PROJECT SUMMARY This administrative supplement is submitted in response to Notice Number: NOT-DA-21-032: Notice of Special Interest (NOSI): Administrative Supplements for research on fentanyl and derivatives. This supplement outlines experiments to extend the parent 5 UG3 DA050325-02 titled, “Use of a GLP-1 Agonist to Treat Opioid Use Disorder in Rats and Man”. Specifically, the studies are designed to test whether a glucagon-like peptide-1 receptor (GLP-1R) agonist, found to safely and effectively reduce heroin taking and seeking in rats in the parent UG3 grant, also can safely and effectively reduce cue-, drug-, and stress-induced reinstatement of fentanyl seeking. This shift in focus is critical because, during the first ten months of 2020, i.e., during onset of the COVID-19 pandemic, overdose deaths increased in almost every state in the nation (see Figure 1) [1] and this increase can be attributed largely to a spike in deaths related to the use of synthetic opioids such as fentanyl [1]. Specific Aim 1, then, will test whether treatment with the GLP-1R agonist, liraglutide, during abstinence and prior to test, can reduce cue-induced fentanyl seeking and drug- and stress-induced reinstatement of fentanyl seeking in male Sprague-Dawley rats. Here, the dose of liraglutide will be titrated as it is for the treatment of obesity and type two diabetes in humans. Specific Aim 2 will address safety by testing the impact of GLP-1R treatment on fentanyl-induced respiratory depression and cardiovascular dysregulation, two primary contributors to opioid overdose death, and on naloxone precipitated withdrawal, a primary precipitator of relapse. We predict that treatment with the GLP-1R agonist, liraglutide, will reduce cue-, drug-, and stress-induced seeking for both the low and the high dose of fentanyl and that the GLP-1R agonist will not exacerbate fentanyl-induced respiratory depression, cardiovascular dysregulation, or withdrawal in fentanyl experienced rats. If our hypotheses are confirmed, we will have demonstrated that liraglutide, a non-opioid, has promise as a safe and effective, non-opioid treatment for opioid use disorder.

NARRATIVE STATEMENT Opioid overdose continues to take the lives of tens of thousands of Americans annually, with a recent surge in deaths during the COVID pandemic due to fentanyl. Here, we will test whether treatment with a promising glucagon-like peptide-1R (GLP-1R) agonist, already approved for the treatment of obesity and type two diabetes mellitus in humans, can safely and effectively reduce cue/drug/stress-induced reinstatement of fentanyl seeking in rats. Additionally, we will examine safety by testing the effect of the GLP-1R agonist on fentanyl-induced respiratory suppression, cardiovascular dysregulation, and on naloxone-precipitated withdrawal. We predict that the GLP-1R agonist will be found both safe and effective in the treatment of fentanyl seeking.