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

Author:

Grecco Gregory G12ORCID,Mork Briana E13ORCID,Huang Jui-Yen45ORCID,Metzger Corinne E6,Haggerty David L1ORCID,Reeves Kaitlin C1,Gao Yong1,Hoffman Hunter1,Katner Simon N7,Masters Andrea R8,Morris Cameron W19,Newell Erin A7,Engleman Eric A1,Baucum Anthony J1910,Kim Jiuen110,Yamamoto Bryan K110,Allen Matthew R611,Wu Yu-Chien1012,Lu Hui-Chen14ORCID,Sheets Patrick L110,Atwood Brady K110ORCID

Affiliation:

1. Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, United States

2. Indiana University School of Medicine, Medical Scientist Training Program, Indianapolis, United States

3. Program in Medical Neuroscience, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, United States

4. Department of Psychological and Brain Sciences, Indiana University, Bloomington, United States

5. The Linda and Jack Gill Center for Biomolecular Sciences, Department of Psychological and Brain Science, Program in Neuroscience, Indiana University, Bloomington, United States

6. Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, United States

7. Deparment of Psychiatry, Indiana University School of Medicine, Indianapolis, United States

8. Clinical Pharmacology Analytical Core-Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, United States

9. Department of Biology, Indiana University-Purdue University, Indianapolis, United States

10. Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, United States

11. Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, United States

12. Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, United States

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.

Funder

National Institute on Alcohol Abuse and Alcoholism

Indiana University

Indiana University Health

IU Simon Cancer Center

Stark Neurosciences Research Institute

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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