Abstract
Chronic alcohol exposure threatens central nervous system homeostasis, linking to interconnected dysregulated emotional behavior and robust neuroinflammation. Clinically, individuals with alcohol use disorder (AUD) frequently present comorbid anxiety and depression, yet whether naltrexone, an established therapeutic, can ameliorate AUD neuroinflammation remains unclear. This study investigated naltrexone's effects on anxiety- and depressive-like behaviors and neuroinflammatory responses in chronically alcohol-exposed mice. Modified 'Drinking-in-the-Dark' protocol for 4 weeks, which induced alcohol-exposed mice, followed by subcutaneous naltrexone (1 mg/kg/day) or equal-volume saline for 14 days. Open field test, elevated plus maze test, and tail suspension test are used to detect anxiety- and depressive-like behaviors - alcohol exposure-induced anxiety- and depressive-like behaviors, which naltrexone reversed. ELISA and immunofluorescence revealed alcohol-elevated pro-inflammatory cytokines (tumor necrosis factor-α, interleukin-6, and interleukin-1β) in the basolateral amygdala (BLA), prefrontal cortex, and hippocampus, and promoted BLA microglia proliferation. Naltrexone attenuated these neuroinflammatory changes. These findings highlight naltrexone's dual-action potential in addressing behavioral and neuroinflammatory consequences of chronic alcohol exposure, providing experimental evidence for its use in AUD, particularly with comorbid anxiety and depression.