The Toll‐like receptor 7 agonist imiquimod increases ethanol self‐administration and induces expression of Toll‐like receptor related genes

There is growing evidence that immune signalling may be involved in both the causes and consequences of alcohol abuse. Toll‐like receptor (TLR) expression is increased by alcohol consumption and is implicated in AUD, and specifically TLR7 may play an important role in ethanol consumption. We administered the TLR7‐specific agonist imiquimod in male and female Long–Evans rats to determine (1) gene expression changes in brain regions involved in alcohol reinforcement, the nucleus accumbens core and anterior insular cortex, in rats with and without an alcohol history, and (2) whether TLR7 activation could modulate operant alcohol self‐administration. Interferon regulatory factor 7 (IRF7) was dramatically increased in both sexes at both 2‐ and 24‐h post‐injection regardless of alcohol history and TLR3 and 7 gene expression was increased as well. The proinflammatory cytokine TNFα was increased 24‐h post‐injection in rats with an alcohol self‐administration history, but this effect did not persist after four injections, suggesting molecular tolerance. Ethanol consumption was increased 24 h after imiquimod injections but did not occur until the third injection, suggesting adaptation to repeated TLR7 activation is necessary for increased drinking to occur. Notably, imiquimod reliably induced weight loss, indicating that sickness behaviour persisted across repeated injections. These findings show that TLR7 activation can modulate alcohol drinking in an operant self‐administration paradigm and suggest that TLR7 and IRF7 signalling pathways may be a viable druggable target for treatment of AUD.