Psychopharmacology of Novel Medications for Cocaine Dependence

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PROJECT SUMMARY (See instructions): Cocaine dependence has been linked closely to deficits in the dopamine (DA) brain system. ChnDnic cocaine users show impairments in cognitive processes known to be regulated by DA (e.g., working memory, decision-making). Consequently, recent medication development efforts have focused on DA-enhancing agents that might "replace" cocaine and thereby normalize DA-related dysfunction, e.g., levodopa/carbidopa. These agents have shown clinical benefit in reducing cocaine; however there is a substantial subgroup of partial and non-responders for whom levodopa/carbidopa is not sufficient. In addition to DA, cocaine dependence is linked to deficits in serotonin (5-HT) system. Chronic cocaine users show impairments in processes know to be regulated by 5-HT (e.g., impulsivity). Our studies of 5-HT agents, including fluoxetine and citalopram, have shown some benefit in reducing cocaine use, although findings have been mixed across trials and patient subgroups. Since cocaine causes dysfunction in DA and 5-HT systems, an ideal replacement therapy would be expected to target both systems. The proposed study is the first placebo controlled study to examine a dualdeficit model by evaluating the combination of a DA and 5-HT agent for treatment of cocaine dependence. It is hypothesized that the co-administration of levodopa and citalopram will reduce cocaine use and increase periods of sustained abstinence substantially more than either medication alone or placebo. This study will also use novel Bayesian subgroup analyses to evaluate the utility of behavioral laboratory measures as predictors of treatment response. We expect that performance on a battery of neuropsychological tasks (working memory, decision-making, impulsivity) known to be associated with dopaminergic and serotonergic function, will be related to level of response to pharmacological treatment targeting these monoamine systems. Finally, relative changes in performance on these behavioral tasks after three weeks of treatment will be measured as potential mediators of medication response.