Substance misuse is highly prevalent in the U.S. and each year a growing number of individuals develop a substance use disorder (SUD) (Mattiuzzi and Lippi, 2019, Martins et al., 2015). In 2022, 48.7 million people in the United States met DSM-5 criteria for a SUD and these disorders have far-reaching negative consequences (Knopf, 2023, Manthey et al., 2021). For instance, SUDs cost the U.S. economy over $880 billion a year and since 2000, drug overdose deaths in America have surpassed one million (Hedegaard et al., 2021, Manthey et al., 2021). Although many of these overdose deaths involved the use of opioids, there has also been an increased prevalence of stimulant-associated overdose deaths which have nearly quintupled between 2011 and 2021 (Spencer et al., 2023). Despite this, there are currently no FDA-approved pharmacotherapies for stimulant use disorders (Chan et al., 2019). As stimulants have a high potential of being misused, it is pertinent that further research is conducted to develop and test efficacious medications that may decrease their reinforcing effects.

Given that reinforcing drugs, including cocaine and d-amphetamine, increase dopamine (DA) concentrations, particularly in the mesolimbic area of the brain, the DA receptor system has been a focus for potential therapeutic targets (Benowitz, 1993). One hypothesis is that targeting the DA D3 receptor (D3R) subtype may provide therapeutic potential without concomitant side effects associated with the activation or blockade of the other DA receptors or the dopamine transporter (DAT) (Keck et al., 2015, Newman et al., 2005, Newman et al., 2022, Newman et al., 2012). Importantly, the D3R, unlike the other DA receptor subtypes, is mainly localized to the mesolimbic system (Galaj et al., 2020, Levant, 1997). Given this focused distribution, D3R-selective ligands are likely to have less off-target effects when compared to compounds that bind to other DA receptor subtypes. Recently, novel D3R partial agonists have been examined as potential pharmacotherapies for SUDs since these partial agonists have the unique pharmacological ability to act both as agonists, when mesolimbic dopamine levels are low, for instance during stimulant abstinence, and as antagonists when a stimulant is onboard (Newman et al., 2005, Newman et al., 2022). This profile is favorable for a stimulant use disorder therapeutic, as a partial agonist could potentially decrease the reinforcing effects during active use by blocking DA from activating D3R, but also alleviate withdrawal during abstinence (Negus and Henningfield, 2015).

Recent drug discovery research has led to the development of a novel D3R partial agonist, (±)VK4–40 (Jordan et al., 2020). This metabolically stable racemic compound binds with high affinity to D3R (K_i = 0.35 nM) and is highly selective (~400-fold) for D3R over D2R (D₂ K_i = 151 nM; D₂/D₃ = 417) (Kumar et al., 2016, Shaik et al., 2019). Previous studies have shown that (±)VK4–40 dose-dependently decreased cocaine self-administration and cocaine-primed reinstatement in rodents (Jordan et al., 2020). Moreover, in rats, (±)VK4–40 decreased optogenetic brain stimulation without producing conditioned place preference or aversion and reduced cocaine-induced elevation in heart rate (Jordan et al., 2019a, Jordan et al., 2020). In short, (±)VK4–40 has a high affinity and/or selectivity for D3Rs and has been shown to produce positive signals in rodent models of cocaine use.

These promising results warrant further investigation on the therapeutic potential of (±)VK4–40 for stimulant use in nonhuman primate models. These analyses would further inform whether this novel compound should progress to clinical trials for the treatment of stimulant/cocaine use disorders. Thus, the primary goal of the present study was to determine whether acute (±)VK4–40 influenced the reinforcing strength and potency of cocaine in rhesus monkeys responding under a progressive-ratio (PR) schedule of reinforcement. A second goal was to directly compare the efficacy of (±)VK4–40 on another misused stimulant, d-amphetamine, in the same monkeys. Furthermore, given that an ideal pharmacotherapy for stimulant misuse would, as a minimum, have a lower probability of being misused when compared to the drug of misuse, a final goal was to evaluate whether (±)VK4–40 functioned as a reinforcer under a PR schedule of reinforcement and how its reinforcing strength compared to that of cocaine and d-amphetamine.