This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Many polydrug abusers take cocaine in combination with heroin by administering the drugs together in the form of a 'speedball'. Previous studies have found that heroin can enhance the behavioral effects of cocaine, although the receptor mechanisms underlying this enhancement are not well understood. The present study investigated the relative role of mu and delta opioid receptor mechanisms in the subjective effects of speedball combinations in rhesus monkeys trained to discriminate intravenous injections of cocaine from saline under a fixed-ratio schedule of food delivery. In substitution studies, the mu opioid receptor agonists heroin and methadone partially reproduced the subjective effects of cocaine, whereas the delta opioid receptor agonist SNC 80 did not. Combined treatment with cocaine and heroin, administered by co-injecting incremental doses of cocaine and heroin while keeping the dose-ratio constant, enhanced the effects of low-to-intermediate doses of cocaine, resulting in an overall leftward shift in the cocaine dose-response function. A similar enhancement of the subjective effects of cocaine was observed with co-administration of methadone. In contrast, co-administration of SNC 80 with cocaine resulted in a less pronounced change in the shape and position of the cocaine dose-response function. In additional studies, the cocaine-enhancing effects of heroin were reversed completely by low doses of the mu opioid receptor antagonist naltrexone; but not by the delta opioid receptor antagonist naltrindo
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