Reinstatement of extinguished drug-taking behavior in rats: effect of the kappa-opioid receptor agonist, U69593

Rationale: Results of a previous study indicated that prior administration of the kappa-opioid receptor agonist, U69593, blocked the ability of cocain e to reinstate extinguished cocaine-taking behavior. Objectives: In order t o determine whether the effect of U69593 was specific to cocaine or was com mon to cocaine seeking produced by other dopamine uptake inhibitors, the ef fects of U69593 on cocaine seeking produced by experimenter-administered in jections of cocaine, the dopamine uptake inhibitor, GBR 12909, or the cocai ne analogs, WIN 35,428 and RTI-55, were compared. Methods: Reinstatement of extinguished cocaine-taking behavior was measured fur rats that received i njections of the kappa-opioid agonist, U69593 (0.0 or 0.32 mg/kg, SC), 15 m in prior to injections of cocaine- (0.0-20.0 mg/kg, IP), GBR 12909- (0.0-30 .0 mg/kg, IP), WIN 35,428- (0.0-3.0 mg/kg, IP) or RTI-55 (0.0-0.50 mg/kg, I P). Results: All of the drugs produced a dose-dependent reinstatement of ex tinguished cocaine-taking behavior. However, only the effects of cocaine an d RTI-55 were attenuated by prior administration of U69593 (0.32 mg/kg, SC) . The U69593-produced attenuation of cocaine-produced cocaine seeking was r eversed by prior administration of the kappa-opioid antagonist, norbinaltor phimine (30.0 mu g, ICV), indicating that the effect was mediated by centra l kappa-opioid receptors. Conclusions: The failure of U69593 to attenuate G BR 12909- or WIN 35,428-produced cocaine seeking suggests that the effect o f this kappa-opioid receptor agonist on cocaine seeking is not mediated by interactions at the dopamine transporter. The ability of U69593 to attenuat e RTI-55-produced cocaine seeking raises the possibility that kappa-opioids and cocaine may interact at common sites on the serotonin transporter.