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 17 publications

(24 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%

Section: Introductionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

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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Maternal exposure to buprenorphine, but not methadone, during pregnancy reduces social play behavior across two generations of offspring

Nyberg,

Bogen,

Nygaard

et al. 2024

Psychopharmacology

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Rationale The prevalence of newborns exposed to medications for opioid use disorder (MOUD), such as methadone or buprenorphine, during pregnancy is increasing. The opioid system plays a crucial role in regulating and shaping social behavior, and children prenatally exposed to opioids face an increased risk of developing behavioral problems. However, the impact of prenatal exposure to MOUD on offspring’s social behavior during adolescence and adulthood, as well as potential intergenerational effects, remains largely unexplored. Objectives Our study employed a translationally relevant animal model to investigate how maternal (F0) exposure to MOUD during pregnancy affects social behavior in young and adult rats across the first (F1) and second (F2) generation of offspring. Methods Female Sprague–Dawley rats were implanted with an osmotic minipump delivering methadone (10 mg/kg/day), buprenorphine (1 mg/kg/day), or sterile water, prior to mating with drug-naïve males. Adult F1 females were mated with treatment-matched F1 males to generate F2 offspring. We assessed social play behavior in juvenile offspring, and social interaction behavior in a three-chamber social interaction test in young adults of the F1 and F2 generations. Results Maternal exposure to buprenorphine, but not methadone, during pregnancy reduced social play behavior in both F1 and F2 offspring, expressed by a reduced number of pounces and pins, which are the two most characteristic parameters of social play in rats. Adult social interactions were unaffected by prenatal MOUD exposure across both generations. Conclusions Maternal exposure to buprenorphine during pregnancy may have adverse effects on social play behavior across two generations of offspring.

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Prenatal Isoflurane Exposure Induces Developmental Neurotoxicity in Rats: the Role of Gut Microbiota

et al. 2022

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

Cited by 17 publications

References 56 publications

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

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

Maternal exposure to buprenorphine, but not methadone, during pregnancy reduces social play behavior across two generations of offspring

Prenatal Isoflurane Exposure Induces Developmental Neurotoxicity in Rats: the Role of Gut Microbiota

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