Tiagabine and Disulfiram for Cocaine Dependence

美沙酮维持患者中共病可卡因依赖干扰治疗结果。双硫仑（D β H抑制剂）和噻加宾（GAT-1阻滞剂）在治疗可卡因依赖方面显示出有希望的结果。虽然D β H活性的抑制被假设为主要在新皮层中增加多巴胺神经传递并加强可卡因使用的烦躁体验，但GABA再摄取的选择性抑制被假设为主要在延髓核中减弱多巴胺神经传递并减少可卡因使用的强化作用。本提案的目的是确定多巴胺β羟化酶（DBH-1021 C->T）功能多态性的前瞻性筛查在多大程度上预测双硫仑和噻加宾在新入院接受美沙酮治疗的患者中的疗效。DBH-1021 C->T通过影响DBH基因表达调节血浆D β H水平。基于我们的初步研究，我们假设低D β H相关T等位基因的携带者将显著减少可卡因的使用，因为他们更容易受到双硫仑对D β H的抑制。相比之下，高DpH相关C等位基因的携带者在使用双硫仑的情况下几乎不会减少可卡因的使用，但在使用噻加宾的情况下可能会显著减少，因为噻加宾在减少多巴胺释放方面的作用相反。这项为期14周的双盲、安慰剂对照随机临床试验将为150名可卡因依赖阿片类药物依赖患者提供治疗。年龄在18-65岁之间的受试者将随机接受双硫仑250 mg/天、噻加宾24 mg/天或安慰剂，同时接受美沙酮治疗。所有参与者每周接受1小时的心理治疗（认知行为治疗）。主要结果将是阿片类药物和可卡因使用的减少，通过自我报告进行评估，并通过每周三次的尿液分析进行确认。这项研究有望更好地了解D β H抑制剂双硫仑和选择性GABA再摄取抑制剂噻加宾对不同DBH-1021 C->T基因型可卡因使用行为的作用。

Comorbid cocaine dependence among methadone maintained patients interferes with treatment outcomes. Disulfiram (DbetaH inhibitor) and Tiagabine (GAT-1 blocker) have shown promising results in the treatment of cocaine dependence. While inhibition of DbetaH activity is hypothesized to increase dopamine neurotransmission primarily in the neocortex and to intensify the dysphoric experience of cocaine use, the selective inhibition of GABA reuptake is hypothesized to attenuate dopamine neurotransmission primarily in the nucleus accumbens and to reduce the reinforcing effects of cocaine use. The objective of this proposal is to determine to what extend does prospective screening for a functional polymorphism of dopamine beta hydroxylase (DBH-1021C->T) predict the treatment efficacy of disulfiram and tiagabine among newly admitted methadone treated patients. DBH -1021C->T regulates plasma DbetaH levels by influencing DBH gene expression. Based on our pilot studies, we hypothesize that carriers of the low-DbetaH associated T allele will have significant reductions in cocaine use, because they are more susceptible to inhibition of DbetaH by disulfiram. In contrast, carriers of the high-DpH associated C allele will have little reduction in cocaine use with disulfiram, but may have significant reductions with tiagabine, because of tiagabine's contrasting action in reducing dopamine release. This 14-week double-blind, placebo controlled randomized clinical trial will provide treatment for 150 cocaine-dependent opioid dependent patients. Participants, aged 18-65 years, will be randomized to receive disulfiram 250mg/day, tiagabine 24mg/day, or placebo while concurrently receiving treatment with methadone. All participants receive weekly 1-hour psychotherapy (Cognitive Behavioral Treatment). The primary outcomes will be reduction in opioid and cocaine use, as assessed by self-report and confirmed by thrice-weekly urinalyses. The proposed study is expected to provide a better understanding of the role of the DbetaH inhibitor disulfiram and the selective GABA reuptake inhibitor tiagabine on cocaine using behavior among distinct DBH -1021C->T genotypes.