Enduring consequences of perinatal fentanyl exposure in mice

Abstract

Opioid use by pregnant women is an understudied consequence associated with the opioid epidemic, resulting in a rise in the incidence of neonatal opioid withdrawal syndrome (NOWS) and lifelong neurobehavioral deficits that result from perinatal opioid exposure. There are few preclinical models that accurately recapitulate human perinatal drug exposure and few focus on fentanyl, a potent synthetic opioid that is a leading driver of the opioid epidemic. To investigate the consequences of perinatal opioid exposure, we administered fentanyl to mouse dams in their drinking water throughout gestation and until litters were weaned at postnatal day (PD) 21. Fentanyl-exposed dams delivered smaller litters and had higher litter mortality rates compared with controls. Metrics of maternal care behavior were not affected by the treatment, nor were there differences in dams' weight or liquid consumption throughout gestation and 21 days postpartum. Twenty-four hours after weaning and drug cessation, perinatal fentanyl-exposed mice exhibited signs of spontaneous somatic withdrawal behavior and sex-specific weight fluctuations that normalized in adulthood. At adolescence (PD 35), they displayed elevated anxiety-like behaviors and decreased grooming, assayed in the elevated plus maze and sucrose splash tests. Finally, by adulthood (PD 55), they displayed impaired performance in a two-tone auditory discrimination task. Collectively, our findings suggest that perinatal fentanyl-exposed mice exhibit somatic withdrawal behavior and change into early adulthood reminiscent of humans born with NOWS.

Keywords: C57BL/6; development; neonatal abstinence syndrome; opiates; postnatal; prenatal.

FIGURE 1

Fentanyl exposure throughout pregnancy and weaning does not influence dam weight (A) or daily liquid intake (B). (C) Fentanyl exposure did not adversely affect maternal care behaviors during the critical period from postnatal days (PDs) 1 to 7. (D) Fentanyl-exposed dams displayed latencies to pup retrieval on PD 8 that were indistinguishable from controls. Dams exposed to fentanyl during pregnancy had smaller litters (E) and a higher litter mortality rate, compared with controls (F). Data depict medians and 95% confidence intervals

FIGURE 2

Perinatal fentanyl exposure induces spontaneous somatic withdrawal behavior 24 hours after drug cessation. Exposed mice have higher global withdrawal scores, compared with vehicle controls. Data depict medians and 95% confidence intervals

FIGURE 3

Perinatal fentanyl exposure influences weight across development. A, Exposed male mice weigh less than controls at weaning (postnatal day [PD] 21). B, By adolescence (PD 35), both male and female mice that were exposed to fentanyl weigh more than controls. C, This weight difference is no longer present once these mice reach early adulthood (PD 55). Data depict medians and 95% confidence intervals

FIGURE 4

Perinatal fentanyl exposure results in aberrant affective-like behaviors in adolescent mice. A,B, Adolescent male mice exposed to fentanyl perinatally exhibit increased anxiety-like behavior, assayed with the elevated plus maze. Exposed male mice spend less time in the open arms of the maze, compared with controls. C, Adolescent female mice exposed to fentanyl perinatally exhibit decreased grooming behavior, as assayed with the sucrose splash test. Data depict medians and 95% confidence intervals

FIGURE 5

Perinatal fentanyl exposure impairs auditory discrimination and task engagement in adult mice. A,B, Exposed mice make fewer correct licks when the target tone is presented. C,D, There is no difference between groups in refraining from licking when the nontarget tone is presented. E,F, Perinatal fentanyl exposure mice have fewer responses than vehicle controls. G,H, Mice exposed to perinatal fentanyl show lower discrimination sensitivity index, compared with vehicle controls. I, All mice have significantly higher discrimination measurements during 20/80 sessions than 80/20 sessions, and there are no differences between groups. J, All mice have higher false alarms during 80/20 sessions than 20/80 sessions and show no difference between groups. Data depict medians and 95% confidence intervals