Evaluation Of Treatments Of Opioid And Cocaine Dependence

我们评估了β-肾上腺素能拮抗剂普萘洛尔是否可以减弱或消除习得性联想或情感记忆，这些联想或情感记忆是由药物相关线索引起的渴望的基础，在记忆被线索重新激活后不久的再巩固窗口期间给予普萘洛尔。在接受美沙酮维持治疗的同时使用可卡因的健康门诊患者被要求在初步访谈中回忆特定的可卡因使用事件和中性事件。在干预会议上，我们给予普萘洛尔（40毫克）或安慰剂之前，介绍个性化的听觉意象脚本和线索集的采访。分组是随机的，药物是匹配的，所以参与者和研究人员都不知道给了什么药物。参与者每周两次返回实验室进行尿液药物筛查。 线索反应性评估渴望规模和生理反应，参与者再次暴露于脚本/线索集普萘洛尔/安慰剂会议后1周和5周。 出乎意料的是，普萘洛尔组的参与者表现出比安慰剂组更大的线索反应。 普萘洛尔给药期间存在这种效应，并且在随后的试验期间似乎持续存在（尽管未达到统计学显著性）。这些结果不支持普萘洛尔用于阿片类药物维持患者的线索/可卡因关联衰减。 在另一项研究中，我们评估了在成瘾的认知行为治疗（CBT）期间，家庭作业任务简化和电子日记提醒对完成书面作业的影响。 所有参与者都接受了我们两种干预措施的所有组合，采用了平衡拉丁方设计。 这两种干预措施都没有增加家庭作业的完成，并且基于生态瞬时评估（EMA），标准但不简化的家庭作业似乎可以缓冲日常生活中环境暴露于药物线索后的渴望。 研究结果表明EMA在评估治疗效果方面的有用性，但不支持简化作业会增加依从性的假设。 我们正在继续评估患者的特征，这些特征可能会指导个性化医疗的发展。 使用诱导型多能干细胞（iPSCs），我们从阿片类药物依赖和对照参与者中产生了多巴胺神经元，这些参与者在多巴胺转运蛋白（DAT或SLC 6A 3）基因中携带不同的3个VNTR（可变数目串联重复序列）多态性。 我们发现，3 VNTR多态性影响DAT的表达和治疗的神经元与丙戊酸改变了多巴胺能功能，包括DAT，Nurr 1和TH的几个重要基因的表达。 丙戊酸还显著增加了D2受体的表达，特别是在来自阿片类药物依赖参与者的细胞系中。 我们的数据表明，人类iPSC衍生的DA神经元是一种有用的体外实验模型，可以研究遗传变异对基因调控的影响，研究成瘾和其他疾病的潜在机制，并作为治疗开发的平台。 最后，我们继续开发地理瞬时评估（GMA），一种测量和理解参与者日常旅行中的情绪，药物使用和环境暴露于心理社会压力之间关系的方法。 GMA在很大程度上是一种描述性的技术，但我们仍然致力于将描述转化为干预。 例如，我们已经证明，电子日记研究可以提供对药物滥用者在治疗期间的日常生活的惊人洞察，以及对即使是短暂禁欲期间的行为变化敏感的数据。 使我们能够在现场收集药物使用，渴望和压力数据的技术也可以用于现场治疗，也许是为了响应患者对先前确定的触发器的运动。

We evaluated whether the beta-adrenergic antagonist propranolol could attenuate or erase the learned associations, or emotional memories, that underlie craving elicited by drug-related cues, administering propranolol during the reconsolidation window shortly after the memories were reactivated by cues. Healthy outpatients who used cocaine while receiving methadone maintenance were asked to recall specific cocaine-use events and neutral events in preliminary interviews. In the intervention sessions, we administered propranolol (40 mg) or placebo before presentation of personalized auditory imagery scripts and cue sets developed from the interviews. Group assignment was randomized, and medications were matched so that neither the participants nor the research staff knew what drug was given. Participants returned to the lab twice a week for urine drug screens. Cue reactivity was assessed by craving scales and physiological responses as participants were reexposed to the script/cue sets 1 week and 5 weeks after the propranolol/placebo session. Unexpectedly, participants in the propranolol group showed greater cue reactivity than those in the placebo group. This effect was present during propranolol administration and seemed to persist (though without reaching statistical significance) during the later test sessions. These results do not support the use of propranolol for attenuation of cue/cocaine associations in opioid-maintained patients. In another study, we evaluated the effects of homework-task simplification and electronic-diary reminders on completion of written homework during cognitive-behavioral therapy (CBT) for addiction. All participants received all combinations of our two interventions in a counterbalanced Latin-square design. Neither of the interventions increased homework completion, and based on ecological momentary assessment (EMA), standard but not simplified homework seemed to buffer the craving that followed environmental exposure to drug cues in daily life. The findings demonstrated the usefulness of EMA in assessing treatment effects, but did not support the hypothesis that homework simplification would increase compliance. We are continuing to evaluate patient characteristics that may guide developments in personalized medicine. Using inducible pluripotent stem cells (iPSCs), we produced DA neurons from opioid-dependent and control participants carrying different 3 VNTR (variable number tandem repeat) polymorphisms in the gene for the dopamine transporter (DAT or SLC6A3). We found that the 3 VNTR polymorphism affected DAT expression and that treatment of the neurons with valproic acid alters the expression of several genes important for dopaminergic functioning, including DAT, Nurr1 and TH. Valproic acid also significantly increased expression of D2 receptors, especially in cell lines derived from the opioid-dependent participants. Our data suggest that human iPSC-derived DA neurons are a useful in vitro experimental model to examine the effects of genetic variation on gene regulation, to examine underlying mechanisms of addiction and other disorders, and to serve as a platform for treatment development. Finally, we continue to develop Geographical Momentary Assessment (GMA), an approach to measurement and understanding of the relationships among mood, drug use, and environmental exposure to psychosocial stressors in participants daily travels. GMA is largely a descriptive technique, but we remain committed to transforming description into intervention. For example, we have shown that electronic-diary studies can provide amazing insight into the daily lives of substance abusers during treatment and data that are sensitive to behavioral changes during even brief periods of abstinence. The technologies that enable us to collect data on drug use, craving, and stress in the field may also be used for delivery of treatment in the field, perhaps in response to the patients movement toward previously identified triggers.