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

Abstract.

Rationale: Results of a previous study indicated that prior administration of the kappa-opioid receptor agonist, U69593, blocked the ability of cocaine to reinstate extinguished cocaine-taking behavior. Objectives: In order to determine whether the effect of U69593 was specific to cocaine or was common to cocaine seeking produced by other dopamine uptake inhibitors, the effects of U69593 on cocaine seeking produced by experimenter-administered injections of cocaine, the dopamine uptake inhibitor, GBR 12909, or the cocaine analogs, WIN 35,428 and RTI-55, were compared. Methods: Reinstatement of extinguished cocaine-taking behavior was measured for rats that received injections of the kappa-opioid agonist, U69593 (0.0 or 0.32 mg/kg, SC), 15 min 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, IP). Results: All of the drugs produced a dose-dependent reinstatement of extinguished cocaine-taking behavior. However, only the effects of cocaine and RTI-55 were attenuated by prior administration of U69593 (0.32 mg/kg, SC). The U69593-produced attenuation of cocaine-produced cocaine seeking was reversed by prior administration of the kappa-opioid antagonist, norbinaltorphimine (30.0 µg, ICV), indicating that the effect was mediated by central kappa-opioid receptors. Conclusions: The failure of U69593 to attenuate GBR 12909- or WIN 35,428-produced cocaine seeking suggests that the effect of this kappa-opioid receptor agonist on cocaine seeking is not mediated by interactions at the dopamine transporter. The ability of U69593 to attenuate RTI-55-produced cocaine seeking raises the possibility that kappa-opioids and cocaine may interact at common sites on the serotonin transporter.