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

Neuropharmacology. 2023 Nov 15:239:109686. doi: 10.1016/j.neuropharm.2023.109686. Epub 2023 Aug 10.


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.

Keywords: GLP-1; Opioid; PYY(3-36); Relapse; Self-administration; VTA; Y2R.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Analgesics, Opioid
  • Animals
  • Fentanyl* / pharmacology
  • Humans
  • Male
  • Opioid-Related Disorders*
  • Rats
  • Rats, Sprague-Dawley
  • Reinforcement, Psychology
  • Self Administration


  • Fentanyl
  • Analgesics, Opioid