Effects of Early Life Adversity on Opioid Addiction Vulnerability

早年不幸经历对阿片类药物成瘾脆弱性的影响

• 批准号: 10316158
• 负责人: Sophia Levis
• 金额: $ 4.07万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-09 至 2024-07-08
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10316158
• 关键词: Affective; Anhedonia; Animal Model; Attenuated; Behavior; Behavioral; Brain; Chronic; Chronic stress; Cocaine; Data; Dependence; Development; Dose; Drug usage; Early Intervention; Economic Models; Environment; Environmental Risk Factor; Epidemic; Extinction (Psychology); Female; Food; Genetic; Goals; Heroin; Human; Incidence; Individual; Intervention; Life; Life Experience; Link; Maternal Patterns of Care; Measures; Mediating; Methods; Modeling; Morbidity - disease rate; Neurons; Nucleus Accumbens; Opiate Addiction; Opioid; Palate; Pharmaceutical Preparations; Phenotype; Play; Postpartum Period; Poverty; Prevention; Prevention strategy; Public Health; Publishing; Rattus; Resistance; Rewards; Risk; Risk Factors; Risk-Taking; Rodent; Role; Self Administration; Severities; Shapes; Stress; Testing; Trauma; United States; Woman; addiction; behavioral economics; biological sex; brain dysfunction; combat; drug seeking behavior; early experience; early life adversity; experience; experimental study; fighting; hedonic; low socioeconomic status; male; mortality; neurobiological mechanism; novel; opioid abuse; opioid epidemic; opioid mortality; opioid use disorder; prevent; pup; recruit; remifentanil; reward circuitry; sex

Project Summary Over the past twenty years, the United States has experienced a growing epidemic of opioid use disorder accompanied by high rates of opioid-related mortality. Effective strategies to combat this crisis are urgently needed, and identifying at-risk individuals before they become addicted will be critical for fighting this growing epidemic. Although genetics play a role in addiction vulnerability, they alone cannot account for the dramatic rise in opioid addiction incidence in recent years. Therefore, successful prevention strategies must also consider environmental risk factors. For example, in humans, early-life adversity (ELA), such as low socioeconomic status, trauma, or chaotic environment, is associated with life-long affective problems that indicate dysfunction of the brain’s reward circuitry, including risk-taking behaviors and drug use. However, the neurobiological mechanisms by which this occurs are unknown. My project will examine effects of ELA on drug-seeking behavior and reward circuit function in rats, in pursuit of a mechanistic understanding that will inform novel translational intervention or prevention strategies for opioid addiction. To this end, I will implement a powerful, naturalistic model of ELA in rats. In this model, poverty is simulated by providing limited bedding and nesting materials to a postpartum dam. This provokes chaotic patterns of maternal care that are analogous to humans experiencing ELA, and the resulting chronic stress induces profound changes in reward circuits. To understand the behavioral implications of these disrupted circuits, I will use established methods for modeling opioid addiction including self- administration, extinction resistance, and reinstatement, as well as a recently-developed, translationally-relevant behavioral economic model of opioid seeking that can also be used to quantify addiction severity in humans. Building upon my recently-published findings that ELA-reared female rats are remarkably vulnerable to developing opioid addiction-like behaviors, I will determine how ELA interacts with biologic sex to alter vulnerability to opioid addiction in a potentially sex-specific manner. To define the neurobiological mechanisms that underlie ELA-induced opioid vulnerability, I will test whether ELA alters heroin-induced activity within the nucleus accumbens (NAc), and whether restoring normal activity in this region reverses augmented opioid- seeking, thereby identifying a causal mechanism by which ELA shapes reward circuity to increase opioid addiction vulnerability. These studies represent a unique opportunity to understand the role of developmental risk factors in opioid addiction and will elucidate the neurobiological mechanisms that underlie these vulnerabilities.

项目概要 过去二十年来，美国阿片类药物使用障碍日益流行 伴随着与阿片类药物相关的高死亡率。应对这场危机的有效策略刻不容缓 需要，在高危人群上瘾之前识别出他们对于对抗这种日益增长的疾病至关重要 流行性。尽管遗传学在成瘾脆弱性中发挥着一定作用，但仅靠遗传学并不能解释成瘾率的急剧上升 近年来阿片类药物成瘾的发生率。因此，成功的预防策略还必须考虑 环境风险因素。例如，对于人类来说，早年逆境（ELA），例如社会经济地位低下， 创伤或混乱的环境与终生的情感问题有关，这些问题表明大脑功能障碍。 大脑的奖励回路，包括冒险行为和药物使用。然而，神经生物学机制 发生这种情况的原因尚不清楚。我的项目将研究 ELA 对药物寻求行为和奖励的影响 大鼠的回路功能，追求机械理解，为新的翻译干预提供信息 或阿片类药物成瘾的预防策略。为此，我将实现一个强大的、自然主义的 ELA 模型 在老鼠身上。在该模型中，通过向产后妇女提供有限的床上用品和筑巢材料来模拟贫困。 坝。这会引发类似于人类经历 ELA 的混乱的孕产妇护理模式，并且 由此产生的慢性压力会引起奖励回路的深刻变化。了解行为影响 对于这些被破坏的电路，我将使用既定的方法来模拟阿片类药物成瘾，包括自我 管理、灭绝抵抗和恢复，以及最近开发的、与翻译相关的 阿片类药物寻求的行为经济模型也可用于量化人类成瘾的严重程度。 根据我最近发表的研究结果，ELA 饲养的雌性老鼠非常容易受到 发展类似阿片成瘾的行为，我将确定 ELA 如何与生物性别相互作用以改变 以潜在的性别特异性方式易受阿片类药物成瘾的影响。定义神经生物学机制 是 ELA 诱导的阿片类药物脆弱性的基础，我将测试 ELA 是否会改变体内海洛因诱导的活动 伏隔核（NAc），以及恢复该区域的正常活动是否可以逆转阿片类药物的增强作用 寻求，从而确定 ELA 塑造奖励回路以增加阿片类药物的因果机制 成瘾脆弱性。这些研究为了解发育的作用提供了独特的机会 阿片类药物成瘾的危险因素，并将阐明这些因素背后的神经生物学机制 漏洞。