Laboratory Models of Cocaine Self-Administration

可卡因依赖问题仍然是一个主要的医疗、社会和法律的问题， 据估计，目前有230万美国人使用可卡因。的结局 除了最近的结果外，药物开发工作总体上令人沮丧 获得双硫仑。一系列临床试验表明，双硫仑治疗 与可卡因使用减少相关，独立于共病药物或酒精使用。的 根据临床试验中观察到的结果验证人体实验室模型将是一个 在开发更有效的可卡因依赖治疗方法方面迈出了重要一步。这是 这是一项至关重要的任务，因为动物或人类实验室之间还没有达成良好的雅阁， 模型发现和临床试验的结果。双硫仑具有多种作用，其中之一是 抑制多巴胺β羟化酶，该酶负责将多巴胺代谢成 去甲肾上腺素最近获得的数据表明，双硫仑是特别有效的患者 具有多巴胺β羟化酶的“T”等位基因; C/T基因型与降低的 酶活性与C/C基因型相比。因此，我们建议评估 双硫仑治疗对可卡因自我给药的遗传特征非治疗 寻找志愿者参与者将被筛选，只有那些与DBH C/T基因型将 包括.可卡因自我给药的影响将使用两个已建立的人类 实验室模型，一个在哥伦比亚大学开发，另一个在约翰 霍普金斯。基于双硫仑治疗在临床试验中观察到的效果，特别是 双硫仑在C/T基因型受试者中的作用，我们预计双硫仑治疗将 减少实验室中的可卡因自我给药。

The problem of cocaine dependence remains a major medical, social, and legal concern, with 2.3 million Americans estimated to be current users of cocaine. The outcome from medications development efforts has generally been discouraging, excepting for results recently obtained for disulfiram. A series of clinical trials have shown that disulfiram treatment was associated with reduced cocaine use, independent of co-morbid drug or alcohol use. The validation of a human laboratory model against outcomes observed in clinical trials would be a major step forward in developing even more effective treatments for cocaine dependence. This is a crucial undertaking, since there has not been good accord between animal or human laboratory model findings and results from clinical trials. Disulfiram has a variety of actions, one of which is to inhibit dopamine beta hydroxylase, the enzyme responsible for metabolizing dopamine into norepinephrine. Recently obtained data indicate that disulfiram is particularly effective in patients with a "T" allele of dopamine beta hydroxylase; the C/T genotype is associated with reduced enzyme activity compared to the C/C genotype. We therefore propose to evaluate effects of disulfiram treatment on cocaine self-administration in genetically characterized non-treatment seeking volunteers. Participants will be screened and only those with the DBH C/T genotype will be included. Effects of cocaine self-administration will be assessed using two established human laboratory models, one developed at Columbia University and the other developed at Johns Hopkins. Based on the observed effects of disulfiram treatment in clinical trials, especially effects of disulfiram in participants with the C/T genotype, we anticipate that disulfiram treatment will decrease cocaine self-administration in the laboratory.