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

Toll-like receptor (TLR) signaling may play an important role in the neuroimmune system's involvement in the development and maintenance of alcohol use disorder (AUD). In the present study we administered the TLR3 agonist poly(I:C) in male and female Long-Evans rats to determine whether TLR3 agonism can increase alcohol consumption on a daily 15% alcohol operant self-administration paradigm. We found few effects when poly(I:C) was given every-other-day at 0.3 or 1.0 mg/kg. However, when 1.0 mg/kg was given on consecutive days, alcohol intake increased in the days following injections specifically in females. In a second experiment, we found that this effect only emerged when rats had a history of multiple poly(I:C) injections. In the final exper-iment the poly(I:C) dose was increased to 3.0 mg/kg on consecutive days which resulted in significant reductions in alcohol intake on injection days in females that were not accompanied by subsequent increases. The poly(I:C) dose was increased to 9.0 mg/kg for one final pair of injections which led to reductions in intake in both males and females followed by a male specific delayed increase in alcohol intake. Overall, repeated poly(I:C) admin-istration was able to increase subsequent alcohol consumption in both sexes, with females showing an increase at a lower dose than males. These findings support TLR3 agonism in contributing to increased alcohol consumption and add to the body of work identifying the neuroimmune system as a potential therapeutic target for AUD.