Alcohol drinking sex-dependently regulates interleukin-1 pro-inflammatory signaling in the prefrontal cortex of mice and rhesus macaques.

Alcohol use disorder (AUD) causes executive dysfunction, leading to reduced treatment adherence, worse clinical outcomes, and relapse. Current medications do not address these symptoms. Targeting the neuroimmune interleukin-1 (IL-1) system has potential, but its mechanistic role in prefrontal cortex (PFC) dysfunction is unclear. Here we investigated how chronic alcohol consumption shifts IL-1 regulation of the rodent and non-human primate PFC. We found that alcohol drinking decreased reference memory and shifted the search strategy in mice of both sexes, and this deficit correlated with altered IL-1 receptor accessory protein (IL-1RAcP) mRNA levels in the medial PFC (mPFC) of male mice. Notably, the IL-1 system triggers either neuroprotective or proinflammatory cascades depending on the IL-1RAcP isoform recruited to the IL-1 receptor 1 complex. Alcohol drinking sex-dependently shifted mPFC IL-1RAcP gene expression (increased neuroprotective IL-1RAcP mRNA in female mice) and IL-1 regulation of mPFC synapses (increased GABA transmission that was specifically prevented by pharmacological blockade of the proinflammatory IL-1RAcP pathway in male mice) to support resilience in females vs. susceptibility in males. Notably, female alcohol-drinking rhesus macaques showed a similar increase in dorsolateral PFC (dlPFC) neuroprotective IL-1RAcP mRNA, with no change in males. Therefore, IL-1RAcP is a key AUD neural substrate that may sex-dependently switch the dl/mPFC from engaging in neuroprotective to proinflammatory synaptic mechanisms. This type of signaling bias is a recent focus of rational drug development and supports development of novel AUD pharmacotherapeutics based on biased IL-1 signaling, particularly for men.