GLUCAGON-LIKE PEPTIDE-1 AGONIST: A PROMISING TREATMENT FOR OPIOID USE DISORDER IN WISTAR RATS​​​​

Opioid Use Disorder (OUD) remains a major public health problem, representing a largely preventable cause of substantial morbidity, mortality and societal burden. Despite the proven benefits of medication-assisted treatment, many individuals experience relapse, largely driven by persistent craving and cue-induced drug seeking. Glucagon-like peptide-1 receptor (GLP-1R) agonists, widely prescribed for metabolic disease, have emerged as potential therapeutics to reduce drug-directed motivation. We tested the effects of the GLP-1R agonist liraglutide in male Wistar rats on opioid intake, motivation, withdrawal and reinstatement-like behavior. Two groups were trained on intravenous self-administration under an FR3 (Fixed Ratio) schedule: long-access fentanyl (6 h/day; 2.5 µg/infusion) and short-access heroin (2 h/day; 20 µg/infusion). After establishing a stable self-administration baseline, rats received - liraglutide (0, 0.03, 0.1 and 0.3 mg/kg s.c.) to test its effect on opioid consumption, motivation, withdrawal and relapse. Results showed that liraglutide significantly reduced the number of lever presses for heroin and fentanyl, under both Fixed Ratio and Progressive Ratio schedule of responding without affecting water self-administration. Using the minimum efficacious dose (0.1 mg/kg), we then performed a 4-day chronic treatment, observing reduced opioid rewards until the emergence of tolerance. In fentanyl exposed rats’ naloxone (5 mg/kg sc)-precipitated substantial withdrawal symptoms that were significantly attenuated by liraglutide (0.03–0.3 mg/kg, s.c.). Finally, liraglutide (0.1 mg/kg, s.c) attenuated relapse-like responding and drug seeking after forced abstinence. In conclusion these findings support liraglutide as a promising candidate for the treatment of OUD. Future work should define the underlying mechanisms and evaluate potential sex-specific effects.