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

摘要‘ 儿童期虐待是物质使用的最重要的风险因素，虐待和家庭 功能障碍约占三分之二的人群药物依赖和静脉注射药物的归因风险 使用。因此，有相当一部分患有物质使用障碍的人经历了 虐待和一个相当大的子集谁没有。那些遭受虐待的人往往发病年龄更早， 病程越重，合并症状越多，治疗后复发率越高，而且更有可能 大脑形态出现异常。一个关键的问题是，受到虐待的生态表型变异 是一种截然不同的障碍，或者仅仅是同一潜在障碍的更严重的表现。我们的 在该奖项的前十年中的先前努力导致了关于类型和类型的重要新发现 虐待的时间、性别差异、易感症状和特定的大脑变化 对遭受虐待的青少年出现药物使用问题的风险进行前瞻性预测。我们在这期间的目标是 该奖项的阶段是比较受虐待和未受虐待的人和有硬性吸毒史的人 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，为生态表型假说提供第一个全面的检验，即存在独特的虐待 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，神经生物学改变与注意缺陷多动有关 在未受虐待的亚型中，障碍是主要的危险因素，而不是相关的脑部变化 早年的生活压力和虐待。验证有两条截然不同的通往实质的途径 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 研究研究，因为每种途径可能需要截然不同的预防、治疗和治疗策略 发现号。该奖项的第二个目标将是确定在敏感时期如何暴露于虐待 月经变得生物性嵌入，并具体确定有多少炎症和睡眠阶段 干扰中介虐待对脑形态测量、脑网络结构和 易服用药物的症状。此目标的目的是确定最重要的调解人为 预防高危虐待青少年出现物质使用障碍的潜在治疗目标。 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 使用阿片类药物和其他物质的受虐个人的康复障碍和靶向这些介体 紊乱可能会促进康复。因此，这个奖项的一个目的是显著地促进我们对 通过检验虐待和ADHD不仅仅是物质使用的风险因素这一假设来检验物质使用 障碍但明显不同的途径，而第二个目标是发现潜在的治疗靶点 防止出现使用物质的情况，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.