Psychopharmacology of Novel Medications for Cocaine Dependence

项目总结（见说明）： 可卡因依赖与多巴胺（DA）脑系统的缺陷密切相关。ChnDnic 可卡因使用者在已知由DA调节的认知过程中表现出损伤（例如，工作记忆， 决策）。因此，最近的药物开发工作集中在DA增强 可能“替代”可卡因并由此使DA相关功能障碍正常化的药物，例如，左旋多巴/卡比多巴。 这些药物在减少可卡因方面显示出临床益处;然而， 左旋多巴/卡比多巴不足的部分和无反应者。 除了多巴胺，可卡因依赖与5-羟色胺（5-HT）系统的缺陷有关。慢性可卡因 使用者在已知受5-HT调节的过程中表现出损伤（例如，冲动）。我们对5-HT的研究 包括氟西汀和西酞普兰在内的药物在减少可卡因使用方面显示出一定的益处， 研究结果在试验和患者亚组中混合。 由于可卡因导致DA和5-HT系统功能障碍，理想的替代疗法是 预计将针对这两个系统。这项研究是第一个安慰剂对照研究，以检查双重缺陷， 模型通过评估DA和5-HT药剂的组合用于治疗可卡因依赖。它 假设左旋多巴和西酞普兰的联合给药将减少可卡因的使用， 持续禁欲的时间大大超过单独药物或安慰剂。 本研究还将使用新的贝叶斯亚组分析来评估行为实验室的效用 作为治疗反应的预测指标。我们希望在电池上的性能 神经心理学任务（工作记忆，决策，冲动）已知与 多巴胺能和多巴胺能功能，将与药物治疗的反应水平相关 针对这些单胺系统。最后，这些行为任务的相对表现变化 治疗三周后，将作为药物反应的潜在介质进行测量。

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.