A GLP-1R/Y receptor/Y receptor triple agonist decreases fentanyl-evoked dopamine release in the nucleus accumbens and attenuates fentanyl taking and seeking in rats.

BACKGROUND AND PURPOSE

Emerging literature indicates that simultaneously targeting glucagon-like peptide-1 receptors (GLP-1Rs) and neuropeptide Y receptors (Y/Y) 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/Y receptor/Y receptor triple agonist, to reduce voluntary fentanyl taking and seeking.

EXPERIMENTAL APPROACH

Rats were allowed to self-administer fentanyl (2.5 μg kg, i.v.) for 21 days. Rats were then pretreated with vehicle or GEP12 (1.57 or 12.53 μg kg, i.p.) prior to fentanyl self-administration test sessions. Opioid taking was then extinguished and rats were pretreated with vehicle or GEP12 (1.57 or 12.53 μg kg, i.p.) prior to subsequent reinstatement test sessions.

KEY RESULTS

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/Y receptor/Y 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.

CONCLUSIONS AND IMPLICATIONS

Together, these findings support the continued development of GLP-1R/Y receptor/Y receptor triple agonists as a novel class of pharmacotherapies for treating OUD.