Prenatal methadone exposure disrupts behavioral development and alters motor neuron intrinsic properties and local circuitry

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.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files. Source data files have been provided for all figures and tables.

Article and author information

Author details

  1. Gregory G Grecco

    Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0700-8633
  2. Briana E Mork

    Medical Neuroscience, Indiana University School of Medicine, Indianapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5249-3738
  3. Jui-Yen Huang

    Psychological & Brain Sciences, Indiana University, Bloomington, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4745-9970
  4. Corinne E Metzger

    Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. David L Haggerty

    Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1455-2557
  6. Kaitlin C Reeves

    Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Yong Gao

    Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Hunter Hoffman

    Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Simon N Katner

    Psychiatry, Indiana University School of Medicine, Indianapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Andrea R Masters

    Simon Cancer Center, Indiana University School of Medicine, Indianapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Cameron W Morris

    Biology, Indiana University-Purdue University, Indianapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Erin A Newell

    Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Eric A Engleman

    Psychiatry, Indiana University School of Medicine, Indianapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Anthony J Baucum

    Biology, Indiana University-Purdue University, Indianapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Jiuen Kim

    Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Bryan K Yamamoto

    Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Matthew R Allen

    Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  18. Yu-Chien Wu

    Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  19. Hui-Chen Lu

    Psychological and Brain Sciences, Indiana University, Bloomington, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6628-7177
  20. Patrick L Sheets

    Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  21. Brady K Atwood

    Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, United States
    For correspondence
    bkatwood@iu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7441-2724

Funding

National Institute on Alcohol Abuse and Alcoholism (R01AA027214)

  • Brady K Atwood

National Institute on Alcohol Abuse and Alcoholism (F30AA028687)

  • Gregory G Grecco

National Institute on Alcohol Abuse and Alcoholism (T32AA07462)

  • David L Haggerty
  • Kaitlin C Reeves

Indiana University

  • Bryan K Yamamoto
  • Hui-Chen Lu
  • Brady K Atwood

Indiana University Health

  • Brady K Atwood

IU Simon Cancer Center

  • Andrea R Masters

Stark Neurosciences Research Institute

  • Gregory G Grecco
  • David L Haggerty
  • Brady K Atwood

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: The animal experimental procedures in this study were approved by the Institutional Animal Care and Use Committee at the Indiana University School of Medicine (Protocol Number 19017). Guidelines set forth by the National Institutes of Health (Maryland, USA) for ethical treatment and care for experimental animals were followed. Whenever possible, we sought to minimize pain and distress of animals. Euthanasia was only performed on mice that were under a deep plane of anesthesia (achieved using isoflurane) which was assessed via the pedal withdrawal reflex.

Reviewing Editor

  1. Alicia Izquierdo, University of California, Los Angeles, United States

Publication history

  1. Received: January 4, 2021
  2. Accepted: March 11, 2021
  3. Accepted Manuscript published: March 16, 2021 (version 1)
  4. Version of Record published: March 24, 2021 (version 2)

Copyright

© 2021, Grecco et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Gregory G Grecco
  2. Briana E Mork
  3. Jui-Yen Huang
  4. Corinne E Metzger
  5. David L Haggerty
  6. Kaitlin C Reeves
  7. Yong Gao
  8. Hunter Hoffman
  9. Simon N Katner
  10. Andrea R Masters
  11. Cameron W Morris
  12. Erin A Newell
  13. Eric A Engleman
  14. Anthony J Baucum
  15. Jiuen Kim
  16. Bryan K Yamamoto
  17. Matthew R Allen
  18. Yu-Chien Wu
  19. Hui-Chen Lu
  20. Patrick L Sheets
  21. Brady K Atwood
(2021)
Prenatal methadone exposure disrupts behavioral development and alters motor neuron intrinsic properties and local circuitry
eLife 10:e66230.
https://doi.org/10.7554/eLife.66230

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