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 怀孕期间的药物使用是一个令人震惊的常见，代替了令人信服的证据 在产前物质暴露的后代中证明了多种神经发育缺陷。尽管 具体来说 怀孕期间，尤其是酒精和阿片类药物，已经变得越来越普遍，包括使用的阿片类药物 用于维护疗法，例如美沙酮。但是，几乎没有理解的合并 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 和幼儿饮酒和阿片类药物的幼儿具有最坏的情绪调节和处理 相对于暴露于一种药物的缺陷，我们和其他人在 临床前模型。有趣的是，基底外侧杏仁核（BLA）内的可塑性与情感有关 通过多巴胺系统调制处理。而且，更重要的是，BLA和多巴胺 系统是产前酒精和阿片类药物的靶标，包括美沙酮，暴露。我们的初步数据 表明雄性对PAE更敏感，而女性对产前美沙酮更敏感 暴露（PME）。基于这一点，我们假设合并的PAE和PME导致社交和 通过性质的DA调节功能失调，在性别中，BLA内的突触可塑性的非社会焦虑 - 具体方式。为了检验我们的假设，我们将使用已建立的PAE和PME模型。目标1意志 确定PAE+PME如何改变相对于暴露于一种的社交和非社会焦虑行为 物质。 AIM 2将测试PAE+PME如何使BLA内突触可塑性的DA调制。这些 及时和创新的研究将检验围绕一个长期影响的新颖和独特的假设 令人惊讶的是，产前暴露的常见模式，并确定潜在的神经靶标作为基础 可以在未来的R01中进一步审问。