On June 2, 2025, Antonia, Enzo, and colleagues published a study in the British Journal of Pharmacology titled ‘A GLP-1R/Y1 receptor/Y2 receptor triple agonist decreases fentanyl-evoked dopamine release in the nucleus accumbens and attenuates fentanyl taking and seeking in rats’. Emerging literature indicates that simultaneously targeting glucagon-like peptide-1 receptors (GLP-1Rs) and neuropeptide Y receptors (Y1/Y2) may represent a new pharmacotherapeutic approach to treating opioid use disorder (OUD). The overall goal of this study was to screen the efficacy of GEP12, a novel GLP-1R/Y1 receptor/Y2 receptor triple agonist, to reduce voluntary fentanyl taking and seeking. GEP12 reduced fentanyl taking in both male and female rats and shifted the fentanyl self-administration dose–response curve downward. Importantly, we identified behaviourally selective doses of GEP12 that were well-tolerated in fentanyl-experienced rats. GEP12 also reduced fentanyl seeking during abstinence in both male and female rats at doses that did not alter food intake or produce adverse malaise-like effects. To identify a central mechanism underlying the efficacy of GLP-1R/Y1 receptor/Y2 receptor triple agonists, we showed that systemic GEP12 penetrated the brain and distributed to the mesolimbic reward system. Using in vivo fibre photometry, we discovered that GEP12 reduced fentanyl self-administration-evoked dopamine release in the nucleus accumbens. Together, these findings support the continued development of GLP-1R/Y1 receptor/Y2 receptor triple agonists as a novel class of pharmacotherapies for treating OUD.

Keywords: dopamine; glucagon‐like peptide‐1; neuropeptide Y; nucleus accumbens; opioid; relapse.
Link to the paper: https://pubmed.ncbi.nlm.nih.gov/40456683/