Prenatal methadone exposure impairs adolescent cognition and GABAergic neurodevelopment in a novel rat model of maternal methadone treatment

Lum, Jeremy S.; Bird, Katrina M.; Wilkie, Jennifer; Millard, Samuel J.; Pallimulla, Sachie; Newell, Kelly A.; Wright, Ian

doi:10.1016/j.pnpbp.2021.110281

Cited by 13 publications

(22 citation statements)

References 56 publications

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“…The electrophysiological changes are accompanied by impairments in female working spatial memory and recognition memory in both sexes. These findings support previous studies showing impairments in recognition memory following PME in young male and female rodents 8–10 and impairments only in adolescent female working memory 9 . Importantly, our data suggest that both effects persist into adulthood.…”

Section: Discussionsupporting

confidence: 92%

“…More specifically, prenatal methadone exposure (PME) significantly reduces IQ scores in children aged 3 to 6 years 6 and increases the rates of reading and math delays at age 9.5 years 7 . These findings have been supported by preclinical studies showing PME leads to impairments in recognition and working memory of adolescent rats 8,9 and long-term spatial memory of young adult rats 10 . These findings indicate that while PME may result in more favorable neonatal outcomes, it may produce similar deficits as shown with prenatal exposures to other opioids, such as oxycodone and morphine, later on.…”

Section: Introductionmentioning

confidence: 54%

“…Finally, the sex-dependent nature of effects from POE has been an interesting phenomenon for several decades 35,36,38,44 , and current studies point to similar sex-dependent characteristics following methadone exposures 9,39,40 . This calls for further examination and continued assessment in both sexes to clarify dynamic effects throughout the lifetime.…”

Section: Discussionmentioning

confidence: 76%

“…We did not find any significant changes to sIPSC frequency, suggesting a postsynaptic alteration in GABA transmission, such as changes in receptor expression or function. Previous work has shown alterations in the hippocampal GABA system, with a pronounced decrease in GAD67 and parvalbumin protein expression particularly in female adolescents following PME 9 .…”

Section: Discussionmentioning

confidence: 87%

“…Additionally, object recognition and spatial memory tasks have been shown to be heavily dependent on adult hippocampal neurogenesis 22,34 , making this a strong candidate for further identification of mechanisms disrupted by this exposure that may coincide to produce the identified behavioral deficits. In support of neurogenesis as a potential mechanism, PME adolescents show reduced mature BDNF 9 , a trophic factor that is critical in regulating neurogenesis.…”

Section: Discussionmentioning

confidence: 99%

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

Gamble

Marfatia

Diaz

2022

Preprint

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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.

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Section: Discussionsupporting

confidence: 92%