PYY3-36 infused systemically or directly into the VTA attenuates fentanyl seeking in male rats

• Published in: Neuropharmacology 2023-11, Vol.239, p.109686-109686, Article 109686
• Main Authors: Caffrey, A., Lavecchia, E., Merkel, R., Zhang, Y., Chichura, K.S., Hayes, M.R., Doyle, R.P., Schmidt, H.D.
• Format: Article
• Language: English
• Subjects: GLP-1; Opioid; PYY3-36; Relapse; Self-administration; VTA; Y2R
• ISSN: 0028-3908; 1873-7064; 1873-7064
• DOI: 10.1016/j.neuropharm.2023.109686

More effective treatments for fentanyl use disorder are urgently needed. An emerging literature indicates that glucagon-like peptide-1 receptor (GLP-1R) agonists attenuate voluntary opioid taking and seeking in rodents. However, GLP-1R agonists produce adverse malaise-like effects that may limit patient compliance. Recently, we developed a dual agonist of GLP-1Rs and neuropeptide Y2 receptors (Y2Rs) that attenuates fentanyl taking and seeking at doses that do not produce malaise-like effects in opioid-experienced rats. Whether activating Y2Rs alone is sufficient to reduce opioid taking and seeking, however, is not known. Here, we investigated the efficacy of the Y2R ligand PYY3-36 to reduce fentanyl self-administration and the reinstatement of fentanyl-seeking behavior, a model of relapse in humans. Male rats were allowed to self-administer fentanyl (2.5 μg/kg, i.v.) for 21 days on a fixed-ratio 5 (FR5) schedule of reinforcement. Rats were then pretreated with vehicle or PYY3-36 (50 μg/kg s.c.; 0.1 and 1.0 μg/100 nL intra-VTA) prior to fentanyl self-administration test sessions. There were no effects of systemic or intra-VTA PYY3-36 on intravenous fentanyl self-administration. Opioid taking was then extinguished. Prior to subsequent reinstatement test sessions, rats were pretreated with vehicle or PYY3-36 (50 μg/kg s.c.; 0.1 and 1.0 μg/100 nL intra-VTA). Both systemic and intra-VTA administration of PYY3-36 attenuated fentanyl reinstatement in male rats at doses that did not affect food intake or produce adverse malaise-like effects. These findings indicate that Y2R agonism alone is sufficient to decrease fentanyl-seeking behavior during abstinence in opioid-experienced rats and further support strategies aimed at targeting Y2Rs for treating opioid use disorders. •Acute systemic PYY3-36 decreased fentanyl reinstatement in male rats.•Systemic PYY3-36 penetrated the brain and distributed to the VTA and NAc.•Intra-VTA infusions of PYY3-36 attenuated fentanyl reinstatement in male rats.