Fentanyl Overdose, Anhedonia and Relapse Risk

Summary Opioid overdoses (OD) have increased dramatically over the past few years, in large part due to the ubiquity of the potent synthetic opioid fentanyl in the drug supply; and while the increased use of the opioid OD reversal drug Narcan® has saved thousands of lives, we now have a growing population of fentanyl OD survivors with little understanding of the neurobehavioral effects associated with such experiences. For those with ongoing opioid use disorder (OUD), relapse and subsequent OD is not uncommon. One factor that is associated with an increased risk of relapse is a diagnosis of depression. Moreover, in people with OUD, the severity of anhedonia, a core symptom of depression, correlates with opioid craving and use. We recently established a fentanyl OD model in Long-Evans male and female rats and our preliminary findings suggest a long-lasting decrease in reward motivation following a fentanyl OD in both sexes. As decreased reward motivation is observed with anhedonia, these findings suggest that fentanyl OD may induce an anhedonic phenotype. Based on these preliminary findings, and the clinical evidence suggesting a significant association between anhedonia and relapse, our working hypothesis is that fentanyl OD leads to the development, or exacerbation, of anhedonia (tested in Aim 1) which then increases the risk of relapse (tested in Aim 2). Further, we hypothesize that the persistent attenuation of reward motivation observed following fentanyl OD is mediated by decreased activation of with specific regions of the ventromedial prefrontal cortex (vmPFC) known to regulate motivated responding (tested in Aim 3). Thus, the goal of this R21 proposal is to determine whether fentanyl OD intensifies the cycle of addiction via alterations in reward processing and will seek to identify underlying neural modifications associated these effects.