Prenatal methadone exposure leads to long-term memory impairments and disruptions of dentate granule cell function in a sex-dependent manner

Abstract

Prenatal opioid exposures lead to extensive cognitive and emotion-regulation problems in children, persisting at least through school-age. Methadone, an opioid typically used for the treatment of opioid use disorder, has been approved for use in pregnant women for several decades. Importantly, however, the impacts of prenatal methadone exposure (PME), particularly on offspring as they progress into adulthood, has not been extensively examined. In recent years, children and young animal models have shown cognitive deficits related to PME, including evidence of hippocampal dysfunction. The present work aims to examine the persistent nature of these deficits, as well as determine how they may differ by sex. Pregnant Sprague Dawley rats either received subcutaneous methadone or water injections twice daily from gestational days 3-20 or were left undisturbed. Following postnatal day 70, male and female offspring were behaviorally tested for impairments in recognition memory using the Novel Object Recognition task and working spatial memory through Spontaneous Alternation. Additionally, using whole-cell patch-clamp electrophysiology, hippocampal dentate granule cell function was examined in adult offspring. Results indicate that methadone-exposed females showed decreased excitability and increased inhibition of these dentate granule cells, while males did not. These findings were accompanied by impairments in female working spatial memory and impaired recognition memory of both sexes. Overall, this work supports the continued investigation of the long-term effects of PME on adult male and female learning and memory, as well as promotes further exploration of adult hippocampal function as a neural mechanism impacted by this exposure.