Early life stress and adolescent cocaine abuse: neurobiological vulnerabilities

摘要 青春期是一个更容易滥用包括可卡因在内的药物的时期 成瘾尽管已知青少年开始滥用可卡因终身成瘾的风险， 在美国，巨大的健康和社会成本，在此期间增加风险的神经生物学机制， 发育期知之甚少。拟议中的研究将在一部小说中探讨这个问题， 高度翻译的青少年非人灵长类动物模型，研究一个重要的 风险/脆弱性因素：早年遭受压力。我们还将确定是否增加 情绪/压力反应增加了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翻译的猕猴模型的早期生活压力（婴儿虐待），以检查 可卡因滥用和复吸脆弱性增加的神经生物学机制 青春期该项目将建立在正在进行的纵向研究的发展变化所展示的 虐待的动物，这已被我们的特点，自出生以来，使用独特的交叉培育 设计排除了遗传性对结果测量的混杂影响。我们有证据表明 负面体验导致情绪反应增加和前额叶连接改变（两者都是）。 结构和功能）在婴儿时期，我们现在将检查这些变化是否（1） 持续在青春期和（2）基础可卡因滥用的风险增加。 我们的目标是调查可卡因滥用增加脆弱性的神经生物学机制 在青春期期间，在具有良好记录的早期生活压力史的动物中，特别关注 多巴胺能和多巴胺能系统的改变以及前额与纹状体的连接， 杏仁核我们假设，虐待动物的情绪反应/焦虑特征增加， 加剧可卡因自我管理和恢复，女性将比男性更容易受到伤害。 男性。该研究还将测试一种药物干预，通过使用药物阻断 5HT2A受体在可卡因戒断期间，以减少复发的风险。这项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被检查。

Abstract 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 5HT2A 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.