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.

Grant Number: 1R21DA061557-01A1
NIH Institute/Center: NIH
Principal Investigator: ELIZABETH BYRNES