Introduction: Methadone is the most common Opioid Replacement Therapy for pregnant woman. However, methadone transverses the placenta, exposing the fetus at a critical period of neurodevelopment. Clinical studies indicate in-utero opioid exposure adversely affects neurocognitive parameters, particularly adolescent academic performance. However, the extent of cognitive deficits, underlying neurological consequences and potential intervention strategies following in-utero exposure is lacking, due to the absence of an animal model which accurately reflects the clinical scenario. Therefore, this study aimed establish a clinically relevant animal model of maternal opioid replacement therapy, to investigate the neurobehavioural impact of in-utero methadone exposure on adolescent offspring.
Methods: Female adult Sprague-Dawley rats were treated with vehicle (0.2% saccharin) or methadone (30 mg/kg/day) two weeks prior to conception, throughout gestation and lactation. Adolescent offspring (postnatal days 35-45) underwent behavioural assessments, including open-field testing (OFT), novel object recognition (NOR) and rewarded T-maze alternation tasks. Furthermore, hippocampal BDNF protein levels were quantified.
Results: Methadone-exposed offspring exhibited altered patterns of exploratory behaviour, despite showing no difference of total locomotor activity in the OFT. Furthermore, methadone-exposed offspring displayed recognition memory deficits in the NOR task, in addition to learning deficits during T-maze tasks, exhibiting an increased percentage of incorrect entries during the training period and increased number of training sessions to acquire the task. In addition, methadone-exposed offspring exhibited reduced hippocampal BNDF expression.
Conclusions: These findings suggest that prenatal methadone exposure produces detrimental effects on cognitive processes in adolescent offspring, similar to clinical findings. In line with these cognitive impairments, methadone-exposed offspring displayed reduced BDNF levels, which is critical for neurocognitive function. The present findings are an essential first step to understanding the neurobiological alterations underpinning in-utero methadone exposure and this model provides a platform to assess potential alternative approaches for improved maternal and/or neonatal care.