Varieties of Impulsivity in Opiate and Stimulant Users

描述（由申请人提供）：该项目的前奏是与保加利亚同事的两次成功合作，我们对阿片类药物和兴奋剂的相对“纯”用户的冲动性进行了全面表征，并收集和储存了许多参与者的遗传物质。这种竞争性更新的总体目标是调查冲动作为药物成瘾的内在表型的作用。虽然冲动性被认为是成瘾的最强候选内在表型之一，但该领域的进展受到以下因素的阻碍：（1）冲动性的异质性，其特征在于多重人格、精神和神经认知维度;（2）成瘾表型的异质性，部分原因是多种物质依赖的高比率;以及（3）遵循完整的内表型标准的研究数量有限，并且缺乏用于最佳内表型选择的客观定量方法。为了应对这些挑战，我们在保加利亚制定了一项成瘾研究方案，保加利亚是海洛因贩运的主要过境国，也是欧洲合成安非他明类兴奋剂的主要生产中心。这使我们能够接触到少数主要依赖单一物质的海洛因和苯丙胺使用者，其中许多人长期戒断。我们的初步研究结果揭示了一个复杂的特质和神经认知（状态）维度的冲动，往往表现在相反的方向在海洛因和苯丙胺依赖的个人之间的关系。飞行员计算模型分析的决策，中央神经认知方面的冲动，证明特别翔实的基础上，不同的机制受损的决策阿片类药物和兴奋剂用户。我们的研究结果强调了检查冲动性的多个和更狭窄定义的维度的效用，并为越来越多的文献做出了重大贡献，这些文献揭示了不同类型的慢性使用者之间的重要差异。 毒品通过这种竞争性的更新申请，我们建议继续合作，为保加利亚的神经遗传成瘾研究建立可持续的基础设施，并解决以下具体目标：（1）评估各种个性，精神病学和神经认知冲动指数（单独或组合）作为药物成瘾的候选内表型的效用，特别是阿片类药物和兴奋剂成瘾。我们建议将传统的内表型选择方法与一种新的、衍生的定量方法进行比较，以实现这一目标。为了重复和验证我们之前的发现，我们将在一个新的队列中使用相同的综合冲动电池，该队列包括100名海洛因使用者和100名兄弟姐妹; 100名安非他明使用者和100名兄弟姐妹;以及100名健康的非相关对照（N=500），两项研究的总人数为N=800;（2）评估将冲动的各种神经认知维度建模为成瘾的新内表型的计算模型参数的可行性;和（3）通过评估最佳内表型与长期戒断的阿片类药物和兴奋剂使用者的HIV和其他危险行为的关联来测试最佳内表型的外部效度，这是一个对成瘾周期这一鲜为人知的阶段的预防和干预工作至关重要的问题。

DESCRIPTION (provided by applicant): The preludes to this project are two successful prior collaborations with Bulgarian colleagues in which we conducted comprehensive characterization of impulsivity in relatively "pure" users of opiates and stimulants and collected and stored genetic material from many of these participants. The overall aim of this competing renewal is to investigate the role of impulsivity as an endophenotype for drug addiction. Although impulsivity is considered one of the strongest candidate endophenotypes for addiction, progress in the field is hampered by: (1) the heterogeneity of impulsivity, characterized by multiple personality, psychiatric, and neurocognitive dimensions; (2) the heterogeneity of addiction phenotypes, due in part to the high rates of polysubstance dependence; and (3) the limited number of studies following the full endophenotype criteria and related lack of objective quantitative methods for optimal endophenotype selection. To address these challenges, we have developed a program of addiction research in Bulgaria, a key transit country for heroin trafficking and a major European center for production of synthetic amphetamine-type stimulants. This has allowed us to access rare populations of predominantly monosubstance-dependent heroin and amphetamine users, many in protracted abstinence. Our preliminary results reveal a complex relationship between trait and neurocognitive (state) dimensions of impulsivity, often manifested in opposite directions in heroin and amphetamine dependent individuals. Pilot computational modeling analyses of decision-making, a central neurocognitive aspect of impulsivity, proved particularly informative by indicating that different mechanisms underlie the impaired decision-making of opiate and stimulant users. Our findings underscore the utility of examining multiple and more narrowly-defined dimensions of impulsivity and contribute significantly to a growing body of literature that reveals important differences between chronic users of different classes of drugs. With this competing renewal application, we propose to continue our collaboration to build sustainable infrastructure for neurogenetic addiction research in Bulgaria and address the following specific aims: (1) Assess the utility of various personality, psychiatric, and neurocognitive indices of impulsivity (either individually or in combination) as candidate endophenotype(s) for drug addiction in general and for opiate and stimulant addictions in particular. We propose to compare the traditional method for endophenotype selection to a novel, empirically-derived quantitative method for optimal endophenotype selection in approaching this aim. To replicate and validate our previous findings, we will use the same comprehensive impulsivity battery in a new cohort of 100 heroin users and 100 siblings; 100 amphetamine users and 100 siblings; and 100 healthy non-related controls (N=500), for a total N=800 across the two studies; (2) Evaluate the viability of computational model parameters modeling various neurocognitive dimensions of impulsivity as novel endophenotype(s) for addiction; and (3) Test the external validity of the optimal endophenotype(s) by evaluating their associations with HIV and other risk behaviors in opiate and stimulant users in protracted abstinence, a question of critical importance for prevention and intervention efforts in this much less-well understood stage of the addiction cycle.