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Methylphenidate and Atomoxetine-Responsive Prefrontal Cortical Genetic Overlaps in “Impulsive” SHR/NCrl and Wistar Rats

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Abstract

Impulsivity, the predisposition to act prematurely without foresight, is associated with a number of neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD). Identifying genetic underpinnings of impulsive behavior may help decipher the complex etiology and neurobiological factors of disorders marked by impulsivity. To identify potential genetic factors of impulsivity, we examined common differentially expressed genes (DEGs) in the prefrontal cortex (PFC) of adolescent SHR/NCrl and Wistar rats, which showed marked decrease in preference for the large but delayed reward, compared with WKY/NCrl rats, in the delay discounting task. Of these DEGs, we examined drug-responsive transcripts whose mRNA levels were altered following treatment (in SHR/NCrl and Wistar rats) with drugs that alleviate impulsivity, namely, the ADHD medications methylphenidate and atomoxetine. Prefrontal cortical genetic overlaps between SHR/NCrl and Wistar rats in comparison with WKY/NCrl included genes associated with transcription (e.g., Btg2, Fos, Nr4a2), synaptic plasticity (e.g., Arc, Homer2), and neuron apoptosis (Grik2, Nmnat1). Treatment with methylphenidate and/or atomoxetine increased choice of the large, delayed reward in SHR/NCrl and Wistar rats and changed, in varying degrees, mRNA levels of Nr4a2, Btg2, and Homer2, genes with previously described roles in neuropsychiatric disorders characterized by impulsivity. While further studies are required, we dissected potential genetic factors that may influence impulsivity by identifying genetic overlaps in the PFC of “impulsive” SHR/NCrl and Wistar rats. Notably, these are also drug-responsive transcripts which may be studied further as biomarkers to predict response to ADHD drugs, and as potential targets for the development of treatments to improve impulsivity.

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Funding

This work was supported by grants from the (1) Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI12C0011), (2) National Research Foundation of Korea (NRF)-2016R1D1A1B02010387, and (3) National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (2015M3C7A1028926). The authors also acknowledge financial support from Loma Linda University School of Pharmacy (LLUSP-360034).

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Authors and Affiliations

  1. Department of Pharmacy, Uimyung Research Institute for Neuroscience, Sahmyook University, 26-21 Kongreung-2-dong, Hwarangro-815, Nowon-gu, Seoul, 139-742, Republic of Korea

    Ike dela Peña & Jae Hoon Cheong

  2. Department of Pharmaceutical and Administrative Sciences, Loma Linda University School of Pharmacy, Loma Linda, CA, 92350, USA

    Ike dela Peña, Irene Joy dela Peña, June Bryan de la Peña & Hee Jin Kim

  3. Department of Neuroscience, School of Medicine, Konkuk University, Seoul, 143-701, Republic of Korea

    Chan Young Shin

  4. Department of Psychiatry, Chung-Ang University Medical School, 102 Heukseok-ro, Dongjak-gu, Seoul, 156-755, Republic of Korea

    Doug Hyun Han

  5. Division of Child and Adolescent Psychiatry, Department of Psychiatry, Seoul National University College of Medicine, 101 Daehak-no, Chongno-gu, Seoul, 03080, Republic of Korea

    Bung-Nyun Kim

  6. Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, 130-701, Republic of Korea

    Jong Hoon Ryu

  7. Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, 130-701, Republic of Korea

    Jong Hoon Ryu

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  1. Ike dela Peña
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  2. Irene Joy dela Peña
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  7. Bung-Nyun Kim
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  9. Jae Hoon Cheong
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Contributions

I dela Peña, JH Cheong and CY Shin conceived and designed the experiments. I dela Peña, IJ dela Peña, JB de la Peña and HJ Kim performed the experiments and wrote the paper. I dela Peña, CY Shin, JH Cheong, DH Han, BN Kim and JH Ryu provided input on data analysis and interpretation. All authors reviewed the manuscript for intellectual content and approved submission.

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Correspondence to Ike dela Peña or Jae Hoon Cheong.

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Conflict of interest

Ike dela Peña, Irene Joy dela Peña, June Bryan de la Peña, Hee Jin Kim, Chan Young Shin, Doug Hyun Han, Bung-Nyun Kim, Jong Hoon Ryu, and Jae Hoon Cheong declare that they have no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. Experiments were performed in accordance with the Principles of Laboratory Animal Care (NIH Publication No. 85-23 revised 1985) and the Animal Care and Use Guidelines of Sahmyook University, South Korea. This article does not contain any studies with human participants performed by any of the authors.

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dela Peña, I., dela Peña, I.J., de la Peña, J.B. et al. Methylphenidate and Atomoxetine-Responsive Prefrontal Cortical Genetic Overlaps in “Impulsive” SHR/NCrl and Wistar Rats. Behav Genet 47, 564–580 (2017). https://doi.org/10.1007/s10519-017-9861-3

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