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. The purpose of this study is to begin the process of determining whether cocaine agonist, substitution, therapy with cocaethylene is a safe and efficacious treatment for cocaine dependence. Cocaethylene may represent a novel approach to the pharmacotherapy of cocaine dependence, a substance use disorder with no approved pharmacotherapy to date. One approach to the treatment of drug dependence is to administer drugs that can substitute for the drug on which the patient is dependent. The successful implementation of such a strategy depends on several factors. These substitution agents should exert their effects at the same site(s) and/or receptor(s) responsible for the reinforcing effects and/or withdrawal symptoms associated with the abused drug and should be longer acting than the drug on which the patient is dependent. Substitution agents should diminish effects or induce tolerance to the effects of the drug that is being abused. Substitution agents would then reduce or eliminate the drug-seeking behaviors so destructive to the individual and society at large. The use of a drug that could block and/or produce tolerance to cocaine effects and that could be administered in a clinical drug abuse treatment setting similar to the present model of methadone treatment of heroin dependence represents a novel approach to the treatment of cocaine dependence. Recent epidemiological data show that while absolute new numbers of cocaine users has stabilized, the number of emergency room visits for acute medical and psychiatric complications from cocaine use have tripled since 1988, indicating a need for more intensive treatment of cocaine dependence. This study will test the concept that substitution treatment for cocaine dependence will reduce or block the effects of acute cocaine administration. This study will test this concept using cocaethylene, the ethyl ester of benzoylecgonine and a prototype benzoyloxytropane, as the cocaine substitution agent. Cocaethylene has been found to have effects similar to cocaine in human studies (6-8), but cocaethylene is less potent than cocaine at plasma concentrations about twice those produced by a comparator dose of cocaine producing similar cardiovascular and behavioral effects.
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