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(SODS)不仅会导致意外死亡，还会带来巨大的医疗和经济成本 因为吸毒过量。青春期是明显接触酒精和其他药物的关键时期 增加了SUD的风险。早期生活逆境(ELA)，包括人际关系创伤和损失、家庭功能障碍 和贫穷，是南部非洲发展障碍的一个非常普遍和公认的风险因素。患有ELA的人有更早的 开始和过渡到sud的发病年龄，更严重和更有害的病程，特点是 与没有ELA的同行相比，复发和治疗反应差的风险更大。神经免疫 网络假说假设ELA使参与威胁和奖励处理的大脑回路变得敏感 炎症，启动这些系统之间的正反馈循环。此外，炎症介质也参与了 这些神经回路，使个人容易情绪失调，以及“自我药剂”行为，如 比如吸烟和吸毒。这种自我用药行为发生在青春期，这是一个神经元可塑性高的时期， 会加剧ELA的神经毒性效应，从使用到紊乱的过渡速度更快。据我们所知， 这一理论还没有经过实证检验。青春期炎症过程的相关研究 TO ELA专注于非特异性系统炎症标记物，这些标记物在年轻、健康的人中可能缺乏敏感性 人们发现致病的早期迹象，以及机制上的特异性，以告知可修改的路径， 在这一发展时期出现健康差距的原因。拟议的调查涉及 这些理论和方法问题主要体现在以下几个方面：(1)我们将招募青少年，以分层为基础 关于ELA和过度抽样高ELA组，没有物质滥用或SUD病史，以检查 在24个月的前瞻性随访中SUD发病的可能性；(2)检查炎性指标 包括纵向综合措施(即上调促炎和双向下调 抗病毒1型干扰素基因，细胞内糖皮质激素受体信号减弱，循环增加 细胞因子和C反应蛋白)部分地解释了ELA和SUD发病之间的联系；(3)评估 在预测易感性方面，ELA是否与某些临床、生物行为和家庭背景因素相互作用 以及(4)探讨SUD的发病是否对精神疾病有调节作用， 生物行为和家庭背景因素。通过识别生物行为风险和保护因素 在关键的发育时期，研究结果可能有助于将ELA研究转向预防和复原力 并为临床试验确定新的生物行为靶点。所识别的生物行为目标可以阐明 干预计划参与了出现之前的潜在心理生物学过程 并确定它们在这一高危人群中的SUD发病机制中的作用。最终， 这些知识可以加强精确护理，降低暴露于ELA的青少年的SUD风险，并使他们能够 充分发挥他们成年后的潜力，减少与早发性SUD相关的社会经济负担。