Ontogenetic Oxycodone Exposure Affects Early Life Communicative Behaviors, Sensorimotor Reflexes, and Weight Trajectory in Mice

Elena Minakova; Simona Sarafinovska; Marwa O Mikati; Kia M Barclay; Katherine B McCullough; Joseph D Dougherty; Ream Al-Hasani; Susan E Maloney

doi:10.3389/fnbeh.2021.615798

Ontogenetic Oxycodone Exposure Affects Early Life Communicative Behaviors, Sensorimotor Reflexes, and Weight Trajectory in Mice

Front Behav Neurosci. 2021 Feb 22:15:615798. doi: 10.3389/fnbeh.2021.615798. eCollection 2021.

Authors

Elena Minakova¹, Simona Sarafinovska^{2

3

4}, Marwa O Mikati^{3

5

6

7

8}, Kia M Barclay^{5

6

7

8}, Katherine B McCullough^{2

3}, Joseph D Dougherty^{2

3

9}, Ream Al-Hasani^{5

6

7

8}, Susan E Maloney^{3

9}

Affiliations

¹ Department of Pediatrics, Washington University in St. Louis, St. Louis, MO, United States.
² Department of Genetics, Washington University in St. Louis, St. Louis, MO, United States.
³ Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States.
⁴ Medical Scientist Training Program, Washington University in St. Louis, St. Louis, MO, United States.
⁵ Division of Biology and Biomedical Sciences, Washington University in St. Louis, St. Louis, MO, United States.
⁶ Department of Anesthesiology, Washington University in St. Louis, St. Louis, MO, United States.
⁷ Washington University Pain Center, Washington University in St. Louis, St. Louis, MO, United States.
⁸ Center for Clinical Pharmacology, St. Louis College of Pharmacy, University of Health Sciences and Pharmacy, St. Louis, MO, United States.
⁹ Intellectual and Developmental Disabilities Research Center, Washington University In St. Louis, St. Louis, MO, United States.

Abstract

Nationwide, opioid misuse among pregnant women has risen four-fold from 1999 to 2014, with commensurate increase in neonates hospitalized for neonatal abstinence syndrome (NAS). NAS occurs when a fetus exposed to opioids in utero goes into rapid withdrawal after birth. NAS treatment via continued post-natal opioid exposure has been suggested to worsen neurodevelopmental outcomes. We developed a novel model to characterize the impact of in utero and prolonged post-natal oxycodone (Oxy) exposure on early behavior and development. Via subcutaneous pump implanted before breeding, C57BL/6J dams were infused with Oxy at 10 mg/kg/day from conception through pup-weaning. At birth, in utero oxy-exposed pups were either cross-fostered (paired with non-Oxy exposed dams) to model opioid abstinence (in utero Oxy) or reared by their biological dams still receiving Oxy to model continued post-natal opioid exposure (prolonged Oxy). Offspring from vehicle-exposed dams served as cross-fostered (in utero Veh) or biologically reared (prolonged Veh) controls. In utero Oxy exposure resulted in sex-dependent weight reductions and altered spectrotemporal features of isolation-induced ultrasonic vocalization (USV). Meanwhile, prolonged Oxy pups exhibited reduced weight and sex-differential delays in righting reflex. Specifically, prolonged Oxy female offspring exhibited increased latency to righting. Prolonged Oxy pups also showed decreases in number of USV calls and changes to spectrotemporal USV features. Overall, ontogenetic Oxy exposure was associated with impaired attainment of gross and sensorimotor milestones, as well as alterations in communication and affective behaviors, indicating a need for therapeutic interventions. The model developed here will enable studies of withdrawal physiology and opioid-mediated mechanisms underlying these neurodevelopmental deficits.

Keywords: behavior; in utero; neonatal abstinence syndrome; opioid; oxycodone; post-natal.

Abstract

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