This project proposes to use an efficient human laboratory screening methodology to examine the effects of various pharmacological treatments that may modulate the effects of cocaine relevant to its abuse. The aim is to contribute to the identification and development of medications that may be useful in the treatment of cocaine abuse. This is an ongoing and productive project, and this is an application for its continuation. The efficient human laboratory screening methodology proposed is one that has been developed during the first years of this project's operation. A methodological refinement to be added during this renewal period is the assessment of pharmacological effects on elicitation of cocaine-related conditioned craving. Pharmacological effects on cocaine's direct effects and on cocaine-elicited craving for cocaine will continue to be assessed. In addition, effects of the pharmacological pretreatments that may be relevant to their safety and/or acceptability will be assessed. Assessment of both cocaine effects and pharmacological pretreatment effects is multi-dimensional, including subjective, behavioral, and physiological effects. The primary general method to be used in these studies is that of double-blind, controlled human laboratory cocaine challenges under various conditions of pharmacological pretreatment. To maximize the practical efficiency of these studies, each cocaine challenge session will involve multiple injections and will produce a cocaine dose-effect function, and the pharmacological pretreatments will be provided on a chronic basis with the dose progressively increasing across days, so that relatively high doses can be assessed and so that effects of chronic treatment can be assessed. While the specific pretreatment drugs most appropriate for testing will be continually reassessed during the course of the project, those judged most promising, appropriate, and/or informative and, therefore, planned at the present time include: naltrexone, cocaine itself (orally), carbamezepine, flupenthixol, bromocriptine, bupropion, fluoxetine, haloperidol, desipramine, ondansetron. These studies are relevant to the treatment of intravenous drug abuse and to efforts to reduce the spread of AIDS and HIV infection by reducing HIV-associated risk behaviors.