Over the last two decades there has been a dramatic increase in the use and misuse of opioids among women of reproductive age and pregnant women. Presently, the recommended therapy for opioid dependence is opioid maintenance treatment (OMT) with methadone or buprenorphine. While this treatment has considerable benefits for the opioid dependent mother, both clinical and preclinical studies suggest negative consequences for the children.

Since multiple risk factors such as polysubstance use and reduced maternal care may affect the human studies and controlled experimental studies with opioids cannot be performed in pregnant women, animal studies are needed to reveal whether there is a causal relationship between prenatal methadone or buprenorphine exposure and the subsequent effects reported in clinical studies.

In this project we have established a model for prenatal methadone or buprenorphine exposure in rats and study pharmacokinetics, short- and long-term effects on behavioral and neurobiological outcomes in the offspring, as well as transgenerational effects.

Research questions

• Does prenatal exposure to methadone or buprenorphine affect neonatal outcomes and cause behavioral changes in young and adult offspring?
• Does the prenatal exposure lead to epigenetic changes that are passed on to the next generation?
• Does reduced maternal care in the first weeks after birth affect the results?
  • Are males and females equally affected?
  • Can the changes in behavior be linked to changes in the expression of specific genes and function of specific proteins?

Ongoing projects

Does prenatal exposure to methadone or buprenorphine affect social behavior and lead to anxiety in the offspring?
Pregnant rats are exposed to methadone (10 mg/kg/day) or buprenorphine (1 mg/kg/day) using osmotic minipumps implanted before mating. In the first to weeks after birth, half of the offspring undergo maternal separation (3 hours/day). Play behavior, social interaction and symptoms of anxiety are measured in young and adult offspring using different behavioral tests. Both males and females are tested to examine possible gender-specific effects. We will also analyze the expression of relevant genes in different brain regions.

Does prenatal exposure to methadone or buprenorphine result in changed behavior in the next generation?
To investigate possible transgenerational effects, male and female offspring from adult rats prenatally exposed to methadone (10 mg/kg/day) or buprenorphine (1 mg/kg/day) are examined using various behavioral tests and genetic studies.

Previous projects

Prenatal exposure to methadone or buprenorphine impairs cognitive performance in young adult offspring
By use of the Morris Water Maze, the Novelty test and the Simultanous Brightness Discrimination test,  impaired learning and memory were shown in young adult offspring prenatally exposed to methadone (10 mg/kg/day) or buprenorphine (1 mg/kg/day). Furthermore, changes in relevant brain proteins and receptor functioning showed that opioids can interfere with neuronal maturation and cause long-term effects in the brain.

Establishment of a protocol for prenatal methadone and buprenorphine exposure
Five days before mating, female rats were implanted with a 28-days osmotic minipump delivering methadone (10 mg/kg/day) or buprenorphine (1 mg/kg/day). This exposure induced stable blood concentrations in the dams which were comparable to those reported in pregnant women in OMT. The administered opioids were also detected in blood and brains from fetuses and newborn offspring.

If you have questions about the project or suggestions for research collaboration, please contact: Jannike Mørch Andersen (jannike.morch.andersen@ous-hf.no), Department of Forensic Sciences, Section for Drug Abuse Research, Oslo University Hospital, Norway

Publications
Andersen JM, Nygaard E. Prenatal exposure to opioids. APA Handbook of Neuropshycology. Accepted

Andersen JM, Høiseth G, Nygaard E (2020) Prenatal exposure to methadone or buprenorphine and long-term outcomes: A meta-analysis. Early Hum Dev. 143:104997. doi: 10.1016/j.earlhumdev.2020.104997

Kongstorp M, Bogen IL, Steinsland S, Nerem E, Salih TW, Stiris T, Andersen JM (2020) Prenatal exposure to methadone or buprenorphine alters µ-opioid receptor binding and downstream signaling in the rat brain. Int J Dev Neurosci. doi: 10.1002/jdn.10043. Online ahead of print

Kongstorp M, Bogen IL, Stiris T, Andersen JM (2020) Prenatal exposure to methadone or buprenorphine impairs cognitive performance in young adult rats. Drug Alcohol Depend. 212:108008. doi: 10.1016/j.drugalcdep.2020.108008

Fjelldal MF, Hadera MG, Kongstorp M, Austdal LPE, Šulović A, Andersen JM, Paulsen RE (2019) Opioid receptor-mediated changes in the NMDA receptor in developing rat and chicken. Int J Dev Neurosci. 78:19-27. doi: 10.1016/j.ijdevneu.2019.07.009

Kongstorp M, Bogen IL, Stiris T, Andersen JM (2019) High accumulation of methadone compared with buprenorphine in fetal rat brain after maternal exposure. J Pharmacol Exp Ther. 371(1):130-137. doi: 10.1124/jpet.119.259531

Andersen JM (2017) Eksperimentelle studier i forsøksdyr. Hva vet vi om langvarige effekter i avkom eksponert for metadon eller buprenorfin i fosterlivet? Finnes det relevante epigenetiske studier? Report for the Norwegian Directorate of Health. Available at https://www.helsedirektoratet.no/