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Prenatal nicotine exposure decreases the release of dopamine in the medial frontal cortex and induces atomoxetine-responsive neurobehavioral deficits in mice

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Abstract

Increased risk of attention-deficit/hyperactivity disorder (AD/HD) is partly associated with the early developmental exposure to nicotine in tobacco smoke. Emerging reports link tobacco smoke exposure or prenatal nicotine exposure (PNE) with AD/HD-like behaviors in rodent models. We have previously reported that PNE induces cognitive behavioral deficits in offspring and decreases the contents of dopamine (DA) and its turnover in the prefrontal cortex (PFC) of offspring It is well known that the dysfunction of DAergic system in the brain is one of the core factors in the pathophysiology of AD/HD. Therefore, we examined whether the effects of PNE on the DAergic system underlie the AD/HD-related behavioral changes in mouse offspring. PNE reduced the release of DA in the medial PFC (mPFC) in mouse offspring. PNE reduced the number of tyrosine hydroxylase (TH)-positive varicosities in the mPFC and in the core as well as the shell of nucleus accumbens, but not in the striatum. PNE also induced behavioral deficits in cliff avoidance, object-based attention, and sensorimotor gating in offspring. These behavioral deficits were attenuated by acute treatment with atomoxetine (3 mg/kg, s.c.) or partially attenuated by acute treatment with MPH (1 mg/kg, s.c.). Taken together, our findings support the notion that PNE induces neurobehavioral abnormalities in mouse offspring by disrupting the DAergic system and improve our understanding about the incidence of AD/HD in children whose mothers were exposed to nicotine during their pregnancy.

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Acknowledgements

This study was supported by the Grants-in-Aids for Scientific Research (26460240 and 15 K08218, 16K10195) from the Japan Society for the Promotion of Science (JSPS); the “Integrated Research on Neuropsychiatric Disorders” and “Bioinformatics for Brain Sciences” carried out under the SRPBS from MEXT; the Research on Regulatory Science of Pharmaceuticals and Medical Devices from the Ministry of Health and Labour Sciences from the Ministry of Health, Labour and Welfare, Japan (MHLW); a grant from the joint research project under the Japan-Korea basic scientific cooperation program (JSPS); and the Research Grants from Takeda Science Foundation, the Nakatomi Foundation, and the SRF.

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Authors and Affiliations

  1. Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan

    Tursun Alkam, Takayoshi Mamiya, Nami Kimura, Aya Yoshida, Daisuke Kihara, Yuki Tsunoda, Yuki Aoyama, Masayuki Hiramatsu & Toshitaka Nabeshima

  2. Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, USA

    Tursun Alkam

  3. Japanese Drug Organization of Appropriate Use and Research, Nagoya, Japan

    Takayoshi Mamiya, Masayuki Hiramatsu & Toshitaka Nabeshima

  4. Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, South Korea

    Hyoung-Chun Kim

  5. Advanced Diagnostic System Research Laboratory, Graduate School of Health Sciences, Fujita Health University, Toyoake, Aichi, 470-1192, Japan

    Toshitaka Nabeshima

  6. Aino University, Ibaraki, Japan

    Toshitaka Nabeshima

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  1. Tursun Alkam
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  2. Takayoshi Mamiya
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  9. Hyoung-Chun Kim
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Correspondence to Toshitaka Nabeshima.

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Tursun Alkam and Takayoshi Mamiya contribute equally to this study.

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Alkam, T., Mamiya, T., Kimura, N. et al. Prenatal nicotine exposure decreases the release of dopamine in the medial frontal cortex and induces atomoxetine-responsive neurobehavioral deficits in mice. Psychopharmacology 234, 1853–1869 (2017). https://doi.org/10.1007/s00213-017-4591-z

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  • DOI: https://doi.org/10.1007/s00213-017-4591-z

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