Impact of prenatal alcohol and methadone exposure on dopamine regulation of BLA plasticity

产前酒精和美沙酮暴露对 BLA 可塑性多巴胺调节的影响

• 批准号: 10753305
• 负责人: Marvin Rafael Diaz
• 金额: $ 41.21万
• 依托单位: STATE UNIVERSITY OF NY,BINGHAMTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-11 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10753305
• 关键词: Adult; Adult Children; Age; Alcohol consumption; Alcohols; Amygdaloid structure; Anxiety; Behavior; Behavioral; Brain; Child; Clinical; Data; Development; Dopamine; Drug Exposure; Electrophysiology (science); Emotional; Emotions; Epidemic; Exhibits; Exposure to; Female; Fetal Alcohol Exposure; Fetal alcohol effects; Foundations; Future; Glutamates; Goals; Impairment; Infant; Infant Behavior; Informal Social Control; Knowledge; Lead; Long-Term Effects; Long-Term Potentiation; Maintenance Therapy; Male Adolescents; Mediating; Messenger RNA; Methadone; Modeling; Molecular; Nervous System; Neurodevelopmental Deficit; Neurodevelopmental Impairment; Newborn Infant; Opioid; Opioid replacement therapy; Pattern; Pharmaceutical Preparations; Pre-Clinical Model; Pregnancy; Process; Rattus; Regulation; Reporting; Risk; Sensory; Slice; Social Behavior; Synapses; Synaptic plasticity; System; Testing; alcohol exposure; anxiety-like behavior; dopamine system; early adolescence; emotion regulation; emotional behavior; fetal substance exposure; gamma-Aminobutyric Acid; in utero; information processing; innovation; male; multiple drug use; neonatal outcome; neural; neural circuit; neurobehavioral; neuromechanism; neuroregulation; novel; offspring; opioid epidemic; opioid exposure; opioid use; opioid use disorder; prenatal; prenatal exposure; prenatal testing; receptor; sex; showing emotion; social; substance misuse; substance use; transmission process

Abstract Substance use during pregnancy is a shockingly common occurrence in lieu of compelling evidence demonstrating a multitude of neurodevelopmental deficits in offspring with prenatal substance exposure. While the consequences of prenatal alcohol exposure (PAE), specifically, are the most understood, poly-drug use during pregnancy, particularly alcohol and opioids, have become increasingly common, including opioids used for maintenance therapy such as methadone. However, there is little to no understanding of the combined effects of prenatal alcohol and opioid exposure on the developing brain. A recent study showed that newborns and young children with combined prenatal alcohol and opioids have worst emotion regulation and processing deficits relative to those with exposure to a single drug, effects that we and others have demonstrated in preclinical models. Interestingly, plasticity within the basolateral amygdala (BLA) is associated with emotion processing through modulation by the dopamine system. And, more importantly, the BLA and dopamine systems are targets of prenatal alcohol and opioid, including methadone, exposure. Our preliminary data suggest that males are more sensitive to PAE, while females are more sensitive to prenatal methadone exposure (PME). Based on this, we hypothesize that combined PAE and PME leads to magnified social and non-social anxiety through dysregulation of DA-modulation of synaptic plasticity within the BLA in a sex- specific manner. To test our hypothesis, we will use our established models of PAE and PME. Aim 1 will determine how PAE+PME alter social and non-social anxiety-like behaviors relative to exposure to only one substance. Aim 2 will test how PAE+PME derails DA modulation of synaptic plasticity within the BLA. These timely and innovative studies will test novel and unique hypotheses surrounding the long-term effects of a surprisingly common pattern of prenatal exposures and identify a potential neural target as a foundation that can be further interrogated in a future R01.

抽象的 怀孕期间使用药物是一种令人震惊的普遍现象，没有令人信服的证据 证明产前物质暴露的后代存在多种神经发育缺陷。尽管 具体而言，产前酒精暴露 (PAE) 的后果是最容易理解的多种药物使用 怀孕期间，特别是酒精和阿片类药物已变得越来越普遍，包括使用阿片类药物 用于维持治疗，例如美沙酮。然而，人们对组合的了解却很少，甚至根本不了解。 产前酒精和阿片类药物暴露对发育中的大脑的影响。最近的一项研究表明，新生儿 产前饮酒和阿片类药物混合使用的幼儿的情绪调节和处理能力最差 相对于那些接触单一药物的缺陷，我们和其他人已经在 临床前模型。有趣的是，基底外侧杏仁核（BLA）内的可塑性与情绪相关 通过多巴胺系统的调节进行处理。更重要的是，BLA 和多巴胺 系统是产前酒精和阿片类药物（包括美沙酮）暴露的目标。我们的初步数据 表明男性对 PAE 更敏感，而女性对产前美沙酮更敏感 暴露（PME）。基于此，我们假设 PAE 和 PME 的结合会导致放大的社会和 通过 DA 调节失调导致 BLA 内突触可塑性的非社交焦虑 具体方式。为了检验我们的假设，我们将使用我们建立的 PAE 和 PME 模型。目标1将 确定 PAE+PME 如何改变相对于仅接触一种的社交和非社交焦虑行为 物质。目标 2 将测试 PAE+PME 如何破坏 BLA 内突触可塑性的 DA 调节。这些 及时和创新的研究将测试围绕长期影响的新颖和独特的假设 令人惊讶的常见产前暴露模式，并确定潜在的神经目标作为基础 可以在未来的 R01 中进一步询问。