Opioid overdose deaths continue to be a significant public health problem worldwide, with fentanyl, the primary driver of these losses of life. Indeed, in the USA, overdose deaths continue despite the availability of three food and drug administration-approved medications for the treatment of opioid use disorder (OUD) due to minimal access to these medications and to stigma. Fortunately, a growing preclinical and clinical literature suggests that glucagon-like peptide-1 receptor (GLP-1R) agonists may serve as new treatments for OUD. Exendin-4/exenatide and liraglutide have been found to reduce opioid intake, cravings, and cue-, drug-, and stress-induced opioid seeking. While these are important findings, exenatide has a higher risk of gastrointestinal distress and, due to its short half-life, requires multiple daily injections for treatment. Liraglutide has a longer half-life, is less likely than exenatide to cause gastrointestinal distress, but still requires daily injections, which many patients find objectionable. Semaglutide, on the other hand, is a GLP-1R agonist with a longer half-life that requires once weekly injections in humans. Some evidence suggests that semaglutide can reduce responding for alcohol, but it is not known whether it can reduce responding for opioids. Here we test whether acute treatment with semaglutide at 0.026, 0.056, and 0.078 mg/kg administered subcutaneously can reduce cue-, drug-, and stress-induced fentanyl seeking in rats. Results show that all doses of semaglutide fully prevented drug- and stress-induced reinstatement of fentanyl seeking elicited by an i.v. infusion of 1.85 µg/kg fentanyl or the i.p. administration of 0.5 mg/kg yohimbine, respectively, while the mid (0.056 mg/kg) and higher doses (0.078 mg/kg) most effectively reduced cue-induced fentanyl seeking. These findings suggest that semaglutide may serve as an additional nonopioid GLP-1R agonist for the treatment of OUD.
