To begin to investigate OUD-associated alterations across striatal cell types, we conducted snRNA-seq on the dorsal striatum from human postmortem brain and compared the cell type-specific molecular signatures between unaffected individuals and individuals with OUD (98,848 total nuclei from the caudate and putamen of males and females, 12 individuals and 24 biological samples). Given the high number of high-quality nuclei per sample, we were able to identify heterogeneous striatal cell types based on anatomical and molecular profiles. By comparing unaffected individuals to individuals with OUD, we found significant alterations in proinflammatory, metabolic and oxidative stress, and DNA damage pathways, particularly within neurons and microglia. Additionally, we identified increased enrichment of molecular markers of DNA damage signaling that was specific to neuronal subtypes (i.e., striatal interneurons). To investigate whether opioids may directly induce accumulation of DNA damage in the brain, we assessed DNA damage markers across striatal cell types of rhesus macaques following chronic opioid administration (~6 months of twice daily opioid administration). Notably, DNA damage markers were significantly elevated across striatal neurons in opioid-exposed rhesus macaques, further implicating neuronal generated
