Senescence, NAD Metabolism, and Insulin Signaling in the Addicted Brain: A Transcriptomic Perspective

Substance use disorders (SUDs) remain a major public health challenge, but the biological steps that connect inherited risk to neuronal dysfunction are still incompletely understood. Large genome-wide association studies have separated some of the genetic signals tied to substance exposure from those tied to dependence, yet those studies offer only limited insight into the functional changes taking place in brain tissue. Here, transcriptome-wide association methods were used to integrate SUD genetic data with expression quantitative trait loci from adult cortex and fetal brain frontal cortex. The analysis centered on curated gene sets involving GLP-1 and insulin secretion, cellular senescence, NAD and nicotinate metabolism, mitochondrial oxidative phosphorylation, AMPK/mTOR signaling, and apoptosis, across contrasts that included cannabis use disorder in brain tissue, opioid use disorder in exposed versus unexposed groups, and alcohol misuse subtype comparisons.The clearest signals emerged in senescence-related pathways, especially in alcohol subtype contrasts, where positive enrichment was seen in cellular senescence and regulatory senescence gene sets. NAD metabolism showed negative shifts in opioid-related unexposed comparisons, largely driven by lower predicted expression of salvage and transport components. Mitochondrial and oxidative phosphorylation pathways showed broad but selective remodeling, with some respiratory genes contributing positive signals while genes involved in import and exchange trended in the opposite direction. Insulin and glucose-responsive secretion pathways were positively enriched in the cannabis use disorder brain contrast, whereas AMPK/mTOR regulation showed direction-specific effects that varied with exposure context. Apoptosis-related signals appeared most clearly in broader SUD analyses and frequently converged with the mitochondrial findings. Several genes were highly variable across contrasts, suggesting strong context dependence.Taken together, the findings fit a model in which mitochondrial dysfunction is an early point of convergence after substance exposure, contributing to NAD depletion and to downstream stress responses such as senescence and apoptosis, while insulin/GLP-1 and energy-sensing pathways show partial compensatory adjustment. These results are consistent with prior genetic evidence distinguishing exposure from dependence and suggest overlapping mechanisms across multiple SUDs. At the same time, the study is limited by the predictive nature of transcriptome-wide analysis and by the lack of cell-type resolution. Follow-up work using single-cell data and functional validation may help clarify how these transcriptomic shifts shape SUD progression and whether they can be targeted therapeutically.