Cocaine abuse and dependence continues to be a critical public health problem that is directly associated with crime and the spread of AIDS and other infectious disease. The development of medication strategies and the identification of candidate therapeutics represent an important effort to address this problem. One of the most well-established approaches for studying drug abuse and dependence is i.v. drug self-administration in nonhuman primates. Yet, techniques to evaluate medication strategies and candidate therapeutics by studying how chronic treatment alters i.v. drug self-administration have been lacking. We propose to address this problem in studies using new procedures that will permit full and reproducible dose-effect functions for cocaine self-administration to be determined within one or two consecutive sessions. We will use these procedures to evaluate the acute and chronic effects of candidate therapeutics that represent different medication strategies including indirect dopamine agonists with long onsets to action and direct dopamine D1 receptor ligands that have either agonist or antagonist effects. These studies will provide needed information regarding the therapeutic utility of different medication strategies and how effective those strategies might be in long-term treatment programs. During both acute and chronic treatments with different medication strategies, we also will conduct experiments in which the response cost for consequent i.v. cocaine injections is varied systematically. The results of these studies will improve our understanding of how pharmacological and contextual treatments for cocaine abuse and dependence can be coordinated in a synergistic manner. We also will perform in vitro autoradiographic analyses to determine how the different chronic treatments alter the densities of cocaine binding sites associated with the doparnine transporter and of dopamine Dl and D2 receptors. In conjunction with our behavioral studies, these analyses will provide essential preclinical information for evaluation of these candidate therapeutics for the treatment of cocaine addiction.
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