Laboratory Models of Cocaine Self-Administration

描述（由申请人提供）：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，估计目前有230万美国人使用可卡因。药物开发工作的结果通常令人沮丧，除了最近获得的双硫仑结果。一系列临床试验表明，双硫仑治疗与可卡因使用减少相关，与合并症药物或酒精使用无关。根据临床试验中观察到的结果验证人体实验室模型将是开发更有效的可卡因依赖治疗方法的一个重大步骤。这是一项至关重要的工作，因为动物或人类实验室模型的发现与临床试验的结果之间还没有很好的雅阁。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为去甲肾上腺素。最近获得的数据表明，双硫仑在多巴胺β羟化酶（DBH）的“T”等位基因患者中特别有效;与C/C基因型相比，C/T基因型与酶活性降低相关。因此，我们建议评估双硫仑治疗对遗传特征的非寻求治疗的志愿者可卡因自我给药的影响。将对参与者进行筛选，仅包括具有DBH C/T基因型的参与者。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进行评估，一个是在哥伦比亚大学开发的，另一个是在约翰霍普金斯开发的。基于在临床试验中观察到的双硫仑治疗效果，特别是双硫仑对C/T基因型受试者的影响，我们预计双硫仑治疗将减少实验室中可卡因的自我给药。

DESCRIPTION (provided by applicant): 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 (DBH); 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.