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PPL-138 (BU10038): a bifunctional NOP/mu partial agonist that reduces cocaine self-administration in rats

  • Andrea Cippitelli
    ,
  • Madeline Martinez
    ,
  • Gilles Zribi
    ,
  • Gerta Cami-Kobeci
    ,
  • Stephen M. Husbands
    ,
  • Lawrence Toll
  • Florida Atlantic University
    ,
  • University of Bath
Research Output: Contribution to journal Article Peer-review

Open access

Abstract

The search for new and effective treatments for cocaine use disorder (CUD) is a priority. We determined whether PPL-138 (BU10038), a compound with partial agonist activity at both nociceptin opioid peptide (NOP) and mu-opioid receptors, reduces cocaine consumption, reinstatement, and whether the compound itself produces reinforcing effects in rats. Using an intermittent access (IntA) cocaine self-administration procedure, we found that PPL-138 (0.1 and 0.3 mg/kg) effectively decreased the total number of cocaine infusions and burst-like cocaine intake in both male and female rats. Responses for food in an IntA model of food self-administration were not altered for either sex, although locomotor activity was increased in female but not male rats. Blockade of NOP receptors with the selective antagonist J-113397 (5 mg/kg) did not prevent the PPL-138-induced suppression of cocaine self-administration, whereas blockade of mu-opioid receptors by naltrexone (1 mg/kg) reversed such effect. Consistently, treatment with morphine (1, 3, and 10 mg/kg) dose-dependently reduced IntA cocaine self-administration measures. PPL-138 also reduced reinstatement of cocaine seeking at all doses examined. Although an initial treatment with PPL-138 (2.5, 10, and 40 μg/kg/infusion) appeared rewarding, the compound did not maintain self-administration behavior. Animals treated with PPL-138 showed initial suppression of cocaine self-administration, which was eliminated following repeated daily dosing. However, suppression of cocaine self-administration was retained when subsequent PPL-138 treatments were administered 48 h apart. These findings demonstrate that the approach of combining partial NOP/mu-opioid activation successfully reduces cocaine use, but properties of PPL-138 seem to depend on the timing of drug administration.

Publication Information

Output type

Research Output: Contribution to journal Article Peer-review

Original language

English

Article number

109045

Journal (Volume, Issue Number)

Neuropharmacology (Volume 211)

Publication milestones

  • Accepted/In press - 21/03/2022
  • Published - 15/06/2022

Publication status

Published - 15/06/2022

ISSN

0028-3908

External Publication IDs

  • handle.net: 10547/626261
  • Scopus: 85127669431
  • PubMed: 35378170

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