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Cited by 125Prenatal Substance Exposure EffectsAttention Deficit Hyperactivity DisorderNeurotransmitter Receptor Influence on Behavior

Prenatal Nicotine Exposure Mouse Model Showing Hyperactivity, Reduced Cingulate Cortex Volume, Reduced Dopamine Turnover, and Responsiveness to Oral Methylphenidate Treatment

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Zhu, J., Zhang, X., Xu, Y., Spencer, T. J., Biederman, J., Bhide, P. G.·2012·Journal of Neuroscience
DOI 10.1523/jneurosci.1041-12.2012PMC PMC3417040
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Abstract

Cigarette smoking, nicotine replacement therapy, and smokeless tobacco use during pregnancy are associated with cognitive disabilities later in life in children exposed prenatally to nicotine. The disabilities include attention deficit hyperactivity disorder (ADHD) and conduct disorder. However, the structural and neurochemical bases of these cognitive deficits remain unclear. Using a mouse model we show that prenatal nicotine exposure produces hyperactivity, selective decreases in cingulate cortical volume, and radial thickness, as well as decreased dopamine turnover in the frontal cortex. The hyperactivity occurs in both male and female offspring and peaks during the "active" or dark phase of the light/dark cycle. These features of the mouse model closely parallel the human ADHD phenotype, whether or not the ADHD is associated with prenatal nicotine exposure. A single oral, but not intraperitoneal, administration of a therapeutic equivalent dose (0.75 mg/kg) of methylphenidate decreases the hyperactivity and increases the dopamine turnover in the frontal cortex of the prenatally nicotine exposed mice, once again paralleling the therapeutic effects of this compound in ADHD subjects. Collectively, our data suggest that the prenatal nicotine exposure mouse model has striking parallels to the ADHD phenotype not only in behavioral, neuroanatomical, and neurochemical features, but also with respect to responsiveness of the behavioral phenotype to methylphenidate treatment. The behavioral, neurochemical, and anatomical biomarkers in the mouse model could be valuable for evaluating new therapies for ADHD and mechanistic investigations into its etiology.

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  • In a mouse model, fetal exposure to nicotine reduces responsiveness to methylphenidate.

    “For example, a mouse model has demonstrated that fetal exposure to nicotine yields hyperactivity, reduces cingulate cortex volume, reduces dopamine turnover and responsiveness to methylphenidate and might thereby lead to the identification of new pharmacotherapies 58 .”

    From Attention-deficit/hyperactivity disorder (2015) · cites this paper as [58]

    The Abstract and Introduction (page unavailable) report that prenatally nicotine-exposed mice responded to oral methylphenidate: it decreased hyperactivity and increased frontal-cortex dopamine turnover. The paper supports reduced baseline dopamine turnover, but says the mice were responsive to methylphenidate, not that nicotine exposure reduced their responsiveness. (LLM, conf=0.90)

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  • In a mouse model, PNE produced hyperactivity associated with selective decreases in cingulate cortical volume and radial thickness and a decrease in drug-induced dopamine release in the frontal cortex.

    “Similarly, a study using a mouse model found that PNE produced hyperactivity that was associated with selective decreases in cingulate cortical volume and radial thickness and a decrease in drug-induced dopamine release in the frontal cortex”

    From Prenatal nicotine exposure during pregnancy results in adverse neurodevelopmental alterations and neurobehavioral deficits (2023) · cites this paper as [36]

    The Results and Discussion report increased locomotor activity and selective reductions in cingulate cortex volume and radial thickness in PNE mice. The dopamine finding is misstated: the paper reports reduced frontal-cortex dopamine turnover, not a measured decrease in drug-induced dopamine release. It says its methods could not distinguish stored from released dopamine and that methylphenidate increased dopamine turnover. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • In a mouse model, fetal exposure to nicotine reduces dopamine turnover.

    “For example, a mouse model has demonstrated that fetal exposure to nicotine yields hyperactivity, reduces cingulate cortex volume, reduces dopamine turnover and responsiveness to methylphenidate and might thereby lead to the identification of new pharmacotherapies 58 .”

    From Attention-deficit/hyperactivity disorder (2015) · cites this paper as [58]

  • In a mouse model, fetal exposure to nicotine reduces cingulate cortex volume.

    “For example, a mouse model has demonstrated that fetal exposure to nicotine yields hyperactivity, reduces cingulate cortex volume, reduces dopamine turnover and responsiveness to methylphenidate and might thereby lead to the identification of new pharmacotherapies 58 .”

    From Attention-deficit/hyperactivity disorder (2015) · cites this paper as [58]

  • In a mouse model, fetal exposure to nicotine yields hyperactivity.

    “For example, a mouse model has demonstrated that fetal exposure to nicotine yields hyperactivity, reduces cingulate cortex volume, reduces dopamine turnover and responsiveness to methylphenidate and might thereby lead to the identification of new pharmacotherapies 58 .”

    From Attention-deficit/hyperactivity disorder (2015) · cites this paper as [58]

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Authors
Zhu, J., Zhang, X., Xu, Y., Spencer, T. J., Biederman, J., & Bhide, P. G.
Affiliations
  • Florida State University (US)
  • Harvard University (US)
ORCID
Venue
Journal of Neuroscience
Publisher
Society for Neuroscience
Published
2012-07-04
Volume
32
Issue
27
Pages
9410-9418
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
DOI
10.1523/jneurosci.1041-12.2012
PMC
PMC3417040
OpenAlex
W2027221598
Cited by
125
References
53
Citations by year
2026: 6 · 2025: 7 · 2024: 5 · 2023: 10 · 2022: 15 · 2021: 7 · 2020: 10 · 2019: 11 · 2018: 10 · 2017: 10 · 2016: 8 · 2015: 10 · 2014: 8 · 2013: 7 · 2012: 1
FWCI
7.29
Type
journal article
Language
en
Open access
Locations
  • Journal of Neuroscience (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
Funders
  • National Institute on Drug Abuse (R21DA027358, R01DA020796)
  • National Institute of Neurological Disorders and Stroke (P30NS045776)
Topics
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Prenatal Substance Exposure Effects
  • Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
prenatal nicotine exposure, attention deficit hyperactivity disorder, methylphenidate, dopamine turnover, cingulate cortex, cortical thickness, hyperactivity, frontal cortex, mouse model, maternal smoking, sex differences
MeSH terms
Animals, Attention Deficit Disorder with Hyperactivity, Disease Models, Animal, Dopamine, Female, Gyrus Cinguli, Male, Methylphenidate, Mice, Inbred C57BL, Models, Neurological, Nicotine, Pregnancy, Prenatal Exposure Delayed Effects, Smoking, Mice

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