Perinatal exposure to methadone or buprenorphine impairs hippocampal-dependent cognition and brain development in juvenile rats

The opioid crisis continues to escalate, disproportionately affecting women of reproductive age. Traditionally the first line of treatment for pregnant women with opioid use disorder is the mu-opioid receptor agonist methadone. However, in recent years, the use of buprenorphine as a replacement therapy has increased as it has fewer sideeffects and longer duration of action. Either drug significantly improves outcomes for the mother, but their impact on the developing infant is less certain. To this end, we directly compared the effects of perinatal methadone (MET; 9 mg/kg/day starting dose) versus buprenorphine (BUP; 1 mg/kg/day starting dose) delivered via mini osmotic pump on the long-term behavior of offspring and associated molecular changes in the brain. Opioid exposure across pregnancy resulted in reduced weight gain and smaller litters compared to sham controls, and female pups in particular gained weight at a slower rate across development. Opioid treatment delayed neuromuscular reflex development, with subtle differences observed between MET and BUP. As juveniles, pups with prenatal MET exposure showed poor object recognition, although both MET and BUP have led to deficits in place recognition task. Immunofluorescence studies found corresponding decreases in astrocytes and myelinpositive cells in the hippocampus in both MET and BUP pups. Overall, both MET and BUP were associated with significant developmental and cognitive delays and changes in markers of neuronal development and inflammation, particularly in the hippocampus. The majority of changes were similar between MET and BUPtreated pups, suggesting that gestational exposure to either drug has a similar long-term negative impact on offspring.