Activation of GLP-1 Receptors Attenuates Oxycodone Taking and Seeking Without Compromising the Antinociceptive Effects of Oxycodone in Rats

Postdoctoral researcher Yafang Zhang recently had a paper published in Neuropsychopharmacology in collaboration with many of our lab members! Congrats Yafang!

Find the abstract below:

Despite the effectiveness of current medications to treat opioid use disorder, there is still a high rate of relapse following detoxification. Thus, there is critical need for innovative studies aimed at identifying novel neurobiological mechanisms that could be targeted to treat opioid use disorder. A growing body of preclinical evidence indicates that glucagon-like peptide-1 (GLP-1) receptor agonists reduce drug reinforcement. However, the efficacy of GLP-1 receptor agonists in attenuating opioid-mediated behaviors has not been thoroughly investigated. Using recently established models of opioid-taking and -seeking behaviors, we showed that systemic administration of the GLP-1 receptor agonist exendin-4 reduced oxycodone self-administration and the reinstatement of oxycodone-seeking behavior in rats. We also identified behaviorally selective doses of exendin-4 that reduced opioid-taking and -seeking behaviors and did not produce adverse feeding effects in oxycodone-experienced rats. To identify a central site of action, we showed that systemic exendin-4 penetrated the brain and bound putative GLP-1 receptors on dopamine D1 receptor- and dopamine D2 receptor-expressing medium spiny neurons in the nucleus accumbens shell. Consistent with our systemic studies, infusions of exendin-4 directly into the accumbens shell attenuated oxycodone self-administration and the reinstatement of oxycodone-seeking behavior without affecting ad libitum food intake. Finally, exendin-4 did not alter the analgesic effects of oxycodone, suggesting that activation of GLP-1 receptors attenuated opioid reinforcement without reducing the thermal antinociceptive effects of oxycodone. Taken together, these findings suggest that GLP-1 receptors could serve as potential molecular targets for pharmacotherapies aimed at reducing opioid use disorder.

The University of Pennsylvania School of Nursing also highlighted our research on opioids and satiety factors in a news article . Find the full paper in Neuropsychopharmacology published here.