This is a competing continuation application to study the interactions between cocaine and a novel series of opioids that are selective for mu, kappa and delta receptors. The goal of the proposed studies is to identify and evaluate new pharmacological approaches for the treatment of cocaine abuse and dependence. Cocaine abuse is a significant public health problem and the development of effective anti-cocaine medications is one of NIDA's top priorities. Mu, kappa and delta receptor subtypes are found in the mesolimbic dopamine system, and activation of these receptors alters dopamine levels. Because cocaine's abuse-related effects are thought to be mediated by dopaminergic systems, opioids with mu, kappa and delta receptor selectivity may provide an alternative to dopaminergic compounds as a novel approach to cocaine abuse treatment. Our medicinal chemistry collaborators have synthesized a new series of opioids that are selective for kappa/mu and delta opioid receptors, and are designed to have a long duration of action with minimal adverse side effects. Preclinical behavioral studies suggest that kappa agonists may function as indirect cocaine antagonists, whereas both delta and mu agonists may mimic or enhance cocaine's abuse-related effects. Moreover, efficacy at opioid receptors appears to influence opioid-cocaine interactions. We propose to test the hypothesis that mixed action kappa and mu agonists, low efficacy mu agonists, and high efficacy delta agonists will alter cocaine's abuse-related effects in preclinical behavioral models. The acute and chronic effects of novel medications will be studied with both drug discrimination and drug self-administration procedures. Cocaine- and food-maintained responding will be studied to determine the relative selectivity of medication effects on cocaine self-administration. A new Rapid Assessment Procedure will be used to evaluate acute medication effects on complete cocaine-dose effect curves. Chronic medication effects on food- and cocaine-maintained responding will be studied to determine the stability of medication effects, and to evaluate adverse side effects, and medication withdrawal signs when treatment is discontinued. The effects of chronic treatment on complete cocaine dose-effect functions will be examined. The most safe and effective medications will be compared using a new Progressive Ratio Procedure to determine if cocaine's reinforcing efficacy is altered. This comprehensive evaluation of the effects of novel mu, kappa and delta selective opioids on cocaine's abuse-related effects should suggest new approaches to cocaine abuse treatment.
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