Early Stress and the Neurobiology of Susceptibility and Resilience to Substance Use Disorders

摘要' 儿童期虐待是吸毒的最重要风险因素，虐待和家庭暴力是吸毒的最重要风险因素。 功能障碍约占三分之二的人口归因于药物依赖和静脉注射药物的风险 使用.因此，有相当一部分患有物质使用障碍的个体经历了 虐待和一个相当大的子集谁没有。受虐待的人往往发病年龄较早， 更严重的过程，更多的共病症状，治疗后复发率更高，更有可能 大脑形态异常一个关键的问题是， 是一种明显不同的疾病，或者仅仅是同一种潜在疾病的更严重表现。我们 在该奖项的前十年中，先前的努力导致了关于类型和 虐待的时间，性别差异，诱发症状和特定的大脑变化， 前瞻性预测受虐待青少年发生物质使用问题的风险。我们的目标是， 该奖项的一个阶段是比较虐待和非虐待的个人与历史的“硬毒品” 物质使用障碍，以阿片类药物为主要滥用药物，以及未暴露的非物质使用 对照组，提供了第一个全面的测试生态表型假说，有独特的虐待 和非虐待物质使用障碍亚型具有明显不同的分子和神经生物学 签名.我们进一步提出，与注意缺陷多动相关的神经生物学改变 疾病作为非虐待亚型的主要风险因素，而不是与之相关的大脑变化。 早期生活压力和虐待有两种截然不同的途径 使用障碍将对未来的预防、治疗和设计产生至关重要的影响。 研究，因为每种途径可能需要明显不同的预防、治疗和 的发现该奖项的第二个目的将是确定如何暴露于虐待期间敏感 周期成为生物嵌入，并具体确定有多少炎症和睡眠阶段 中断介导了虐待对脑形态测量学、脑网络结构和 易受物质使用影响的症状。这一目标的目的是确定最重要的调解人， 潜在的治疗目标，以防止高风险受虐待青年出现药物使用障碍。 此外，炎症和睡眠中断对神经生物学和行为的持续影响可能是一个重要的因素。 恢复障碍，并在使用阿片类药物和其他物质的受虐待者中靶向这些介质 疾病可以促进恢复。因此，这个奖项的目的之一是显着提高我们的理解， 通过检验虐待和多动症不仅仅是物质使用的危险因素这一假设， 疾病，但明显不同的途径，而第二个目标是发现潜在的治疗靶点， 预防药物使用的出现，并促进康复。

Summary' Childhood maltreatment is the most important risk factor for substance use, with maltreatment and household dysfunction accounting for about two thirds of the population attributable risk for drug dependence and iv drug use. Hence, there is a substantial subset of individuals with substance use disorders who experienced maltreatment and a substantial subset who did not. Those with maltreatment tend to have an earlier age of onset, more severe course, more comorbid symptoms, higher rates of relapse following treatments, and are more likely to have abnormalities in brain morphology. A critical question is whether the maltreated ecophenotypic variant is a distinctly different disorder or simply a more severe manifestation of the same underlying disorder. Our previous efforts during the first ten years of this award resulted in important new discoveries regarding type and timing of maltreatment, gender differences, predisposing symptoms and specific brain changes that were prospectively predictive of risk for developing substance use problems in maltreated youths. Our goal during this phase of the award is to compare maltreated and non-maltreated individuals with histories of “hard drug” substance use disorders, with opioids as primary drug of abuse, as well as unexposed non-substance using controls, to provide the first comprehensive test of the ecophenotype hypothesis that there are unique maltreated and non-maltreated substance use disorder subtypes with distinctly different molecular and neurobiological signatures. We further propose that neurobiological alterations associated with attention deficit hyperactivity disorder serve as the primary risk factor in the non-maltreated subtype rather than brain changes associated with early life stress and maltreatment. Verifying that there are two distinctly different pathways to substance use disorders would have critically important implications for prevention, treatment and design of future research studies, as each pathway may require distinctly different strategies for prevention, treatment and discovery. The second aim of the award will be to determine how exposure to maltreatment during sensitive periods becomes biologically embedded and to specifically determine how much inflammation and sleep stage disruption mediate the effects of maltreatment on brain morphometry, brain network architecture and symptoms predisposing to substance use. The purpose of this aim is to identify the most important mediators as potential therapeutic targets to prevent the emergence of substance use disorders in high-risk maltreated youth. Further, ongoing effects of inflammation and sleep disruption on neurobiology and behavior may serve as a barrier to recovery and targeting these mediators in maltreated individuals with opioid and other substance use disorders may facilitate recovery. Hence, one aim of this award is to markedly advance our understanding of substance use by testing the hypothesis that maltreatment and ADHD are not just risk factors for substance use disorder but distinctly different pathways, while the second aim is to discover potential therapeutic targets to prevent emergence of substance use and to facilitate recovery.