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


OBJECTIVE
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.


METHODS
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).


RESULTS
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.


CONCLUSIONS
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.
Negus
S Stevens
SS
Alcohol and Drug Abuse Research Center; Harvard Medical School, McLean Hospital, 115 Mill St., Belmont, MA 02478, USA. negus@mclean.harvard.edu
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D016739:Behavior, Addictive / Q000188:drug therapy; D002755:Choice Behavior / Q000187:drug effects* / Q000502:physiology; D003042:Cocaine / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects* / Q000502:physiology; D008253:Macaca mulatta; D008297:Male; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*
D017473:Receptors, Opioid, kappa; C051844:norbinaltorphimine; D009271:Naltrexone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D003042:Cocaine