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

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 function are, at least partially, dependent on TLR3. Together, these results strongly suggest that TLR3-dependent signaling drives excessive alcohol drinking behavior.HighlightsActivation of TLR3 via poly(I:C) increased alcohol intake.Poly(I:C) and ethanol must be present together to change drinking behavior.Increased alcohol intake due to poly(I:C) is independent of MYD88.Increased alcohol intake due to poly(I:C) is dependent on TLR3.

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“…In turn, these cytokines and chemokines can lead to peripheral lymphocyte translocation across the blood-brain barrier (BBB) and further CNS inflammation. [65][66][67][68] Alcohol also modulates the adaptive immune system in a dose-dependent manner. Chronic moderate alcohol consumption leads to T and B cell activation and proliferation, 69 while chronic heavy consumption is associated with T and B cell depletion and apoptosis as well as an increase in immunoglobulins.…”