Effects of the selective dopamine D-3 receptor antagonist PG01037 on morphine-induced hyperactivity and antinociception in mice

• Type of Material: Article
• Authors: Christian A Botz-Zapp, Emory University; Stephanie L Foster, Emory University; Desta M Pulley, Rowan University; Briana Hempel, National Institute on Drug Abuse-Intramural Research Program, NIH, Baltimore; Guo-Hua Bi, National Institute on Drug Abuse-Intramural Research Program, NIH, Baltimore; Zheng-Xiog Xi, National Institute on Drug Abuse-Intramural Research Program, NIH, Baltimore; Amy Hauck Newman, National Institute on Drug Abuse-Intramural Research Program, NIH, Baltimore; David Weinshenker, Emory University; Daniel F Manvich, Emory University
• Language: English
• Date: 2021-08-09
• Publisher: ELSEVIER
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2021 Elsevier B.V. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.bbr.2021.113506
• Title of Journal or Parent Work: BEHAVIOURAL BRAIN RESEARCH
• Volume: 415
• Start Page: 113506
• End Page: 113506
• Grant/Funding Information: This work was supported by the National Institutes of Health grants from the National Institute on Drug Abuse [DA044726 (SLF), DA038453, DA049257 (DW), DA039991 (DFM)] and the Intramural Research Program of the National Institutes of Health [National Institute on Drug Abuse; DA000424 (ZXX/AHN)].
• Keywords: Science & Technology; Behavioral Sciences; Neurosciences & Neurology; VENTRAL TEGMENTAL AREA; NEURON SYSTEMS; Neurosciences; HIGH-AFFINITY; Catalepsy; Life Sciences & Biomedicine; D3 RECEPTOR; Opioid analgesia; Locomotor activity; Morphine; 6-OHDA LESIONS; CONDITIONED PLACE PREFERENCE; INDUCED LOCOMOTOR-ACTIVITY; Dopamine D-3 receptor; CURRENT PERSPECTIVES; NUCLEUS-ACCUMBENS; PG01037; INDUCED CATALEPSY

Abstract

Recent preclinical studies have reported that pretreatment with the novel and highly-selective dopamine D3 receptor (D3R) antagonists R-VK4-40 or VK4-116 attenuates the abuse-related behavioral effects of oxycodone while enhancing its analgesic properties. However, whether these observed effects are generalizable to the broad class of D3R antagonists and/or extend to opioids other than oxycodone has not been extensively explored. The present study sought to assess the impact of pretreatment with another selective D3R antagonist, PG01037, on several behavioral effects of morphine in mice. C57Bl/6 J mice were pretreated with PG01037 (0–10 mg/kg) and tested for 1) hyperlocomotion induced by acute morphine (5.6–56 mg/kg), 2) locomotor sensitization following repeated morphine (56 mg/kg), 3) antinociception following acute morphine (18 mg/kg), and 4) catalepsy following administration of PG01037 alone or in combination with morphine (56 mg/kg). PG01037 dose-dependently attenuated morphine-induced hyperlocomotion and morphine-induced antinociception at doses that did not alter basal locomotion or nociception alone, but did not prevent the induction of locomotor sensitization following repeated morphine administration. Moreover, PG01037 did not induce catalepsy either alone or in combination with morphine. These results suggest that attenuation of acute opioid-induced hyperactivity may be a behavioral effect shared among D3R-selective antagonists, thus supporting continued investigations into their use as potential treatments for opioid use disorder. However, PG01037 is unlike newer, highly-selective D3R antagonists in its capacity to reduce opioid-induced antinociception, indicating that modulation of opioid analgesia may vary across different D3R antagonists.