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Effects of selective dopamine D3 receptor partial agonist/antagonists on oxycodone self-administration and antinociception in monkeys

Neuropsychopharmacology volume 48, pages 1716–1723 (2023)Cite this article

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Abstract

Recent studies suggest that dopamine D3 receptors (D3R) may be a therapeutic target for opioid use disorders (OUD). This study examined the effects of the D3R partial agonist (±)VK4-40 and the D3R-selective antagonist (±)VK4-116, compared to the mu-opioid receptor antagonist naltrexone (NTX), in nonhuman primate models of OUD and antinociception. Adult male and female (N = 4/sex) cynomolgus monkeys were trained to self-administer oxycodone (0.003–0.1 mg/kg/injection) first under a fixed-ratio (FR) and then a progressive-ratio (PR) schedule of reinforcement during daily 1- and 4-hr sessions, respectively. Under the FR schedule, intravenous NTX (0.01–0.1 mg/kg), (±)VK4-116 (1.0–10 mg/kg), and (±)VK4-40 (1.0–10 mg/kg) were studied in combination with the peak oxycodone dose and a dose on the descending limb of the dose-effect curve; NTX and (±)VK4-40 were also studied at the peak of the PR dose-response curve (N = 4). Following saline extinction, each compound was examined on oxycodone-induced reinstatement. Finally, these compounds were assessed in adult male rhesus monkeys (N = 3) in a warm-water (38 °C, 50 °C, 54 °C) tail withdrawal assay. NTX decreased responding on the peak of the FR oxycodone dose-response curve, but increased responding on the descending limb. (±)VK4-40, but not (±)VK4-116, significantly decreased peak oxycodone self-administration; (±)VK4-40 did not increase responding on the descending limb. NTX and (±)VK4-40, but not (±)VK4-116, attenuated oxycodone-induced reinstatement. Under PR responding, NTX and (±)VK4-40 decreased breakpoints. Oxycodone-induced antinociception was attenuated by NTX, but not by (±)VK4-40 or (±)VK4-116. Together, these results suggest that further research evaluating the effects of (±)VK4-40 as a novel pharmacotherapy for OUD is warranted.

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Fig. 1: Effects of naltrexone, (±)VK4-116, and (±)VK4-40 on oxycodone self-administration under a fixed-ratio schedule of reinforcement.
Fig. 2: Effects of naltrexone, (±)VK4-116, and (±)VK4-40 on oxycodone reinstatement.
Fig. 3: Effects of (±)VK4-40 on oxycodone self-administration under a PR schedule of reinforcement.
Fig. 4: Effects of naltrexone, (±)VK4-116, and (±)VK4-40 on oxycodone-induced antinociception.

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Acknowledgements

We would like to thank Michael Coller, Jillian H. Odom, Christopher Haggerty and Jianjing Cao for technical assistance.

Funding

This research was supported by DA017763, DA06634, DA037287, T32DA007027 and the NIDA Intramural Research Program Z1ADA000424.

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Author notes

  1. These authors contributed equally: Kendall Woodlief, Mia I. Allen.

Authors and Affiliations

  1. Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, 27157, NC, USA

    Kendall Woodlief, Mia I. Allen & Michael A. Nader

  2. Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, 23298, VA, USA

    Jeremy C. Cornelissen & Matthew L. Banks

  3. Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse – Intramural Research Program, National Institutes of Health, Baltimore, 21224, MD, USA

    Amy Hauck Newman

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Contributions

KW, MLB, AHN and MAN designed the experiment. KW, JCC conducted experiments. MIA conducted data analyses. KW, MIA, MLB, AHN and MAN wrote the manuscript. All authors reviewed the manuscript.

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Correspondence to Michael A. Nader.

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Woodlief, K., Allen, M.I., Cornelissen, J.C. et al. Effects of selective dopamine D3 receptor partial agonist/antagonists on oxycodone self-administration and antinociception in monkeys. Neuropsychopharmacol. 48, 1716–1723 (2023). https://doi.org/10.1038/s41386-023-01590-8

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