Chronic alcohol consumption sex-dependently affects IL-6 modulation of GABAergic synapses in the central amygdala of rhesus macaques

The implications of the neuroimmune system in the pathogenesis of alcohol use disorders (AUD) have been undeniable. Understanding how chronic alcohol dysregulates inflammatory pathways in the brain leading to altered neuronal functions could provide insight into specific mechanisms and neuroadaptations that may contribute to drinking behaviors. For example, the neuroadaptations at inhibitory GABAergic synapses in the central nucleus of the amygdala (CeA) of rodents and macaques involve the recruitment of neuroimmune pathways. This study tested the hypothesis that chronic alcohol consumption dysregulates the pro-inflammatory cytokine, interleukin 6 (IL-6) in the CeA of rhesus macaques. Male and female rhesus macaques were provided continuous choice to drink either 4 % (w/v) ethanol or water for 22 h/day, every day, for more than one year. We assessed the impact of chronic ethanol drinking on the cytokine abundance, including IL-6, in the blood, and adaptive changes in the CeA GABAergic transmission and transcriptome. We observed a main effect of sex on the IL-6 circulating plasma levels at necropsy, with higher IL-6 plasma levels in females, but no main effect of ethanol nor an interaction between sex and ethanol drinking. IL-6 decreased CeA GABA release (sIPSC frequency) in both control and alcohol drinkers, however chronic ethanol drinking significantly potentiated the IL-6 effects in both sexes. While, IL-6 had no effects on the sIPSC amplitudes in the control group, we observed a main effect of ethanol drinking on IL-6-induced decrease of sIPSC amplitude in both male and female drinkers. IL-6 also significantly prolonged the kinetics (decay times) of sIPSCs in male controls and drinkers, but not in the females, regardless of drinking. These data suggest that IL-6 modulation of GABAergic transmission within the CeA via a presynaptic reduction in GABA release independent of sex, whereas postsynaptic GABA receptor mediated functions (sIPSC amplitude and decay time) show sex- and ethanol specific effects. Lastly, transcriptomic analysis of the IL-6-immune-related genes in the CeA between high and low ethanol drinkers identified several DEGs (differentially expressed genes) implicating the neural and glial processes, and extracellular matrix as a generalized inflammatory response to ethanol in the high drinkers.