Effects of Early Life Adversity on Substance Use Problems in Adolescents: Biobehavioral Risk Mechanisms

早期生活逆境对青少年药物使用问题的影响：生物行为风险机制

• 批准号: 10719048
• 负责人: UMA RAO
• 金额: $ 72.26万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-15 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10719048
• 关键词: Accidents; Address; Adolescence; Adolescent; Adult; Adverse event; Age; Age of Onset; Alcohol dependence; Behavior; Behavioral; Behavioral Symptoms; Binding; Biological; Blood; Brain; C-reactive protein; Cells; Cessation of life; Childhood; Clinical; Clinical Trials; Communities; Coping Skills; Development; Disease; Dose; Drug Addiction; Drug usage; Dryness; Early Diagnosis; Economic Burden; Emotions; Environmental Risk Factor; Exhibits; Exposure to; Family; Feedback; Female; Functional disorder; Gene Expression; Genes; Genetic Transcription; Glucocorticoid Receptor; Hair; Health; Health Care Costs; Hydrocortisone; Illicit Drugs; Immune; Immunologic Markers; Immunology procedure; Incidence; Individual; Inflammation; Inflammation Mediators; Inflammatory; Interferons; Investigation; Knowledge; Link; Measures; Mediating; Mental disorders; Methodology; Methods; Neuroimmune; Neuronal Plasticity; Nicotine; Nuclear; Onset of illness; Overdose; Parent-Child Relations; Participant; Pathogenesis; Pathology; Pathway interactions; Performance; Personal Satisfaction; Persons; Pharmaceutical Preparations; Poverty; Prevention; Prevention program; Probability; Process; Receptor Signaling; Recording of previous events; Reporting; Research; Rewards; Risk; Risk Factors; Role; Sampling; Severities; Smoking; Social Impacts; Social support; Specificity; Spottings; Stimulus; Substance Use Disorder; Sympathetic Nervous System; Symptoms; System; Testing; Viral; Whole Blood; Youth; adverse childhood events; alcohol and other drug; alcohol exposure; alcohol misuse; behavioral response; biobehavior; comorbidity; contextual factors; critical developmental period; critical period; cytokine; disorder risk; early life adversity; early onset substance use; economic cost; emotion dysregulation; executive function; experience; follow-up; foster care; genomic profiles; health disparity; high risk; high risk population; hypothalamic-pituitary-adrenal axis; indexing; inflammatory marker; interpersonal trauma; intervention program; longitudinal design; mortality; neural circuit; neurotoxic; novel; personalized care; prospective; protective factors; psychiatric symptom; psychobiologic; psychologic; recruit; relapse risk; resilience; response; reward processing; risk mitigation; socioeconomics; substance misuse; substance use; theories; transcription factor; treatment response

