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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

基本信息

批准号：
10640231
负责人：
Sophia Levis
金额：
$ 5.27万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
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/10640231
关键词：
Affective Anhedonia Animal Model Attenuated Beds Behavior Behavioral Brain Chronic Chronic stress Cocaine Data Dependence Development Dissociation Dose Drug usage Early Intervention Economic Models Economics Environment Environmental Risk Factor Epidemic Extinction Female Food Genetic Goals Heroin Human Incidence Individual Intervention Life Experience Link Maternal Patterns of Care Measures Mediating Methods Modeling Morbidity - disease rate Neurons Nucleus Accumbens Opiate Addiction Opioid 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 translational approach

项目摘要

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.

项目摘要在过去的二十年里，美国经历了阿片类药物使用障碍的日益流行伴随着与阿片类药物有关的高死亡率。应对这一危机的有效战略迫切需要需要，并确定在他们上瘾之前的风险个人将是至关重要的打击这种增长疫情尽管遗传学在成瘾脆弱性中发挥了作用，但它们本身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病率。因此，成功的预防战略还必须考虑到环境风险因素。例如，在人类中，早期生活逆境（ELA），如低社会经济地位，创伤，或混乱的环境，与终身的情感问题，表明功能障碍，大脑的奖励回路，包括冒险行为和药物使用。然而，神经生物学机制这种情况发生的原因是未知的。我的项目将研究ELA对药物寻求行为和奖励的影响电路功能的大鼠，在追求一个机械的理解，将通知新的翻译干预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模型对大鼠在这个模型中，贫困是通过向产后妇女提供有限的床上用品和筑巢材料来模拟的。大坝这引发了混乱的孕产妇护理模式，类似于人类经历ELA，而由此产生的慢性压力会引起奖赏回路的深刻变化。为了理解行为暗示在这些被破坏的回路中，我将使用建立阿片类药物成瘾模型的方法，包括自我- 管理，灭绝抗性，恢复，以及最近开发的，预防性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。基于我最近发表的发现，ELA饲养的雌性大鼠非常容易受到发展阿片类药物成瘾样行为，我将确定ELA如何与生物性别相互作用，以改变对阿片类药物成瘾的脆弱性在一个潜在的性别特异性方式。为了明确神经生物学机制这是ELA诱导的阿片类药物脆弱性的基础，我将测试ELA是否改变海洛因诱导的活动，丘脑核（NAc），以及恢复该区域的正常活动是否会逆转阿片样物质的增加，寻求，从而确定ELA形成奖励回路以增加阿片类药物的因果机制成瘾的脆弱性这些研究代表了一个独特的机会，以了解发展的作用，阿片类药物成瘾的危险因素，并将阐明神经生物学机制，这些基础漏洞

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Developmental Trajectories of Anhedonia in Preclinical Models.

DOI：
10.1007/7854_2021_299
发表时间：
2022
期刊：
Current topics in behavioral neurosciences
影响因子：
0
作者：
Birnie, Matthew T;Levis, Sophia C;Mahler, Stephen V;Baram, Tallie Z
通讯作者：
Baram, Tallie Z

The Developmental Origins of Opioid Use Disorder and Its Comorbidities.

DOI：
10.3389/fnhum.2021.601905
发表时间：
2021
期刊：
Frontiers in human neuroscience
影响因子：
2.9
作者：
Levis SC;Mahler SV;Baram TZ
通讯作者：
Baram TZ

Neurodevelopmental origins of substance use disorders: Evidence from animal models of early-life adversity and addiction.

药物使用障碍的神经发育起源：早期逆境和成瘾动物模型的证据。

DOI：
10.1111/ejn.15223
发表时间：
2022-05
期刊：
The European journal of neuroscience
影响因子：
0
作者：
Levis SC;Baram TZ;Mahler SV
通讯作者：
Mahler SV

Enduring disruption of reward and stress circuit activities by early-life adversity in male rats.

DOI：
10.1038/s41398-022-01988-w
发表时间：
2022-06-16
期刊：
TRANSLATIONAL PSYCHIATRY
影响因子：
6.8
作者：
Levis, Sophia C.;Birnie, Matthew T.;Bolton, Jessica L.;Perrone, Christina R.;Montesinos, Johanna S.;Baram, Tallie Z.;Mahler, Stephen V.
通讯作者：
Mahler, Stephen V.