Tiagabine and Disulfiram for Cocaine Dependence

美沙酮维持患者中的共病可卡因依赖干扰了治疗结果。双硫兰(DbetaH抑制剂)和替加宾(GAT-1阻滞剂)在治疗可卡因依赖方面显示出良好的效果。抑制DbetaH活性被认为增加了主要在新皮质的多巴胺神经传递，并加强了使用可卡因的焦虑感，而选择性抑制GABA再摄取被假设为减弱了主要在伏核的多巴胺神经传递，并减少了可卡因使用的强化效应。这项建议的目的是确定前瞻性筛查多巴胺β羟基酶功能多态性(DBH-1021C-&GT；T)在多大程度上预测新入院的美沙酮治疗患者的双硫兰和替加宾的治疗效果。DBH-1021C-&GT；T通过影响DBH基因表达来调节血浆DbetaH水平。根据我们的初步研究，我们假设低DbetaH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二磺胺对DbetaH的抑制。相比之下，携带高DPH相关C等位基因的携带者在使用双硫兰时可卡因使用量几乎没有减少，但使用替加宾可能会显著减少可卡因使用量，因为替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岁的受试者将被随机分成三组，分别接受双硫兰250 mg/天、替加他滨24 mg/天或安慰剂治疗，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)。主要结果将是减少阿片类药物和可卡因的使用，这是通过自我报告评估的，并得到每周三次尿液分析的证实。这项拟议的研究有望更好地了解DbetaH抑制剂双硫兰和选择性GABA再摄取抑制剂替加宾在不同DBH-1021C-&GT；T基因型别的可卡因使用行为中的作用。

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.