TBI and opioid interactions in addiction-related outcomes

PROJECT SUMMARY Numerous clinical studies demonstrate correlations between traumatic brain injury (TBI) and substance abuse, and it has been estimated that 10-20% of patients develop a new diagnosis of substance use disorder after TBI. Among all drugs, opioids had the highest increase in incidence, with hazard ratios of 6.14 and 3.98 for days 1-30 and days 31-180 following injury, respectively. Despite extensive evidence of increased substance abuse following TBI and high rates of opioid prescriptions to people that sustain TBI, little is known about how TBI and opioids may physiologically interact to increase the risk of opioid abuse following injury. We have been addressing this problem using well-validated rodent models of brain injury and self-administration (SA) models for several drugs of abuse. Our studies of oxycodone have been particularly striking. After TBI was induced using repeated blast TBI (rbTBI), rats self-administered lower oxycodone than controls. Despite this lower intake, rbTBI rats had elevated drug seeking, an effect we have replicated in three published studies. Using functional MRI, we identified interactive effects of TBI and oxycodone self-administration that manifested in widespread increases in functional connectivity. We also identified significant correlations between drug seeking and/or intake and infralimbic prefrontal cortex (IL) connectivity in two efferent circuits. While these data are striking, there are unknown factors that may drive increases in oxycodone seeking after SA. In this proposal, we will test the hypothesis that TBI and oxycodone interact to increase the reinforcing efficacy of opioids. We will also test the hypothesis that persistent oxycodone seeking does not reflect a general deficit in extinction learning. Finally, we will test the hypothesis that inhibition of circuits identified by functional MRI to be correlated with drug seeking in injured rats reduces the increased drug seeking observed following TBI. Aim 1: Measure the effects of TBI and oxycodone on opioid reinforcement, seeking, and relapse. Aim 2: Measure the effects of modulating IL networks on TBI-associated addiction-related outcomes. Aim 3: Measure the effects of gabapentin and environmental enrichment on functional connectivity and addiction-related outcomes.