Maternal Continuous Oral Oxycodone Self-Administration Alters Pup Affective/Social Communication but not Spatial Learning or Sensory-Motor Function

Abstract

The broad use and misuse of prescription opioids during pregnancy has resulted in a surge of infants diagnosed with Neonatal Opioid Withdrawal Syndrome (NOWS). Shortterm irritability and neurological complications are hallmarks of NOWS, but the longterm consequences are unknown. Our newly-developed preclinical model of oxycodone self-administration enables adult female rats to readily drink oxycodone (0.06-0.12 mg/ml, ~10/mg/kg/day) continuously before and during pregnancy and after delivery, to achieve similar liquid intake in oxycodone moms relative to water-only controls.Oxycodone levels were detected in the serum of mothers and pups. Growth parameters in dams and pups, and litter mass and size were similar to controls. Maternal behavior at postnatal day 1 (PN1) was unchanged by perinatal oxycodone consumption.Regarding the plantar thermal response, there were no differences in paw retraction latency between oxycodone and control pups at PN2 or PN14. Oxycodone and control pups had similar motor coordination, cliff avoidance, righting time, pivoting, and olfactory spatial learning from PN3 through PN13. Separation-induced ultrasonic vocalizations at PN8 revealed higher call frequency in oxycodone pups relative to controls. Finally, during naltrexone precipitated withdrawal at PN9, oxycodone males vocalized more than control pups, consistent with a previously-published withdrawal phenotype. Thus, our rat model of continuous oral oxycodone self-administration in pregnancy shows exacerbated affect/social communication in pups in a sex-dependent manner but spared cognition and locomotion. Our preclinical, high face validity NOWS model reproduces key aspects of human opioid use during pregnancy, enabling longitudinal analysis of how maternal oxycodone changes emotional behavior in the offspring. HIGHLIGHTS•Female rats self-administered oxycodone at clinically relevant doses before and during pregnancy and for the first two weeks after parturition. 2 •Both dams and pups, for the14 day postnatal experimental period, had detectable levels of oxycodone in their blood •Dams drinking oxycodone only or water only did not differ in weight gain, water intake, or the number of pups born and their pups did not differ in weight throughout.•Sensory and motor function in the pups was not altered, nor was hippocampal dependent spatial learning. •Oxycodone exposed pups were physically dependent and displayed increased withdrawal behaviors with or without the opioid antagonist naltrexone.•Pups expressed more negative affect, expressed by increased ultrasonic vocalizations, following naltrexone precipitated withdrawal or when separated from their mother.

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

“…However, currently the literature on maternal care following Oxy exposure is conflicting. Two recent rodent studies found no changes in maternal behavior or maternal motivation following dam Oxy exposure ( Watters et al, 2020 ; Zanni et al, 2020 ). Notably, in our study, in utero Oxy exposed offspring demonstrated comparable USV means to Veh controls.…”

“…The dosage of Oxy (Sigma-Aldrich, Saint Louis, MO, United States; Lot#: SLBX4974) administration was guided by previous literature with concentrations ranging from 0.5 to 33 mg/kg/day ( Enga et al, 2016 ; Sithisarn et al, 2017 ; Zanni et al, 2020 ). Based on this dosage range, we generated our own dosage curve through continuous Oxy administration to pregnant dams at 5, 10, or 15 mg/kg/day using the subcutaneous Alzet 2006 model pump (Durect Corporation, Cupertino, CA, United States; Lot #: 10376-17).…”

“…Righting reflex was assessed at P14 as follows: each mouse was placed prone onto its abdomen and quickly pronated 180° to its back in a smooth motion. The time for the mouse to right itself with all four paws positioned underneath the abdomen was recorded ( Zanni et al, 2020 ). Each mouse underwent three timed trials, which were averaged for analysis.…”

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

“…The dosage of Oxy (Sigma-Aldrich, Saint Louis, MO; Lot#: SLBX4974) administration was guided by previous literature with concentrations ranging from 0.5 mg/kg/day to 33 mg/kg/day [19][20][21] . Based on this dosage range, we generated our own dosage curve through continuous Oxy administration to pregnant dams at 5, 10, or 15 mg/kg/day using the subcutaneous Alzet 2006 model pump (Durect Corporation, Cupertino, CA; Lot #: 10376-17).…”

“…Righting reflex was assessed at P14 as follows: each mouse was placed prone onto its abdomen and quickly pronated 180° to its back in a smooth motion. The time for the mouse to right itself with all four paws positioned underneath the abdomen was recorded 20 . Each mouse underwent three timed trials, which were averaged for analysis.…”