Early life stress and adolescent cocaine abuse: neurobiological vulnerabilities

描述(由申请人提供)：青春期是药物滥用，包括可卡因成瘾的易感性增加的时期。尽管已知青春期开始滥用可卡因终身成瘾的风险，以及它在美国的巨大健康和社会代价，但这一发育期风险增加的神经生物学机制尚不清楚。拟议的研究将在一个新的、高度平移的青少年非人类灵长类动物模型中研究这个问题，调查一个重要的风险/脆弱因素的影响：暴露在早期生活压力中。我们还将确定，情绪/压力反应性的增加是否会增加女性对可卡因成瘾的易感性，包括复发。我们将使用早期生活应激(婴儿虐待)的高度翻译猕猴模型来研究青春期对可卡因滥用和复发易感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，自出生以来，我们小组一直使用独特的交叉培养设计，排除遗传性对结果衡量的混淆影响。我们有证据表明，在婴儿期，不利的经历会导致情绪反应增强和前额叶连接(结构和功能)的改变，现在我们将检查这些改变是否(1)在青春期持续存在，(2)导致滥用可卡因的风险增加。我们的目标是研究青春期有良好记录的早期生活应激史的动物对可卡因滥用易感性增加的神经生物学机制，特别是多巴胺和5-羟色胺能系统的变化以及前额叶与纹状体和杏仁核的连接。我们假设，受到虐待的动物的情绪反应/焦虑特征的增加加剧了可卡因的自我管理和恢复，并且雌性将比雄性更脆弱。这项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。这项提议的一个关键方面是它对青春期的关注，因为青春期是人类开始吸食毒品的发育期，在关于可卡因滥用的非人类灵长类动物研究中很少被研究。

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.