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 addicti ve drugs, we investigated whether U50,488, a selective kappa opioid re ceptor agonist, would alter cocaine-induced increases in extracellular dopamine in the nucleus accumbens using in vivo microdialysis in awak e and freely moving rats. Cocaine (20 mg/kg i.p.) produced a 10-fold i ncrease in extracellular dopamine levels. Pretreatment (20 min beforeh and) with U50,488 (10 mg/kg i.p.), which alone caused a modest decreas e in dopamine levels, produced a 50% decrease in the effect of cocaine on dopamine levels. This attenuation was completely reversed by admin istration of a kappa opioid receptor antagonist, nor-binaltorphimine ( 10 mg/kg s.c.), 20 min before the agonist challenge. Treatment with no r-binaltorphimine alone induced a brief increase in dopamine levels. T hese findings indicate that activation of kappa receptors attenuates c ocaine's effects and that kappa opioid receptor agonists may, therefor e, be useful as functional cocaine antagonists.