Prenatal methadone exposure disrupts behavioral development and alters motor neuron intrinsic properties and local circuitry.
Prenatal methadone exposure disrupts behavioral development and alters motor neuron intrinsic properties and local circuitry.
复制标题
DOI：
10.7554/elife.66230
复制
发表时间：
2021-03-16
期刊：
影响因子：
7.7
通讯作者：
Atwood BK
中科院分区：
文献类型：
--
作者：
Grecco GG;Mork BE;Huang JY;Metzger CE;Haggerty DL;Reeves KC;Gao Y;Hoffman H;Katner SN;Masters AR;Morris CW;Newell EA;Engleman EA;Baucum AJ;Kim J;Yamamoto BK;Allen MR;Wu YC;Lu HC;Sheets PL;Atwood BK
尽管阿片类药物使用障碍孕妇接受美沙酮治疗的比例不断上升，但美沙酮对神经行为发育的影响仍不清楚。我们开发了一种产前美沙酮暴露（PME）的转化小鼠模型，类似于孕妇使用阿片类药物的典型模式，先使用羟考酮，然后改用美沙酮维持药物治疗，随后在维持美沙酮的情况下怀孕。我们采用物理、生化和行为评估的多学科方法以及脑切片电生理学和体内磁共振成像，研究了 PME 对身体发育、感觉运动行为和运动神经元特性的影响。美沙酮在胎盘和胎儿大脑中积聚，但后代的美沙酮水平在出生时迅速下降，这与新生儿阿片类药物戒断症状和行为有关。 PME 对后代的身体生长、开放领域的活动和感觉运动里程碑的获得产生了严重的损害。此外，这些行为改变与运动皮层神经元密度的降低以及运动神经元固有特性和局部电路连接的破坏有关。本研究通过提供关于 PME 如何扰乱后代身体和神经行为发育的全面的、转化相关的特征，对 PME 的有限工作进行了补充。影响深远的阿片类药物危机也波及到怀孕期间服用处方药或非法阿片类药物的母亲所生的婴儿。羟考酮和美沙酮等阿片类药物可以自由穿过胎盘从母亲传给婴儿。随着阿片类药物滥用和成瘾的增加，过去十年中出生时依赖阿片类药物的婴儿数量急剧增加。尽管这些婴儿在子宫内只是被动接触阿片类药物，但他们在出生时仍然会出现戒断症状。这种戒断的特点是烦躁、过度哭泣、身体颤抖、进食问题、发烧和腹泻。尽管人们对治疗新生儿阿片类药物戒断给予了相当多的关注，但人们对这些儿童在生命第一年的发育情况知之甚少。这在一定程度上是因为研究人员很难将药物相关的影响与儿童家庭环境中的其他因素分开，这些因素也会扰乱他们的发育。此外，阿片类药物相关的婴儿发育损害的生物学机制也仍不清楚。动物模型已被用来研究怀孕期间阿片类药物暴露（称为产前暴露）对婴儿的影响。然而，这些模型可以改进，以更好地复制孕妇使用阿片类药物的典型模式。认识到这一差距，Grecco 等人。开发了一种产前美沙酮暴露的小鼠模型，之前依赖羟考酮的雌性小鼠在整个怀孕期间接受美沙酮治疗。美沙酮是一种阿片类药物，通常用于治疗孕妇阿片类药物使用障碍，人们发现美沙酮在小鼠胎儿大脑中积聚水平很高，但在出生后迅速下降。后代也出现了戒断症状。格雷科等人。然后检查了接受阿片类药物治疗的母亲所生小鼠的身体、行为和大脑发育。其中包括对动物生命前四个星期的运动技能、感觉反射和行为的评估。其他实验测试了大脑中神经细胞的特性，以检查细胞水平的变化。评估显示，子宫内接触美沙酮会损害后代的身体生长，这种情况会持续到“青春期”。产前接触美沙酮也会延迟关键发育里程碑的进展，并导致三周大的小鼠过度活跃。此外，格雷科等人。发现这些小鼠控制运动的大脑部分的神经元密度和细胞间连接性降低。这些发现揭示了产前接触美沙酮对婴儿身体、行为和大脑发育的潜在影响。该模型还可用于研究怀孕期间接触阿片类药物的后代的新的潜在治疗或干预策略。
Despite the rising prevalence of methadone treatment in pregnant women with opioid use disorder, the effects of methadone on neurobehavioral development remain unclear. We developed a translational mouse model of prenatal methadone exposure (PME) that resembles the typical pattern of opioid use by pregnant women who first use oxycodone then switch to methadone maintenance pharmacotherapy, and subsequently become pregnant while maintained on methadone. We investigated the effects of PME on physical development, sensorimotor behavior, and motor neuron properties using a multidisciplinary approach of physical, biochemical, and behavioral assessments along with brain slice electrophysiology and in vivo magnetic resonance imaging. Methadone accumulated in the placenta and fetal brain, but methadone levels in offspring dropped rapidly at birth which was associated with symptoms and behaviors consistent with neonatal opioid withdrawal. PME produced substantial impairments in offspring physical growth, activity in an open field, and sensorimotor milestone acquisition. Furthermore, these behavioral alterations were associated with reduced neuronal density in the motor cortex and a disruption in motor neuron intrinsic properties and local circuit connectivity. The present study adds to the limited body of work examining PME by providing a comprehensive, translationally relevant characterization of how PME disrupts offspring physical and neurobehavioral development. The far-reaching opioid crisis extends to babies born to mothers who take prescription or illicit opioids during pregnancy. Opioids such as oxycodone and methadone can freely cross the placenta from mother to baby. With the rising misuse of and addiction to opioids, the number of babies born physically dependent on opioids has risen sharply over the last decade. Although these infants are only passively exposed to opioids in the womb, they can still experience withdrawal symptoms at birth. This withdrawal is characterized by irritability, excessive crying, body shakes, problems with feeding, fevers and diarrhea. While considerable attention has been given to treating opioid withdrawal in newborn babies, little is known about how these children develop in their first years of life. This is, in part, because it is difficult for researchers to separate drug-related effects from other factors in a child’s home environment that can also disrupt their development. In addition, the biological mechanisms underpinning opioid-related impairments to infant development also remain unclear. Animal models have been used to study the effects of opioid exposure during pregnancy (termed prenatal exposure) on infants. These models, however, could be improved to better replicate the typical pattern of opioid use among pregnant women. Recognizing this gap, Grecco et al. have developed a mouse model of prenatal methadone exposure where female mice that were previously dependent on oxycodone were treated with methadone throughout their pregnancy. Methadone is an opioid drug commonly prescribed for treating opioid use disorder in pregnant women and was found to accumulate at high levels in the fetal brain of mice, which fell quickly after birth. The offspring also experienced withdrawal symptoms. Grecco et al. then examined the physical, behavioral and brain development of mice born to opioid-treated mothers. These included assessments of the animals’ motor skills, sensory reflexes and behavior in their first four weeks of life. Additional experiments tested the properties of nerve cells in the brain to examine cell-level changes. The assessments showed that methadone exposure in the womb impaired the physical growth of offspring and this persisted into ‘adolescence’. Prenatal methadone exposure also delayed progress towards key developmental milestones and led to hyperactivity in three-week-old mice. Moreover, Grecco et al. found that these mice had reduced neuron density and cell-to-cell connectivity in the part of the brain which controls movement. These findings shed light on the potential consequences of prenatal methadone exposure on physical, behavioral and brain development in infants. This model could also be used to study new potential treatments or intervention strategies for offspring exposed to opioids during pregnancy.