The ability of cues previously associated with cocaine to trigger craving, even after long intervals of abstinence, has been hypothesized to be an important determinant of relapse. We have found that cocaine cues increase homovanillic acid, ACTH and cortisol. We now plan to study the relationship of these neurochemical changes to subjective cue- induced increases in anxiety, craving and euphoria. Subjects will be pretreated with medications that suppress a neurochemical response to cocaine cues and the subjective response to cocaine cues will then be evaluated. The kappa agonist butorphanol and the dopamine autoreceptor agonist pramixpexole will be used to inhibit dopamine release. The steroid synthesis inhibitor ketoconazole will be used to inhibit cue- induces increases in cortisol (component 1, Cue Reactivity) If medications can be identified that suppress cue-induced craving and other subjective responses, this would enable future clinical trials to evaluate the hypothesized relationship between cue-induced craving and relapse. Identifying such medications is a major goal of this proposal. The safety of these medications interactions with cocaine needs to be established before any clinical trials can be undertaken. Therefore, medications will also be evaluated for the safety of their interaction with cocaine infusion effects and cocaine pharmacokinetics (component 2, Jones laboratory). The most promising of the three medications in terms of efficacy, safety and side effect profile will be the subject of a 6-week pilot double blind study in 80 DSM-IV cocaine dependent patients (component 3, Pilot Clinical Trial). This trial will determine whether the study medication is as effective in attenuating cocaine cue- induced craving after chronic administration in the clinical trial as compared to acute pretreatment in the human laboratory setting, and whether treatment retention and abstinence (defined by quantitative urinary levels of the cocaine metabolite benzoylecgonine) are enhanced. This will provide the basis for a more definitive clinical trial of the relationship between cue-induced cocaine craving and relapse.
