Early life stress and adolescent cocaine abuse: neurobiological vulnerabilities

描述（由申请人提供）：青春期是一个更容易发展药物滥用的时期，包括可卡因成瘾。尽管已知的风险青少年开始可卡因滥用终身成瘾，其巨大的健康和社会成本在美国，神经生物学机制的风险增加，在这一发展时期知之甚少。拟议的研究将在一个新的和高度转化的青少年非人灵长类动物模型中研究这个问题，调查一个重要的风险/脆弱性因素的影响：暴露于早期生活压力。我们还将确定是否增加情绪/压力反应增加脆弱性可卡因成瘾，包括复发，在女性。我们将使用一个高度翻译的猕猴模型的早期生活压力（婴儿虐待），以检查神经生物学机制的基础上增加脆弱性可卡因滥用和复发在青春期。该项目将建立在正在进行的虐待动物所表现出的发育变化的纵向研究的基础上，我们的研究小组自出生以来就使用独特的交叉培养设计来确定其特征，该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，在婴儿时期，不良经历会导致情绪反应的增加和前额叶连接（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，以及（2）是否是可卡因滥用风险增加的基础。我们的目标是调查的神经生物学机制的基础上增加的脆弱性可卡因滥用在青春期的动物有充分的记录的历史，早期生活压力，特别关注多巴胺能和多巴胺能系统和前额叶连接纹状体和杏仁核的改变。我们假设，虐待动物的情绪反应/焦虑特征的增加加剧了可卡因自我管理和恢复，女性将比男性更脆弱。该研究还将测试药物干预，通过在可卡因戒断期间使用5-HT 2A受体的药物阻断剂来降低复发的风险。这一建议的一个关键方面是其重点是青春期，因为这是人类开始吸毒的发育期，在可卡因滥用的非人类灵长类动物研究中很少进行研究。

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.