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

摘要 怀孕期间使用药物是一个令人震惊的普遍现象，而不是令人信服的证据 证明了在产前物质暴露的后代中存在大量神经发育缺陷。而 产前酒精暴露（PAE）的后果，特别是，是最了解的，多种药物的使用， 在怀孕期间，特别是酒精和阿片类药物越来越普遍， 维持治疗如美沙酮然而，很少或根本不了解 产前酒精和阿片类药物暴露对发育中大脑的影响。最近的一项研究表明，新生儿 同时服用产前酒精和阿片类药物的幼儿的情绪调节和处理能力最差 相对于那些暴露于单一药物的人，我们和其他人已经证明了这种影响， 临床前模型。有趣的是，基底外侧杏仁核（BLA）的可塑性与情绪有关 通过多巴胺系统的调节进行处理。更重要的是血乳酸和多巴胺 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 提示男性对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相结合会导致放大的社会和 通过性别中BLA内突触可塑性的DA调节失调引起的非社交焦虑- 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如何改变社交和非社交焦虑样行为，相对于仅暴露于一种 实质内容。目的2将测试PAE+PME如何破坏BLA内突触可塑性的DA调制。这些 及时和创新的研究将测试新的和独特的假设周围的长期影响， 令人惊讶的常见模式产前暴露，并确定一个潜在的神经靶点作为基础， 可以在将来的R 01中进一步询问。

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.