PROJECT SUMMARY The opioid epidemic is a persistent public health crisis that has been worsened by the COVID19 pandemic. Efforts to curtail this epidemic have had minimal success in halting its continued progression. There is a critical need to more fully understand the neurobiology of opioid use disorder so that highly novel therapeutics can be developed. Recent clinical and preclinical studies have found that opioid use increases the levels of phosphory- lated tau protein in the brain, especially in the prefrontal cortex. The prefrontal cortex plays a significant role in the control of opioid use. Hyperphosphorylated tau is a hallmark of neurodegenerative tauopathy-related dis- eases such as Alzheimer’s Disease and frontotemporal dementia. However, opioid use does not appear to be a major predisposing factor in the development of these diseases. This begs the question of whether opioid-in- duced increases in phosphorylated tau are a simple byproduct of opioid use with no significant role in brain health, or if this increase has significant biological relevance for mediating the neurobehavioral consequences of opioid use. Focusing research efforts on whether opioid use produces neurodegenerative diseases may lead to a missed opportunity to explore a non-neurodegenerative role for opioid-induced changes in tau biology. It is known that hyperphosphorylated tau can and tau oligomerization alter neurotransmission long before tau-related pathology is observable. Therefore, we reason that opioid-induced increases in phosphorylated tau and tau oli- gomerization may alter prefrontal cortical neurotransmission in the absence of any overt pathology. This project proposal tests the hypothesis that opioids produce enhanced tau phosphorylation and oligomerization in the prefrontal cortex leading to synaptic dysfunction and elevated opioid consumption. We will focus on the opioid oxycodone in this project due its long-term use to treat pain as well as its common misuse in those with opioid use disorder. We will use a multidisciplinary approach to test for a causative role for prefrontal cortical tau in producing synaptic dysfunction and enhancing oxycodone consumption. This project is high-risk, high-reward. It is conceivable that opioid-induced changes in tau have nothing to do with synaptic changes or oxycodone con- sumption. However, if there is a connection between opioid-induced changes in tau biology and synaptic changes and opioid use, then this will be a paradigm shift for the opioid research field. In the future, after some additional exploration, we may be able to leverage therapeutics originally designed to treat neurodegenerative tauopathies to treat opioid use disorder. This would be an entirely new avenue for combatting the opioid epi- demic.