Altered molecular signaling pathways in the hippocampus of rhesus monkeys following chronic alcohol use

Context-induced relapse is a significant factor limiting recovery from alcohol use disorder (AUD). However, the molecular processes in the hippocampus, critical for contextual memory, impacted by chronic alcohol use, remain poorly understood. We used a non-human primate model to test the hypothesis that chronic alcohol use impacts hippocampal molecular pathways that may serve as therapeutic targets for memory processing in chronic alcohol use. We conducted RNAseq profiling on hippocampal samples from adult male rhesus monkeys with chronic alcohol use (n = 7) and controls (n = 5). We identified 2,575 differentially expressed genes in subjects with chronic alcohol use, including genes implicated in genome-wide association studies of alcohol dependence, such as GLP2R and GABBR2. Downregulated pathways included chemical synaptic transmission, trans-synaptic signaling, and neuron development, and upregulated pathways involved mitochondrial function. Targeted pathway analysis highlighted downregulation of synaptic signaling and upregulation of mitochondrial processes. Leading-edge gene analysis revealed downregulated genes involved in synaptic signaling and upregulated genes involved in mitochondrial processes. Drug repurposing analysis identified several potential therapeutic targets, including epidermal growth factor receptor inhibitors and L-type calcium channel blockers. Our results provide critical insights into molecular pathways underlying hippocampal pathology in chronic alcohol use and offer potential novel therapeutic targets.