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

基本信息

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
项目类别：
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

项目摘要

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) 会造成巨大的医疗保健和经济成本以及意外死亡青春期是暴露于酒精和其他药物的关键时期。增加早年逆境（ELA）的风险，包括人际创伤和损失、家庭功能障碍。和贫困是 SUD 的普遍存在和明确的风险因素，患有 ELA 的人较早出现这种情况。开始和转变为 SUD 的发病年龄，更严重和更有害的病程，其特点是与没有 ELA 的学分相比，复发和治疗反应不佳的风险更大。网络假说假设 ELA 通过以下方式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，炎症介质也参与其中。这些神经回路使个体容易出现情绪失调和“自我治疗”行为，例如例如青少年时期的吸烟和吸毒，这是神经元高度可塑性的时期。据我们所知，可以加剧 ELA 的神经毒性作用，并更快地从使用转变为紊乱。该理论尚未经过有关炎症过程特征的青少年研究的验证。 ELA 专注于炎症的非特异性全身标志物，这些标志物在年轻、健康的人群中可能缺乏敏感性人们检测发病机制的早期迹象，以及告知可修改途径的机制特异性，拟议的调查旨在解决这一发展时期出现的健康差异。这些理论和方法论问题可以通过以下方式解决：（1）我们将招募青少年，分层为基础对 ELA 并对高 ELA 组进行过采样，没有药物滥用或 SUD 的既往史，以检查 24 个月的前瞻性随访中 SUD 发生的概率 (2) 检查是否存在炎症指数；包括垂直整合的措施（即上调促炎症和相互下调抗病毒 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 (3)评估 ELA 在预测脆弱性时是否与某些临床、生物行为和家庭背景因素相互作用或预防 SUD；以及 (4) 探讨 SUD 的发作是否对精神、通过识别生物行为风险和保护因素。关键的发育时期，研究结果可能有助于将 ELA 研究转向预防和恢复力并确定用于临床试验的新的生物行为目标。所确定的生物行为目标可以阐明。干预计划涉及出现之前的潜在心理生物学过程行为症状并确定其在该高危人群 SUD 发病机制中的作用。这些知识可以加强精准护理，降低暴露于 ELA 的青少年的 SUD 风险，并让他们能够充分发挥成年人的潜力，并减轻与早发性 SUD 相关的社会经济负担。