Effects of the kappa opioid agonist U50,488 and the kappa opioid antagonist nor-binaltorphimine on choice between cocaine and food in rhesus monkeys

Abstract

Selective kappa opioid receptor agonists usually decrease cocaine self-administration in procedures that use rate-based measures of reinforcement; however, the rate-altering effects of kappa agonists complicate interpretation of these findings. To evaluate the effects of the selective kappa agonist U50,488 and the selective kappa antagonist nor-binaltorphimine (nor-BNI) on concurrent choice between cocaine and food in rhesus monkeys. The concurrent-choice procedure provides a rate-independent measure of the relative reinforcing effects of cocaine in comparison with food. Four rhesus monkeys were trained to respond under a concurrent-choice schedule for food (1-g pellets) or cocaine (0-0.1 mg/kg per injection). Saline and increasing doses of U50,488 (0.0032-0.1 mg/kg per h) were administered by pseudo-continuous i.v. infusion (one infusion every 20 min) during sequential 3-day blocks. In a separate experiment, monkeys were treated with nor-BNI (3.2 mg/kg, i.v.), and cocaine choice was re-determined during pseudo-continuous infusion with saline or U50,488 (0.1 mg/kg per h). During saline treatment, cocaine maintained a dose-dependent and monotonic increase in cocaine choice. Monkeys responded primarily for food when low cocaine doses were available (0-0.01 mg/kg per injection) and primarily for cocaine when higher cocaine doses were available (0.032-0.1 mg/kg per injection). U50,488 produced a dose-dependent increase in cocaine choice, manifested as leftward shifts in the cocaine-choice, dose-effect curve. U50,488 also dose-dependently decreased overall response rates. Nor-BNI did not alter cocaine choice, but it attenuated the effects of U50,488. These results suggest that continuous treatment with U50,488 produces a kappa receptor-mediated increase in the relative reinforcing effects of cocaine in comparison with food.