Lasting Neurological Effects of Perinatal Opioids

项目摘要 近年来，阿片类药物的使用、依赖和成瘾增加到流行的比例，导致 沉重的财政和社会健康负担。参加医疗补助的孕妇中，超过20%的人 处方类阿片类药物；近年来，孕妇自身的比例增加了14倍。 报告阿片类药物滥用。因此，使用阿片类药物的母亲所生婴儿的发病率增加了400%。 在2000至2012年间。这些新生儿经常接受阿片类药物治疗，进一步增加了他们对 这些物质。宫内接触阿片类药物的婴儿神经发育风险增加 问题或不良的感觉、认知、精神运动和行为结果，持续的负面结果 从童年开始，很可能终生如此。目前，几乎没有关于神经回路的信息。 在早期生命中发生的适应与阿片类药物的接触。 我们开发了一种小鼠模型，在该模型中，动物在相应的时间段内接受芬太尼治疗 人类的孕育。这些小鼠在特定于性别的情绪行为上表现出持久的变化。 暴露于围产期芬太尼的青春期男性表现出增强的焦虑样行为，而青春期 女性表现出更弱的动力。我们的研究将调查内侧前额叶皮质(MPFC)的变化。 以及已知参与这些情绪行为的伏隔核(NAC)回路。我们会调查的 围产期应用芬太尼的mPFC和NAC细胞亚型的细胞、可塑性和分子适应性 小鼠在早期断奶后一直到青春期。我们将以不同细胞中已识别的分子适应为目标 亚型以确定其在围产期芬太尼引起的环路和情绪行为障碍中的作用 曝光。我们的研究将首次揭示细胞、回路和分子适应发生在 围产期暴露芬太尼和确定介导长期神经生物学异常的回路 与围产期阿片类药物接触有关。

Project Summary Opioid use, dependence, and addiction have increased to epidemic proportions in recent years, leading to substantial financial and societal health burdens. More than 20% of pregnant women enrolled in Medicaid are prescribed opioids; In recent years there was a 14-fold increase in the proportion of pregnant women self- reporting opioid abuse. As a result, the incidence of infants born to opioid-using mothers has increased >400% between 2000 and 2012. These newborns are often treated with opioids, further increasing their exposure to these substances. Infants with intrauterine exposure to opioids have an increased risk for neurodevelopmental problems or adverse sensory, cognitive, psychomotor, and behavioral outcomes, negative outcomes that last through childhood, and likely throughout life. Currently, there is virtually no information regarding neural-circuit adaptations occurring in with opioid exposure during early life. We developed a mouse model in which animals are treated with fentanyl during a period corresponding to human gestation. These mice display lasting alterations in emotional behaviors that are specific to sex. Adolescent males exposed to perinatal fentanyl show enhanced anxiety-like behavior, while adolescent females show reduced motivation. Our studies will investigate alterations in medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) circuitry known to be involved in these emotional behaviors. We will investigate cellular, plasticity, and molecular adaptations in mPFC and NAc cell subtypes in perinatal fentanyl exposed mice at early post weaning until adolescence. We will target identified molecular adaptations in distinct cell subtypes to determine their role in circuit and emotional behavioral disruptions occurring with perinatal fentanyl exposure. Our studies will, for the first time, uncover cellular, circuit, and molecular adaptations occurring after perinatal exposure to fentanyl and determine the circuitry mediating the long lasting neurobiological anomalies that occur with perinatal opioid exposure.