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

基本信息

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
项目类别：
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

项目摘要

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）：青春期是增加滥用药物（包括可卡因成瘾）的脆弱性时期。尽管已知的终身成瘾造成可卡因滥用的风险及其在美国的巨大健康和社会成本的风险，但在这一发育时期，风险增加的神经生物学机制知之甚少。拟议的研究将在新颖且高度转化的非人类灵长类动物模型中研究这个问题，研究重要的风险/脆弱性因素的影响：暴露于早期生活压力。我们还将确定增加的情绪/压力反应性是否会增加女性对可卡因成瘾的脆弱性，包括复发。我们将使用早期生命应力的高度转化猕猴模型（婴儿虐待）来检查青春期中对可卡因滥用和复发的脆弱性的神经生物学机制。该项目将基于虐待动物所表现出的发育变化的持续纵向研究，自从出生以来，我们的小组使用独特的交叉促进设计来表征，这些设计排除了遗传性对结果指标的混乱影响。我们有证据表明，不利的经历会导致情绪反应性的提高和婴儿期间额叶连通性（结构和功能）的改变，现在我们将检查这些改变（1）在青春期中是否持续存在，以及（2）（2）对可卡因滥用的风险增加的基础。我们的目的是研究在青春期遭受可卡因滥用的脆弱性的神经生物学机制，这些动物具有据可记录的早期生活压力史，特别关注多巴胺能和血清素能系统的改变以及与纹状体和杏仁核的前额外连接性的变化。我们假设，虐待动物的情绪反应性/焦虑症的增加加剧了可卡因自我管理和恢复原状，而女性将比男性更脆弱。该研究还将通过在禁欲期间使用5-HT2A受体的药理阻断来测试药理干预措施，以降低复发的风险。该提案的一个关键方面是它的重点是青春期，因为这是人类启动药物消耗的发展时期，并且在非人类的可卡因滥用方面很少检查。