Other relevant pathways to OUD included oxidative stress, mitochondrial respiration, and neuroprotection. The coordinated alterations in the expression of genes involved in these pathways may reflect compensation to changes in neural activity impacted by opioid use. For example, glutamatergic hyperactivity at striatal MSNs111 may cascade towards excitotoxicity and elevated DNA damage112, both of which have been recently associated with OUD113. GRM5 was specifically downregulated in astrocytes in OUD. GRM5 is transiently expressed in astrocytes to detect and respond to extracellular glutamate, suggesting downregulation in OUD may be due to changes in glutamatergic activity in striatal neurons114. Alterations in other glutamatergic and GABAergic transcripts were also found in specific cell types in OUD (e.g., downregulation of GRIA1 in astrocytes and upregulation of GABRG2 in microglia). In parallel, enrichment of neurodegenerative-related and neuronal activity markers in certain striatal cells in OUD may be a result of high energetic demand on MSNs to maintain a hyperpolarized state, a possible mechanism of vulnerability of striatal MSNs proposed in Huntington’s disease115. We also found OUD-associated changes in neuronal energetics with the downregulation of nicotinamide riboside
