Our previous research has shown an enhancement of cocaine's discriminative stimulus effects by morphine-like drugs, perhaps reflecting an ability of these drugs to enhance the interoceptive effects of cocaine. Morphine-like drugs (i.e., opioids) exert their effects via the f-opioid receptor. Interestingly, however, recent evidence has implicated a role for the k-opioid receptor in behavioral action of the commonly abused opioid, heroin. The present study assessed the ability of selective f and k opioids to alter cocaine's DS effects, in order to determine the receptor mechanism involved in the cocaine-enhancing effects of this class of abused drugs. Squirrel monkeys were trained to discriminate intramuscular injections of 0.3 mg/kg cocaine from saline under a fixed-ratio 10 schedule of food presentation. Cumulative doses of cocaine (0.03-1.0 mg/kg) engendered dose-related increases in drug-lever responding to a maximum of 100%. Cumulative doses of SNC 80 (0.03-1.0 mg/kg) engendered dose-related increases in drug-lever responding to a maximum of 100%. Cumulative doses of SNC 80 (0.03-1.0 mg/kg) or fentanyl (0.001-0.01 mg/kg) resulted in a maximum of 22% and 48% drug lever responding, respectively. Administration of either SNC 80 (0.1-1.0 mg/kg) or fentanyl (0.001-0.01 mg/kg) prior to cumulative doses of cocaine produced dose-dependent leftward shifts in the cocaine dose-response function. When the selective k antagonist naltrindole (1.0 mg/kg) was combined with SNC 80 (1.0 mg/kg) or fentanyl (0.01 mg/kg) prior to cumulative doses of cocaine, the leftward shift of the cocaine dose-response function produced by SNC 80 was blocked, whereas the leftward shift produced by fentanyl was not. By contrast, the f antagonist naltrexone (0.3 mg/kg) blocked the cocaine-enhancing effects of fentanyl, but not of SNC 80. These results suggest that opioid enhancement of the discriminative stimulus effects of cocaine can be mediated independently by k- and f-receptor mechanisms.
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