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

Abstract

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. In the present study we administered TLR3 agonist poly(I:C) in male and female Long-Evans rats to determine whether TLR3 agonism can increase alcohol consumption in 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 instead 1.0 mg/kg was given on consecutive days alcohol intake increased in the days following injections specifically in females. Furthermore, 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 experiment the dose was increased to 3.0 mg/kg on consecutive days which resulted in significant reductions on injection days in females that were not accompanied by subsequent increases. The dose was increased to 9 mg/kg for one final pair of injections which led to reductions in intake in both males and females but only increased subsequent alcohol consumption in males. Overall, poly(I:C) was able to increase subsequent alcohol consumption in both sexes, with females being sensitive to lower doses than males both in terms of changes in alcohol consumption and general locomotor reduction. These findings show that TLR3 agonism may be involved in driving increased alcohol consumption and add to the body of work identifying the neuroimmune system as a potential therapeutic target for AUD.