Maternal Opioid Exposure Culminates in Perturbed Murine Neurodevelopment and Hyperactive Phenotype in Adolescence. (21st May 2021)

• Record Type: Journal Article
• Authors: Schlagal, Caitlin R.; Dunn, Tiffany J.; Xu, Pei; Felsing, Daniel E.; Merritt, Christina R.; Manja, Sanjana; Fox, Robert G.; Buffington, Shelly A.; Saade, George; Dineley, Kelly T.; Yu, Yongjia; Cunningham, Kathryn A.; Wu, Ping
• Is Part Of: Neuroscience. Volume 463(2021)
• Page Start: 272
• Page End: 287
• Publication Date: 2021-05-21
• Subjects: ADHD attention deficit hyperactivity disorder -- BUP buprenorphine -- CRL crown-rump length -- Ctip2 COUP, TF-interacting protein 2 -- Cux1 cut-like homeobox 1 protein -- E18.5 embryonic day 18.5 -- GFP green fluorescent protein -- MOUD medications for opioid use disorder -- NOWS neonatal opioid withdrawal syndrome -- NSC neural stem cell -- NS/PCs neural stem and intermediate progenitor cells -- OUD opioid use disorder -- OXY oxycodone -- OXY + BUP oxycodone plus buprenorphine -- PND postnatal day -- RELN reelin -- ROI region of interest -- SATB2 special AT-rich sequence-binding protein 2 -- Sox2 sex determining region y-box 2 -- Tbr2 T-box brain protein 2 -- TH tyrosine hydroxylase -- VTA ventral tegmental area -- VZ/SVZ ventricular zone/subventricular zone; opioids -- medication for opioid use disorder -- pregnancy -- neurodevelopment -- adolescent -- hyperactivity; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2021.03.014
• Languages: English
• ISSNs: 0306-4522

Abstract

Highlights: A new murine model is developed to mimic maternal opioid use in humans. Maternal opioid use adversely impairs brain development in mouse embryos. Adolescent offspring exposed to maternal opioid use exhibit hyperactivity. Maternal opioid use causes abnormal dopamine neurogenesis in adolescent offspring. Abstract: Opioid use by women during pregnancy has risen dramatically since 2004, accompanied by a striking increase in the prevalence of neonatal opioid withdrawal syndrome (NOWS) and other long-term neurological deficits. However, the mechanisms underlying the impact of prenatal opioid exposure on fetal neurodevelopment are largely unknown. To translate from the clinical presentation, we developed a novel mouse model to study the neurodevelopmental consequences of maternal opioid use and management. Female mice were treated with oxycodone (OXY) before mating to mimic opioid use disorder (OUD) in humans. Following pregnancy confirmation, dams were switched to buprenorphine (BUP) via oral administration, simulating medication management of OUD (MOUD) in pregnant women. Here, we document critical changes in fetal brain development including reduced cortical thickness, altered corticogenesis, and ventriculomegaly in embryos from dams that were treated with opioids before and throughout pregnancy. Maternal care giving behavior was slightly altered without affecting gross growth of offspring. However, adolescent offspring exposed to maternal opioid use during pregnancy exhibited hyperactivity in late adolescence. Remarkably, we also show increased generation of dopaminergic neurons within the ventral tegmental area (VTA) of mice exposed to prenatal opioids. These data provide critical evidence of teratogenic effects of opioid use during pregnancy and suggest a causal relationship between maternal opioid use and neurodevelopmental/behavioral anomalies in adolescence.