Figure 2.

Simplified pathways illustrating the potential mechanisms that underlie associations between alcohol use disorder (AUD) and major depression (MD), with a compelling neuroimmune contribution. Heavy alcohol drinking may render gut wall permeable to bacterial proteins such as lipopolysaccharide (LPS) through the activation of toll-like receptors. Ethanol and LPS upregulate the transcription factor NF-κB and cause immune cells in the periphery as well as glial cells to produce pro-inflammatory cytokines. The pro-inflammatory cytokines within the brain activate the indolamine 2,3-dioxygenase enzyme, which metabolizes tryptophan away from serotonin production toward a potentially neurotoxic kynurenine pathway. MD accompanies altered monoamines, oxidative and nitrosative damage, and neurodegeneration. Depression is associated with chronic inflammatory conditions such as cancer and cardiovascular diseases, which together with sickness symptoms can feed the neuroimmune dysregulation causing further neurodegeneration, negative affect, and anxiety-like behavior and loss of behavioral control—all features characterized in AUD.