Effects of prenatal exposure to methadone or buprenorphine and maternal separation on anxiety-like behavior in rats

Background: The use of medications for opioid use disorder such as methadone or buprenorphine is increasing among pregnant women. However, long-term effects of this treatment on the children's health are not well understood. A key challenge is distinguishing the effects of opioid exposure from other confounding factors associated with human opioid use, such as reduced maternal care. In this study, we therefore used a multi-risk factor design to examine anxiety-like behavior in rats prenatally exposed to methadone or buprenorphine, with or without maternal separation the first two weeks after birth.

Methods: Female Sprague Dawley rats were exposed to methadone (10mg/kg/day), buprenorphine (1mg/kg/day) or sterile water throughout gestation. Half of the offspring in each litter experienced maternal separation for 3h per day from postnatal day 2 to 12. Male and female offspring (6-9 weeks) were tested in the open field, light-dark transition and elevated plus maze tests to assess anxiety-like behavior.

Results: Offspring exposed to buprenorphine and not subjected to maternal separation displayed increased anxiety-like behavior in 3 out of 6 outcomes in the light-dark transition and elevated plus maze tests. Maternal separation did not exacerbate, but rather diminished this behavior. Males and females responded differently to methadone, with a trend towards reduced anxiety for males and increased anxiety for females.

Conclusions: Prenatal exposure to methadone or buprenorphine may increase the risk of developing anxiety-like behavior later in life, but the effect depends on specific subgroup characteristics. Further research is required to draw definitive conclusions.