An unexpected yet intriguing result was the enrichment in metabolic-related BP and pathways in the proteomic network of differentially expressed proteins. The enrichment was observed for multiple metabolic pathways including those involving amino acids, nucleic acids, fatty acids, and sugars. Alcohol is primarily metabolized by the liver to acetaldehyde and eventually acetate, generating reduced NADH (nicotinamide adenine dinucleotide) in the process. This increase in the NADH/NAD+ ratio directly and indirectly modulates lipid, carbohydrate, protein, lactate, and uric acid metabolism (Zakhari 2013). Furthermore, alcohol-derived acetate produced by peripheral sources can regulate neuronal gene transcription producing long lasting changes in behavior (Mews et al. 2019). A recent proteomic analysis of human prefrontal and motor cortex tissue from individuals with AUD revealed diverse changes in many energetic metabolic enzymes associated with increased alcohol-derived acetate utilization in the brain of AUD subjects (Enculescu et al. 2019). Although the animals used in this study were alcohol-naïve, it is quite possible that mice selected over generations for high vs low alcohol preference could have basal differences in metabolic pathways that alcohol and its metabolites interfere with
