Maternal Opioid Exposure Culminates in Perturbed Murine Neurodevelopment and Hyperactive Phenotype in Adolescence

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.