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.