Early Life Stress, Chronic Drug Use and Neuroplasticity in Nonhuman Primate Models of Cocaine Abuse: Relevance to Treatment Strategies

非人类灵长类动物滥用可卡因模型中的早期生活压力、慢性吸毒和神经可塑性：与治疗策略的相关性

• 批准号: 10380099
• 负责人: Michael A Nader
• 金额: $ 80.81万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10380099
• 关键词: Abstinence; Address; Adolescence; Adolescent; Adult; Adverse event; Affect; Age; Amygdaloid structure; Animals; Anxiety; Behavioral; Birth; Brain; Brain region; Child Abuse and Neglect; Child Development; Chronic; Cocaine; Cocaine Abuse; Cocaine Dependence; Cocaine use disorder; Control Animal; Data; Development; Disease; Dopamine; Dopamine Receptor; Drug Addiction; Drug abuse; Drug usage; Effectiveness; Emotional Stress; Emotions; Female; Funding; Goals; Health Care Costs; Heritability; Human; Individual; Intake; Intervention; Life; Longitudinal Studies; Macaca; Macaca mulatta; Magnetic Resonance Imaging; Measures; Mental Depression; Modeling; Monkeys; National Institute of Drug Abuse; Neurobiology; Neuronal Plasticity; Nucleus Accumbens; Pharmaceutical Preparations; Pharmacology; Pharmacology Study; Population; Populations at Risk; Positron-Emission Tomography; Prefrontal Cortex; Process; Psychological reinforcement; Psychopathology; Recording of previous events; Recovery; Reinforcement Schedule; Relapse; Reporting; Research; Rewards; Risk; Risk Factors; Serotonin; Sex Differences; Social status; Stress; Substance Use Disorder; System; United States National Institutes of Health; Ventral Striatum; Woman; addiction; base; cocaine exposure; cocaine self-administration; cocaine use; cognitive development; cohort; comorbidity; early life stress; emotion regulation; experience; fetal drug exposure; in vivo; infant maltreatment; male; maltreatment; neurobiological mechanism; neuroimaging; nonhuman primate; novel; personalized medicine; prospective; receptor; research study; response; serotonin receptor; sex; societal costs; treatment strategy

Abstract Despite the risks of adolescent initiation of drug use for lifelong addiction and its tremendous health and societal costs, the neurobiological factors leading to increased vulnerability to substance use disorders (SUDs), including cocaine (COC) use disorder (CUD), are poorly understood. Early life stress (ELS), including adverse experiences such as childhood maltreatment (MALT), is a major risk factor for psychopathologies like SUDs, anxiety and depression, which are often comorbid. Indeed, individuals with histories of childhood MALT are more vulnerable to COC addiction, and deficits in emotional regulation predisposes them to stress-induced relapse, contributing to spiraling of drug taking. Despite these risks, how ELS and COC abuse during adolescence interact to alter brain development, increasing vulnerability to CUD later in life, has not been elucidated. There are also strong sex differences in progression from initiation of drug use during adolescence (experimentation) to the onset of drug dependence, with women showing increased vulnerability, although the underlying neurobiological mechanisms are unclear. The goal of this proposal is to examine long-term ELS- related impact and neurobiological mechanisms of increased risk to CUD during adulthood. To accomplish this, we are using a unique and highly translational nonhuman primate (NHP) model of infant MALT with adolescence COC self-administration (SA) and addressing sex differences. The studies proposed here with a cohort of adult macaques that experienced infant MALT followed by COC SA during adolescence, and characterized longitudinally since birth, are unparalleled. They will provide information of critical relevance for the human HEALthy Brain and Child Development (HBCD) and Adolescent Brain Cognitive Development (ABCD) NIH studies by examining early risk factors and neurobiological mechanisms for SUDs. The studies leverage this unique cohort of animals during adulthood to examine the long-term impact of ELS and adolescence COC SA on neurobiology of reward and stress/emotion regulatory circuits following a year of COC abstinence (Aim 1), neurobiological changes in dopamine (DA) and serotonin (5-HT) receptors and functional connectivity (FC) of prefrontal cortex (PFC) with ventral striatum (nucleus accumbens) and amygdala following re-exposure to COC SA (Aim 2), and the rate of recovery of DA and 5-HT receptors and FC during abstinence from long-term COC, to investigate whether it predicts COC-induced relapse and responses to pharmacological interventions targeting DA and 5-HT receptors; PET data will inform personalized medicine approaches (Aim 3). We hypothesize differential effectiveness of DA and 5-HT receptor compounds (alone vs. mixtures) in MALT than Control animals, and in females versus males. We propose that ELS, in addition to adolescence COC exposure, leads to the dysregulation of reward and stress/emotional systems typically reported in human psychiatric conditions, resulting in increased risk to CUD in adulthood, in comparison to animals with COC adolescence exposure but no ELS history.

抽象的 尽管青少年开始吸毒存在终生成瘾的风险及其巨大的健康和 社会成本、导致物质使用障碍（SUD）脆弱性增加的神经生物学因素、 包括可卡因 (COC) 使用障碍 (CUD) 在内，人们对此知之甚少。早期生活压力（ELS），包括不利的 童年虐待 (MALT) 等经历是 SUD 等精神病理学的主要危险因素， 焦虑和抑郁往往是共存的。事实上，有童年 MALT 病史的人 更容易对 COC 成瘾，并且情绪调节缺陷使他们容易受到压力诱发 复发，导致吸毒量急剧上升。尽管存在这些风险，ELS 和 COC 在 青春期相互作用会改变大脑发育，从而增加晚年患 CUD 的可能性，但尚未得到证实 阐明了。从青春期开始吸毒起的进展也存在很大的性别差异 （实验）到药物依赖的发作，妇女表现出越来越脆弱，尽管 潜在的神经生物学机制尚不清楚。该提案的目标是研究长期 ELS- 成年期 CUD 风险增加的相关影响和神经生物学机制。为了实现这一目标， 我们正在使用一种独特且高度转化的非人类灵长类动物 (NHP) 婴儿 MALT 模型 青春期 COC 自我管理（SA）并解决性别差异。这里提出的研究 成年猕猴队列，在青春期经历了婴儿 MALT 和 COC SA 后， 从出生起就纵向特征，是无与伦比的。他们将提供至关重要的相关信息 人类健康大脑和儿童发育（HBCD）和青少年大脑认知发展 (ABCD) NIH 通过检查 SUD 的早期危险因素和神经生物学机制进行的研究。 这些研究利用这一独特的成年动物群体来检验 ELS 的长期影响 和青春期 COC SA 在一年后关于奖励和压力/情绪调节回路的神经生物学 COC 戒断（目标 1）、多巴胺 (DA) 和血清素 (5-HT) 受体的神经生物学变化以及 前额皮质 (PFC) 与腹侧纹状体（伏核）的功能连接 (FC) 和 再次暴露于 COC SA 后的杏仁核（目标 2），以及 DA 和 5-HT 受体的恢复率以及 FC 在长期戒断 COC 期间进行，以研究它是否可以预测 COC 引起的复发和 对针对 DA 和 5-HT 受体的药物干预的反应； PET 数据将告知 个性化医疗方法（目标 3）。我们假设 DA 和 5-HT 受体的有效性不同 MALT 中的化合物（单独与混合物）与对照动物相比，以及雌性与雄性动物中的化合物（单独与混合物）。我们建议 ELS，除了青春期 COC 暴露之外，还会导致奖励和压力/情绪的失调 通常在人类精神疾病中报告的系统，导致成年后患 CUD 的风险增加 与青春期接触 COC 但没有 ELS 历史的动物进行比较。