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之前的两次成功合作，我们对相对“纯粹”的阿片类药物和兴奋剂使用者的冲动性进行了全面的表征，并收集和储存了许多参与者的遗传物质。这个竞争性更新的总体目标是调查冲动性作为药物成瘾的一种内表型的作用。虽然冲动性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)冲动性的异质性，其特征是多重人格、精神病学和神经认知维度；(2)成瘾表型的异质性，部分原因是多物质依赖的高发生率；(3)遵循完整的内表型标准的研究数量有限，缺乏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计划。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主要依赖单一物质的海洛因和安非他命使用者的罕见人群，其中许多人长期戒断。我们的初步结果揭示了冲动性的特征和神经认知（状态）维度之间的复杂关系，在海洛因和安非他明依赖个体中往往表现为相反的方向。决策是冲动性的中枢神经认知方面，对决策的初步计算建模分析表明，鸦片剂和兴奋剂使用者的决策受损背后有不同的机制，这证明了它特别有用。我们的研究结果强调了检查冲动性的多个和更狭义的维度的效用，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别的长期使用者之间的重要差异

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.