Early life stress and adolescent cocaine abuse: neurobiological vulnerabilities

早期生活压力和青少年可卡因滥用：神经生物学脆弱性

• 批准号: 8936366
• 负责人: LEONARD L HOWELL
• 金额: $ 60.51万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8936366
• 关键词: Abstinence; Adolescence; Adolescent; Adult; Adverse event; Affect; Affective; Amygdaloid structure; Animals; Anxiety; Area; Attenuated; Behavior Control; Birth; Brain; Characteristics; Child; Child Abuse and Neglect; Cocaine; Cocaine Abuse; Cocaine Dependence; Consumption; Corpus striatum structure; Cues; Development; Disease; Drug abuse; Drug usage; Emotional; Emotional Stress; Exhibits; Exposure to; Extinction (Psychology); Female; Fostering; Functional Magnetic Resonance Imaging; Goals; HTR2A gene; Health; Heritability; Human; Individual; Infant; Intervention; Life; Life Stress; Link; Longitudinal Studies; Macaca; Measures; Modeling; Monkeys; Mood Disorders; Mothers; Neurobiology; Nucleus Accumbens; Outcome; Outcome Measure; Pharmaceutical Preparations; Physiology; Population; Positron-Emission Tomography; Prefrontal Cortex; Process; Psychopathology; Recording of previous events; Regulation; Relapse; Reporting; Rest; Rewards; Risk; Risk Factors; Role; Secondary to; Self Administration; Serotonergic System; Serotonin; Sex Characteristics; Staging; Stress; Substance abuse problem; System; Testing; Trauma; Withdrawal; Woman; addiction; base; clinically relevant; cost; design; emotion regulation; emotional behavior; male; maltreatment; men; neural circuit; neurobiological mechanism; nonhuman primate; novel; prospective; receptor; relating to nervous system; stress reactivity

DESCRIPTION (provided by applicant): Adolescence is a period of increased vulnerability for the development of substance abuse, including cocaine addiction. Despite the known risk of adolescence initiation of cocaine abuse for lifelong addiction, and its tremendous health and societal costs in the US, the neurobiological mechanisms of increased risk during this developmental period are poorly understood. The proposed studies will examine this question in a novel and highly translational adolescent nonhuman primate model, investigating the effect of an important risk/vulnerability factor: exposure to early life stress. We will also determine whether increased emotional/stress reactivity increases vulnerability to cocaine addiction, including relapse, in females. We will use a highly translational macaque model of early life stress (infant maltreatment) to examine the neurobiological mechanisms underlying increased vulnerability to cocaine abuse and relapse during adolescence. The project will build on ongoing longitudinal studies of developmental alterations exhibited by the maltreated animals, which have been characterized by our group since birth using a unique cross fostering design that rules out confounding effects of heritability on outcome measures. We have evidence that the adverse experience leads to increased emotional reactivity and alterations of prefrontal connectivity (both structural and functional) during the infant period, and we will now examine whether these alterations (1) persist during adolescence and (2) underlie increased risk to cocaine abuse. Our goal is to investigate the neurobiological mechanisms underlying increased vulnerability to cocaine abuse during adolescence in animals with a well-documented history of early life stress, with a particular focus on alterations in the dopaminergic and serotonergic systems and prefrontal connectivity with the striatum and amygdala. We hypothesize that the increased emotional reactivity/anxiety characteristic of maltreated animals exacerbates cocaine self-administration and reinstatement, and that females will be more vulnerable than males. The study will also test a pharmacological intervention, through the use of pharmacological blockade of the 5-HT2A receptor during cocaine abstinence to reduce the risk of relapse. A critical aspect of this proposal is its focus on adolescence, as it is the developmental period when humans initiate drug consumption and has been rarely examined in nonhuman primate studies of cocaine abuse.

描述（由申请人提供）：青春期是一个容易滥用药物的时期，包括可卡因成瘾。尽管已知青少年开始滥用可卡因终身成瘾的风险，以及它在美国巨大的健康和社会成本，但在这一发育时期增加风险的神经生物学机制知之甚少。这些研究将在一个新颖的、高度可翻译的青少年非人灵长类动物模型中检验这个问题，调查一个重要的风险/脆弱性因素的影响：早期生活压力的暴露。我们还将确定情绪/压力反应的增加是否会增加女性对可卡因成瘾的脆弱性，包括复发。我们将使用一个高度可翻译的猕猴早期生活压力模型（婴儿虐待）来研究青春期可卡因滥用和复发易损性增加的神经生物学机制。该项目将建立在对受虐待动物所表现出的发育变化的持续纵向研究的基础上，这些动物自出生以来就具有我们小组的特点，使用独特的交叉培养设计，排除了遗传性对结果测量的混淆影响。我们有证据表明，不良经历导致婴儿时期情绪反应增强和前额叶连通性（结构和功能）的改变，我们现在将研究这些改变是否(1)在青春期持续存在，(2)导致可卡因滥用风险增加。我们的目标是研究具有良好记录的早期生活压力史的动物在青春期易受可卡因滥用的神经生物学机制，特别关注多巴胺能和血清素能系统以及前额叶与纹状体和杏仁核连接的改变。我们假设，受虐待动物的情绪反应/焦虑特征的增加加剧了可卡因的自我给药和恢复，并且雌性比雄性更容易受到伤害。该研究还将测试一种药物干预，通过在可卡因戒断期间使用5-HT2A受体的药物阻断来降低复发的风险。这一建议的一个关键方面是其对青春期的关注，因为这是人类开始吸毒的发育时期，很少在非人类灵长类动物可卡因滥用研究中进行检查。