Differential effects of the dopamine D3 receptor antagonist PG01037 on cocaine and methamphetamine self-administration in rhesus monkeys

Abstract

The dopamine D3 receptor (D3R) has been shown to mediate many of the behavioral effects of psychostimulants associated with high abuse potential. This study extended the assessment of the highly selective D3R antagonist PG01037 on cocaine and methamphetamine (MA) self-administration to include a food-drug choice procedure. Eight male rhesus monkeys (n=4/group) served as subjects in which complete cocaine and MA dose-response curves were determined daily in each session. When choice was stable, monkeys received acute and five-day treatment of PG01037 (1.0–5.6 mg/kg, i.v.). Acute administration of PG01037 was effective in reallocating choice from cocaine to food and decreasing cocaine intake, however, tolerance developed by day 5 of treatment. Up to doses that disrupted responding, MA choice and intake were not affected by PG01037 treatment. PG01037 decreased total reinforcers earned per session and the behavioral potency was significantly greater on MA-food choice compared to cocaine-food choice. Furthermore, the acute efficacy of PG01037 was correlated with the sensitivity of the D3/D2R agonist quinpirole to elicit yawning. These data suggest (1) that efficacy of D3R compounds in decreasing drug choice is greater in subjects with lower D3R, perhaps suggesting that it is percent occupancy that is the critical variable in determining efficacy and (2) differences in D3R activity in chronic cocaine vs. MA users. Although tolerance developed to the effects of PG01037 treatment on cocaine choice, tolerance did not develop to the disruptive effects on food-maintained responding. These findings suggest that combination treatments that decrease cocaine-induced elevations in DA may enhance the efficacy of D3R antagonists on cocaine self-administration.

Effects of 7-day continuous d-amphetamine, methylphenidate, and cocaine treatment on choice between methamphetamine and food in male rhesus monkeys

“…Consistent with previous methamphetamine self-administration studies in nonhuman primates (Banks and Blough, 2015; John et al, 2014, 2015) and humans (Kirkpatrick et al, 2012; Pike et al, 2014), increasing methamphetamine doses resulted in an increased preference over an alternative, nondrug reinforcer. In contrast, the present study was inconsistent with two previous rat methamphetamine choice studies (Caprioli et al, 2015; Ping and Kruzich, 2008).…”

“…Moreover, to the best of our knowledge, subchronic d-amphetamine or methylphenidate treatment effects on preclinical methamphetamine self-administration have not been previously reported. Furthermore, there are reported differences between cocaine choice and methamphetamine choice in monkeys (John et al, 2015) and the degree to which amphetamine treatment differentially alters cocaine choice vs. methamphetamine choice remains unknown. In addition, we also determined continuous 7-day cocaine treatment effects on methamphetamine choice.…”

Effects of 7-day repeated treatment with the 5-HT2A inverse agonist/antagonist pimavanserin on methamphetamine vs. food choice in male rhesus monkeys

“…The present behavioral results suggest this may not be a therapeutically advantageous treatment option for methamphetamine addiction. The present results are consistent with previous methamphetamine vs. food choice studies in nonhuman primates evaluating “antagonist-like” pharmacological treatments such as dopamine antagonists PG01037, buspirone, and risperidone or the dopamine D3 partial agonist PG619 (Banks and Blough, 2015; John et al, 2015a, 2015b). Furthermore, both the dopamine partial agonist aripiprazole and the dopamine antagonist risperidone have failed to reduce methamphetamine choice in the human laboratory (Stoops et al, 2013) or methamphetamine use in clinical trials (Coffin et al, 2013; Nejtek et al, 2008; Tiihonen et al, 2007).…”

Insights from Preclinical Choice Models on Treating Drug Addiction

“…When repeated buspirone treatment was evaluated under a cocaine versus food choice procedure in nonhuman primates, buspirone failed to attenuate cocaine choice [93,94]. Similar treatment results have also been reported for methamphetamine versus food choice [93,95]. However, more nuanced effects of buspirone on cocaine versus food choice was unmasked when group-housed nonhuman primates were categorized based on their social hierarchy, highlighting one potential utility of nonhuman primate studies utilizing preclinical choice procedures [94].…”