Substance use disorders (SUDs) have substantial healthcare and economic costs as well as accidental deaths from drug overdose. Adolescence is a critical period in which exposure to alcohol and other drugs markedly increases the risk for SUD. Early-life adversity (ELA), including interpersonal trauma and loss, family dysfunction and poverty, is highly prevalent and a well-established risk factor for SUD. Individuals with ELA have an earlier age of onset for the initiation and transition to SUD, greater severity and a more pernicious course, marked by a greater risk for relapse and poor treatment response, compared to counterparts without ELA. The neuroimmune network hypothesis postulates that ELA sensitizes the brain circuits involved in threat and reward processing via inflammation, initiating positive feedback loops between these systems. Also, inflammatory mediators engage these neural circuits, predisposing individuals to emotional dysregulation, and “self-medicating” behaviors, such as smoking and drug use. Such self-medicating behaviors in adolescence, a period of high neuronal plasticity, can exacerbate the neurotoxic effects of ELA, with a quicker transition from use to disorder. To our knowledge, this theory has not been tested empirically. Adolescent studies characterizing inflammatory processes in relation to ELA focused on non-specific systemic markers of inflammation which may lack sensitivity in young, healthy persons to detect the early signs of pathogenesis, and the mechanistic specificity to inform modifiable pathways, by which health disparities emerge during this developmental period. The proposed investigation addresses these theoretical and methodological issues in the following ways: (1) we will recruit adolescents, stratified based on ELA and oversampling the high-ELA group, without a prior history of substance misuse or SUD, to examine the probability of SUD onset over a 24-month prospective follow-up; (2) examine whether an inflammatory index comprising of vertically integrated measures (namely upregulated proinflammatory and reciprocal downregulated antiviral type 1 interferon genes, diminished intracellular glucocorticoid receptor signaling, increased circulating cytokines, and c-reactive protein) accounts for, partly, the association between ELA and SUD onset; (3) assess whether ELA interacts with certain clinical, biobehavioral and family-contextual factors in predicting vulnerability to, or protection against, SUD; and (4) explore whether SUD onset has a modulating influence on psychiatric, biobehavioral and family-contextual factors. By identifying the biobehavioral risk and protective factors during a critical developmental period, the study findings may help shift ELA research toward prevention and resilience and identify novel biobehavioral targets for clinical trials. The identified biobehavioral targets may elucidate for whom the intervention programs engage the underlying psychobiological processes that precede the emergence of behavioral symptoms and determine their role in the pathogenesis of SUD in this high-risk group. Ultimately, such knowledge can enhance precision care in mitigating SUD risk in ELA-exposed youth and allowing them to reach their full potential as adults and reducing the socioeconomic burden associated with early-onset SUD.

物质使用障碍（SUD）具有巨大的医疗保健和经济成本以及意外死亡 因为吸毒过量青春期是一个关键时期，在这一时期，酒精和其他药物的暴露显着 增加了SUD的风险。早期生活逆境（ELA），包括人际创伤和损失，家庭功能障碍 和贫困，是非常普遍的，是一个公认的风险因素，为SUD。患有ELA的人较早 开始和转变为SUD的发病年龄，更严重和更有害的过程，以 与未使用ELA的患者相比，复发风险更大，治疗反应较差。神经免疫 网络假说假设ELA通过以下方式使参与威胁和奖励处理的脑回路敏感化： 炎症，启动这些系统之间的正反馈循环。此外，炎症介质参与 这些神经回路，使个体易患情绪失调和“自我治疗”行为， 吸烟和吸毒。这种自我治疗的行为发生在青春期，这是一个神经元高度可塑的时期， 可能会加剧ELA的神经毒性作用，从使用到紊乱的转变更快。据我们所知， 这一理论尚未经过经验检验。青少年研究表征炎症过程与 ELA专注于炎症的非特异性全身标志物，这些标志物可能在年轻，健康 人检测发病的早期迹象，和机制特异性，以告知可修改的途径， 在这一发展阶段出现的健康差异。拟议的调查涉及 这些理论和方法的问题，在以下几个方面：（1）我们将招募青少年，分层为基础 对ELA和高ELA组进行过采样，没有药物滥用或SUD的既往史，以检查 在24个月的前瞻性随访中SUD发作的概率;（2）检查炎症指数是否 包括垂直整合的测量（即上调的促炎性和相互下调的促炎性）， 抗病毒1型干扰素基因，减少细胞内糖皮质激素受体信号传导，增加循环 细胞因子和c-反应蛋白）部分解释了ELA和SUD发作之间的相关性;（3）评估 ELA是否与某些临床、生物行为和家庭背景因素相互作用来预测脆弱性 （4）探讨SUD发作是否对精神疾病， 生物行为和家庭环境因素。通过识别生物行为风险和保护因素， 关键的发展时期，研究结果可能有助于将ELA研究转向预防和恢复力 并为临床试验确定新的生物行为靶点。所确定的生物行为目标可以阐明 干预项目涉及的是出现之前的潜在心理生物学过程， 的行为症状，并确定其在SUD的发病机制中的作用，在这一高风险群体。最后， 这些知识可以加强精确护理，减轻ELA暴露青年的SUD风险，并使他们 充分发挥成年人的潜力，减少与早发性SUD相关的社会经济负担。