PT  - JOURNAL ARTICLE
AU  - Vanesa Nieto-Estévez
AU  - Jennifer J. Donegan
AU  - Courtney McMahon
AU  - Hannah B. Elam
AU  - Teresa A. Chavera
AU  - Parul Varma
AU  - Kelly A. Berg
AU  - Daniel J. Lodge
AU  - Jenny Hsieh
TI  - Buprenorphine exposure alters the development and migration of interneurons in the cortex
AID  - 10.1101/2020.10.26.356022
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.10.26.356022
4099  - http://biorxiv.org/content/early/2020/10/26/2020.10.26.356022.short
4100  - http://biorxiv.org/content/early/2020/10/26/2020.10.26.356022.full
AB  - The misuse of opioids has reached epidemic proportions over the last decade, with over 2.1 million people in the U.S. suffering from substance use disorders related to prescription opioid pain relievers. This increase in opioid misuse affects all demographics of society, including women of child-bearing age, which has led to a rise in opioid use during pregnancy. Opioid use during pregnancy has been associated with increased risk of obstetric complications and adverse neonatal outcomes, including neonatal abstinence syndrome. Currently, opioid use disorder in pregnant women is treated with long-acting opioid agonists, including buprenorphine. Although buprenorphine reduces illicit opioid use during pregnancy and improves infant outcomes at birth, few long-term studies of the neurodevelopmental consequences have been conducted. The goal of the current experiments was to examine the effects of buprenorphine on the development of the cortex using fetal brain tissue, 3D brain cultures, and rodent models. First, we demonstrated that we can grow cortical and subpallial spheroids, which model the cellular diversity, connectivity, and activity of the developing human brain. Next, we show that cells in the developing human cortex express the nociceptin opioid (NOP) receptor and that buprenorphine can signal through this receptor in cortical spheroids. Using subpallial spheroids to grow inhibitory interneurons, we show that buprenorphine can alter interneuron development and migration into the cortex. Finally, using a rodent model of prenatal buprenorphine exposure, we demonstrate that alterations in interneuron distribution can persist into adulthood. Together, these results suggest that more research is needed into the long-lasting consequences of buprenorphine exposure on the developing human brain.Competing Interest StatementThe authors have declared no competing interest.