Effects of buspirone and the dopamine D3 receptor compound PG619 on cocaine and methamphetamine self-administration in rhesus monkeys using a food-drug choice paradigm

Abstract

Rationale The dopamine (DA) D2 and D3 receptors have been associated with cocaine abuse. A recent study with the D3 receptor (D3R) partial agonist PG619 found that it attenuated cocaine-induced reinstatement and the D2-like receptor antagonist buspirone has shown positive outcomes in two studies of cocaine abuse in monkeys. However, a recent clinical trial indicated that buspirone did not improve abstinence in treatment-seeking cocaine abusers. Objective The objective of the study was to examine PG619 and buspirone under a food-drug choice paradigm in order to better model the clinical findings. In addition, we extended the characterization of both compounds to include methamphetamine (MA) self-administration (SA). Methods Six adult male rhesus monkeys were trained to respond under a concurrent food (1.0-g pellets) and drug (0.01–0.3 mg/kg/injection cocaine or MA) choice paradigm in which complete SA dose-response curves were determined each session (N=3/group). Monkeys received 5 days of treatment with either PG619 (0.1–3.0 mg/kg, i.v.) or buspirone (0.01–1.0 mg/kg, i.m.). In a follow-up study, the SA doses were reduced (0.003–0.1 mg/kg/injection) to increase reinforcement frequency and buspirone was retested. Results PG619 did not affect cocaine or MA choice, while buspirone increased low-dose cocaine choice. Changing the SA doses increased the number of reinforcers received each session, but buspirone did not decrease drug choice. Conclusions Consistent with clinical findings, these results do not support the use of buspirone for psychostimulant abuse and suggest that food-drug choice paradigms may have greater predictive validity than the use of other schedules of reinforcement.

Effects of Oral and Intravenous Administration of Buspirone on Food–Cocaine Choice in Socially Housed Male Cynomolgus Monkeys

“…Oral and intravenous buspirone and cocaine choice in monkeys PW Czoty and MA Nader (Banks and Negus, 2012), and hence our recent findings in individually housed monkeys showing negative effects of buspirone supported this hypothesis (John et al, 2014). Data from subordinate monkeys treated acutely with i.v.…”

“…However, a recent clinical trial indicated that buspirone was ineffective in maintaining abstinence in treatmentseeking cocaine abusers (Winhusen et al, 2014). To examine whether the predictive nature of preclinical models could be enhanced, a recent study in monkeys showed that 5 days of treatment with buspirone did not decrease cocaine selfadministration when studied under a food-cocaine choice paradigm, consistent with the clinical trials findings (John et al, 2014). In the present experiments, we extended these results by characterizing the effects of buspirone on the reinforcing strength of cocaine relative to food using a choice procedure in socially housed male cynomolgus monkeys and compared these effects with those of a highaffinity (K i ¼ 0.7, 93.3, and 375.0 nM at human hD 3 , D 2 , and D 4 receptors, respectively) and highly selective (133-fold versus D 2 and 540-fold versus D 4 receptors) D 3 receptor antagonist PG01037 (Grundt et al, 2007).…”

Evaluation of the “Pipeline” for Development of Medications for Cocaine Use Disorder: A Review of Translational Preclinical, Human Laboratory, and Clinical Trial Research

“…However, decreases in overall responding were observed, particularly early in the session (as in Bergman et al, 2013), indicating a lack of behavioral selectivity of the effect. In the latter study in rhesus monkeys (John et al, 2015), buspirone was unequivocally ineffective in decreasing cocaine selfadministration. In addition to the difference in schedules of reinforcement (FR and second-order versus a concurrent FR-based choice procedure), daily cocaine intake may have played a role in the discrepant results across these studies; monkeys self-administered much less cocaine each day under the choice procedure (see John et al, 2015).…”

Effects of Environmental Manipulations and Treatment with Bupropion and Risperidone on Choice between Methamphetamine and Food in Rhesus Monkeys

“…Although there is a rich scientific literature of preclinical choice procedures, there are a paucity of published methamphetamine vs food choice studies (Caprioli et al, 2015;John et al, 2015a;Ping and Kruzich, 2008). There were two major aims of the present study.…”