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The Effects of Dopamine D3 Receptor Compounds on Oxycodone Self-Administration and Reinstatement in Female Cynomolgus Monkeys

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Evaluating novel pharmacotherapies for the treatment of opioid use disorder (OUD) is essential. In the United States, there currently exists an opioid crisis as a result of the high prevalence of people abusing opioids and staggering number of overdose deaths. Animal models have been used extensively to understand the biological basis of substance abuse and to behaviorally characterize novel compounds. Studying nonhuman primates in drug self-administration is most predictive of the clinical condition in humans, thus, provides important clinically translational insight into medications development for treatment of substance abuse. Most drugs of abuse alter dopamine (DA) concentrations and recent studies indicate the DA D3 receptor (D3R) as a potential therapeutic target for OUD. In addition, sex differences have been identified in opioid pharmacology, yet few preclinical studies have examined opioid self-administration in female subjects. The present thesis 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. Specific Aims were to establish oxycodone self-administration under a fixed-ratio (FR) schedule of reinforcement in female cynomolgus monkeys and examine the effects of (±)VK4-40 and (±)VK4-116 versus the mu-opioid receptor antagonist naltrexone (NTX), and to investigate the efficacy of these compounds to block oxycodone-induced reinstatement in the same monkeys. Adult female (N=4) cynomolgus monkeys were trained to self-administer oxycodone (0.001-0.17 mg/kg/injection) under a fixed-ratio (FR) 30 schedule of reinforcement during daily 60-min sessions. Effects of 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, NTX dose-dependently decreased self-administration and shifted the oxycodone dose-response curve to the right when tested with a higher oxycodone dose. (±)VK4-40, but not (±)VK4-116, decreased peak rates of oxycodone self-administration; (±)VK4-40 did not increase responding when tested with an oxycodone dose on the descending limb. 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 5.6 mg/kg, IV), attenuated oxycodone-induced reinstatement. These findings further implicate direct effects of D3R on opioid reinforcement and conditioned stimuli, suggesting that co-administration of D3R compounds may attenuate the abuse liability of opioids. Currently, the reinforcing strength of oxycodone is being evaluated in the same monkeys self-administering oxycodone under a PR schedule of reinforcement. Preliminary findings suggest between-monkey differences in sensitivity to the reinforcing effects of oxycodone under FR and PR reinforcement schedules.
dopamine D3 receptors
opioid use disorder
sex differences
Woodlief, Kendall Ashton (author)
Nader, Michael A (committee chair)
Martin, Thomas J (committee member)
Banks, Matthew L (committee member)
2019-05-24T08:35:28Z (accessioned)
2019-11-23T09:30:26Z (available)
2019 (issued)
Neuroscience (discipline)
2019-11-23 (terms)
http://hdl.handle.net/10339/93903 (uri)
en (iso)
Wake Forest University
The Effects of Dopamine D3 Receptor Compounds on Oxycodone Self-Administration and Reinstatement in Female Cynomolgus Monkeys

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