Abstract
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.
Highlights
Pregnant women and their developing fetuses represent a vulnerable population severely impacted by the opioid crisis
We developed a more translational mouse model that resembles the typical pattern of opioid use in a pregnant woman who is first dependent on oxycodone, begins methadone maintenance treatment, and subsequently becomes pregnant while maintained on methadone
We found that prenatal methadone exposure (PME) reduces physical growth in offspring which persists into adolescence and disrupts the development of locomotor activity and ultrasonic vocalization (USV) during the preweaning period
Summary
Pregnant women and their developing fetuses represent a vulnerable population severely impacted by the opioid crisis. Neonatal opioid withdrawal syndrome (NOWS) increased from 1.2 to 5.8 per 1000 hospital births from 2000 to 2012 with some geographical regions near 33 cases per 1000 (Ko et al, 2016; Patrick et al, 2015) Opioid maintenance therapies, such as methadone and buprenorphine, continue to represent the firstline treatments for pregnant women with OUD because these therapies benefit overall maternalfetal outcomes at parturition (ACOG, 2017). A recent, large study using data from the Adolescent Brain Cognitive Development study reported reduced motor cortical volumes and surface area in children with prenatal opioid exposure (Hartwell et al, 2020) These differences remained significant when controlling for multiple additional factors (e.g. socioeconomic factors and prenatal alcohol/tobacco), indicating opioid exposure in utero may disrupt motor cortex development and potentially impact motor behavior (Hartwell et al, 2020). A translationally relevant animal model of prenatal opioid exposure is desperately needed to examine the neurological and behavioral consequences of opioid exposure in the absence of confounding variables
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