor. MyD88 null mutants showed poly(I:C)-induced increases in alcohol intake. In contrast, mice pretreated with a TLR3/dsRNA complex inhibitor reduced their alcohol intake, suggesting poly(I:C)-induced escalations in alcohol intake are, at least partially, dependent on TLR3. Together, these results strongly suggest that TLR3-dependent signaling drives excessive alcohol drinking behavior.

Original languageEnglish (US)
Pages (from-to)55-65
Number of pages11
JournalBrain, Behavior, and Immunity
Volume77
DOIs
StatePublished - Mar 1 2019

Fingerprint

Toll-Like Receptor 3
Poly I-C
Alcohol Drinking
Alcohols
Drinking Behavior
Toll-Like Receptors
Ethanol
Alcoholics
Brain

Keywords

  • Alcohol use disorder
  • Cytokines
  • Drinking
  • Ethanol
  • Neuroimmune
  • Poly(I:C)
  • Toll-like receptors

ASJC Scopus subject areas

  • Immunology
  • Endocrine and Autonomic Systems
  • Behavioral Neuroscience

Cite this

Toll-like receptor 3 activation increases voluntary alcohol intake in C57BL/6J male mice. / Warden, Anna S.; Azzam, Moatasem; DaCosta, Adriana; Mason, Sonia; Blednov, Yuri A.; Messing, Robert O; Mayfield, R. Dayne; Harris, R A.

In: Brain, Behavior, and Immunity, Vol. 77, 01.03.2019, p. 55-65.

Research output: Contribution to journalArticle

Warden, Anna S. ; Azzam, Moatasem ; DaCosta, Adriana ; Mason, Sonia ; Blednov, Yuri A. ; Messing, Robert O ; Mayfield, R. Dayne ; Harris, R A. / Toll-like receptor 3 activation increases voluntary alcohol intake in C57BL/6J male mice. In: Brain, Behavior, and Immunity. 2019 ; Vol. 77. pp. 55-65.
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