Selective dopamine D3 receptor partial agonist (±)VK4-40 reduces the reinforcing strength of d-amphetamine but not cocaine in rhesus monkeys responding under a progressive-ratio schedule of reinforcement

Background

Although countless studies have aimed to identify and test novel therapeutics for stimulant misuse, there are still no FDA-approved pharmacotherapies for stimulant use disorders. One potential treatment target is the dopamine D3 receptor (D3R) and studies in rodents have suggested that the novel D3R partial agonist (±)VK4–40 may be effective at decreasing cocaine self-administration. However, no previous studies have examined the efficacy of (±)VK4–40 in reducing cocaine self-administration in nonhuman primates nor the generality of effects by examining self-administration of other stimulants using a within-subjects design.

Methods

Experiment 1 examined how acute treatment with (±)VK4–40 (1.7–3.0 mg/kg, i.v.) influenced cocaine and d-amphetamine self-administration in three rhesus monkeys responding under a progressive-ratio (PR) schedule of reinforcement. In Experiment 2, the reinforcing effects of (±)VK4–40 were evaluated under a PR schedule and compared to cocaine and d-amphetamine.

Results

When given as a pretreatment, (±)VK4–40 significantly reduced the reinforcing strength of d-amphetamine but not cocaine. In general, the effects of (±)VK4–40 on d-amphetamine responding were parallel downward shifts in the self-administration dose-response curve. When (±)VK4–40 was substituted for cocaine, it functioned as a reinforcer in 2 of 3 monkeys. However, the reinforcing strength of (±)VK4–40 was significantly lower than cocaine and d-amphetamine, suggesting lower potential for misuse.

Conclusions

Overall, these findings support further exploration of D3R partial agonists, including (±)VK4–40, for treatment of d-amphetamine misuse or potentially in combination with d-amphetamine for treatment of cocaine use disorder.