U50,488, a kappa opioid receptor agonist, attenuates cocaine-induced increases in extracellular dopamine in the nucleus accumbens of rats.

Because an increase in extracellular levels of dopamine in the nucleus accumbens has been associated with the reinforcing effects of addictive drugs, we investigated whether U50,488, a selective kappa opioid receptor agonist, would alter cocaine-induced increases in extracellular dopamine in the nucleus accumbens using in vivo microdialysis in awake and freely moving rats. Cocaine (20 mg/kg i.p.) produced a 10-fold increase in extracellular dopamine levels. Pretreatment (20 min beforehand) with U50,488 (10 mg/kg i.p.), which alone caused a modest decrease in dopamine levels, produced a 50% decrease in the effect of cocaine on dopamine levels. This attenuation was completely reversed by administration of a kappa opioid receptor antagonist, nor-binaltorphimine (10 mg/kg s.c.), 20 min before the agonist challenge. Treatment with nor-binaltorphimine alone induced a brief increase in dopamine levels. These findings indicate that activation of kappa receptors attenuates cocaine's effects and that kappa opioid receptor agonists may, therefore, be useful as functional cocaine antagonists.