Cocaine-opioid interactions in groups of rats trained to discriminate different doses of cocaine

Rationale: The growing abuse of cocaine combined with morphine-like opiates ("speedballs") in human addicts has prompted efforts to characterize the r oles of different opioid receptor subtypes in mediating their combined effe cts. Previous drug discrimination studies in rats have been inconsistent in showing significant interactions between cocaine and opioid agonists in su bjects trained to discriminate a relatively high dose of cocaine from vehic le. It is known, however, that the training dose of cocaine can play a key role in drug-substitution and drug-interaction profiles and, therefore, tra ining rats to discriminate a relatively low dose of cocaine may influence i ts interactions with opioid agonists. Objectives: The objectives of this st udy were to examine the degree to which a relatively high (10 mg/kg) versus a relatively low (3.0 mg/kg) cocaine training dose influenced the:interact ions between cocaine and either the mu opioid agonist morphine or the kappa opioid agonist U50,488. Methods: Substitution tests with cumulative doses of cocaine, morphine and U50,488 were conducted, as were studies in which s elected doses of morphine or U50,488 were administered prior to cumulative doses of cocaine. Results: In substitution tests, cocaine was 2.9 times mor e potent under the low- than the high-dose training condition. Morphine sub stituted fully for cocaine in the majority of subjects trained to discrimin ate the low, but not the high, dose of cocaine. U50,488 engendered mainly s aline-lever responses under both training conditions. In pretreatment studi es, morphine enhanced and U50,488 attenuated the discriminative stimulus ef fects of cocaine in low-dose, but not high-dose, trained rats. In low-dose trained rats, cocaine was five- to eightfold more potent after morphine and three- to fourfold less potent after U50,488 pretreatments, Conclusions: T he results demonstrate that cocaine-opioid interactions are dependent on th e training dose of cocaine in rats and suggest an opposing influence of mu and kappa opioid receptors in modifying the discriminative stimulus effects of cocaine.