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的合作，在这两次合作中，我们对相对“纯粹”的阿片剂和兴奋剂使用者的冲动进行了全面的表征，并从许多参与者那里收集和存储了遗传物质。这一竞争性更新的总体目标是研究冲动作为药物成瘾的内在表型所起的作用。尽管冲动被认为是成瘾的最强候选内表型之一，但该领域的进展受到以下因素的阻碍：(1)冲动的异质性，以多个人格、精神和神经认知维度为特征；(2)成瘾表型的异质性，部分原因是多物质依赖率高；以及(3)遵循完整内表型标准的研究数量有限，以及相关的客观定量方法缺乏最优内表型选择。为了应对这些挑战，我们在保加利亚制定了一个成瘾研究计划，保加利亚是海洛因贩运的主要中转国，也是欧洲主要的合成苯丙胺类兴奋剂生产中心。这使我们能够接触到以单一药物依赖为主的海洛因和苯丙胺使用者的罕见人群，其中许多人处于长期戒断状态。我们的初步结果揭示了冲动的特质和神经认知(状态)维度之间的复杂关系，通常在海洛因和苯丙胺依赖者中表现为相反的方向。对决策的试点计算模型分析是冲动性的一个中枢神经认知方面，通过表明不同的机制是鸦片和兴奋剂使用者决策受损的基础，证明了特别有意义的。我们的发现强调了考察冲动的多个更狭义的维度的效用，并显著促进了越来越多的文献揭示了不同类别的慢性冲动使用者之间的重要差异 毒品。通过这一竞争性的更新申请，我们建议继续合作，为保加利亚的神经遗传学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、精神和神经认知指标(单独或组合)作为总体药物成瘾，特别是阿片和兴奋剂成瘾的候选内表型(S)的实用性。为了达到这一目标，我们建议将传统的内表型选择方法与一种新的、经验式衍生的最优内表型选择的定量方法进行比较。为了重复和验证我们之前的发现，我们将在100名海洛因吸毒者和100名兄弟姐妹、100名苯丙胺吸毒者和100名兄弟姐妹以及100名健康的非相关对照(N=500)中使用相同的综合冲动电池，在两项研究中总共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(S)的计算模型参数的可行性；以及(3)通过评估最优内表型(S)与阿片剂和兴奋剂使用者长期戒烟中艾滋病毒和其他危险行为的相关性来测试其外部有效性，这是一个在成瘾周期的这个鲜为人知的阶段进行预防和干预工作的关键问题。

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.