Translational evidence for increased central amygdala IL-6 activity in alcohol dependence

Alcohol use disorder (AUD) is one of the most prevalent mental health disorders worldwide yet effective therapeutics remain limited. Mounting evidence indicates that dysregulated immune signaling in the brain plays a role in AUD pathophysiology. Activation of pro-inflammatory pathways like the interleukin-6 (IL-6) pathway represents a potential point of convergence between synaptic dysfunction and motivational changes in AUD that remain undiscovered. Thus, using a translational neuroscience approach and well-established model of chronic alcohol intake, we investigated the cell-type specific role of IL-6 signaling in the central amygdala, a critical region in the development and maintenance of alcohol dependence. We demonstrate that chronic alcohol exposure recruits IL-6-related pathways in humans and rodents via astrocytic, neuronal, and microglial mechanisms, and that IL-6 inhibits central amygdala GABAergic transmission. Notably, systemic administration of an IL-6 receptor antibody decreased alcohol drinking in alcohol-dependent female mice. Collectively, our findings support IL-6 inhibition as a novel-neuroimmune-targeted therapeutic strategy to reduce excessive drinking in the context of AUD.