Activation of GLP-1 receptors attenuates oxycodone taking and seeking without compromising the antinociceptive effects of oxycodone in rats

• Published in: Neuropsychopharmacology (New York, N.Y.) Vol. 45; no. 3; pp. 451 - 461
• Main Authors: Zhang, Yafang, Kahng, Michelle W, Elkind, Jaclynn A, Weir, Vanessa R, Hernandez, Nicole S, Stein, Lauren M, Schmidt, Heath D
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.02.2020; Springer International Publishing
• Subjects: Activation; Agonists; Analgesics; Analgesics - administration & dosage; Analgesics, Opioid - administration & dosage; Animals; Behavior; Detoxification; Dopamine; Dopamine D1 receptors; Dopamine D2 receptors; Dose-Response Relationship, Drug; Drug addiction; Drug therapy; Drug-Seeking Behavior - drug effects; Drug-Seeking Behavior - physiology; Food intake; Glucagon; Glucagon-like peptide 1; Glucagon-Like Peptide-1 Receptor - agonists; Glucagon-Like Peptide-1 Receptor - metabolism; Male; Narcotics; Nucleus accumbens; Opioid receptors; Oxycodone; Oxycodone - administration & dosage; Pain Measurement - drug effects; Pain Measurement - methods; Pain Measurement - psychology; Pain perception; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Reinforcement; Reinstatement; Self-administration; Spiny neurons
• ISSN: 0893-133X; 1740-634X
• DOI: 10.1038/s41386-019-0531-4

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.