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

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 degrees C, 50 degrees C, 54 degrees 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.