Effects of Dopamine D3 Receptor Compounds on Oxycodone Self‐Administration, Reinstatement and Antinociception in Monkeys
Authors: Woodlief Kendall , Cornelissen Jeremy C. , Odom Jillian H. , Coller Michael , Cao Jianjing , Banks Matthew L. , Newman Amy H. , Nader Michael A. 
Published: June 2021

Opioid use disorder (OUD) has become a national problem, resulting in the current overdose epidemic. Although effective for treating pain, mu opioids have been shown to have high abuse liability. In addition, sex differences have been identified in opioid pharmacology, yet few preclinical studies have examined opioid self‐administration in female subjects. Most drugs of abuse alter dopamine (DA) concentrations and recent studies indicate the DA D3 receptor (D3R) as a potential therapeutic target for OUD (You et al., Neuropharmacology 126:190–199, 2017). The present study examined the effects of two novel and highly selective D3R compounds, the partial receptor agonist (±)VK4‐40 and the D3R‐selective antagonist (±)VK4‐116 in monkey models of opioid abuse and antinociception. Adult male (N=4) and female (N=4) cynomolgus monkeys were trained to self‐administer oxycodone (0.0009–0.17 mg/kg/injection) under a fixed‐ratio schedule of reinforcement during daily 60‐min sessions. Oxycodone self‐administration was characterized as an inverted U‐shaped function of dose in all monkeys; there were no significant sex differences in response rates, intake, or sensitivity. Next, the effects of the muopioid receptor antagonist naltrexone (NTX; 0.001–0.1 mg/kg), (±)VK4‐116, and (±)VK4‐40 (both at 1.0–10 mg/kg), administered intravenously (IV) 5‐min before sessions, were studied in combination with the oxycodone dose that resulted in peak responding and a dose on the descending limb of the oxycodone dose‐response curve. At the oxycodone dose that maintained peak responding, naltrexone dose‐dependently decreased responding and increased responding when tested with a dose on the descending limb, shifting the oxycodone dose‐response curve to the right. (±)VK4‐40, but not (±)VK4‐116, significantly decreased oxycodone self‐administration; (±)VK4‐40 did not increase responding when tested with an oxycodone dose on the descending limb. (±)VK4‐40 was more effective in decreasing oxycodone self‐administration in male compared to female monkeys. Next, saline was substituted for oxycodone and when responding declined by >80% of baseline, oxycodone (0.1 or 0.17 mg/kg, IV) was administered 1‐min prior to the session to reinstate oxycodone seeking. NTX (0.01–0.1 mg/kg, IV) and (±)VK4‐40 (3.0–5.6 mg/kg, IV), but not (±)VK4‐116 (up to 10 mg/kg, IV), attenuated 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. Oxycodone‐induced antinociception was attenuated by NTX, but not by (±)VK4‐40 or (±)VK4‐116. These findings suggest direct effects of D3R on opioid reinforcement and conditioned stimuli, but not antinociception. Future research aims to extend these studies to models of reinforcing strength, using progressive‐ratio and concurrent oxycodone‐food schedules of reinforcement.Support or Funding InformationDA017763, DA06634, DA037289, ZIA DA000424This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.