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Behav Genet. 2017 Sep;47(5):564-580. doi: 10.1007/s10519-017-9861-3. Epub 2017 Jul 25.

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

Author information

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. idelapena@llu.edu.
2
Department of Pharmaceutical and Administrative Sciences, Loma Linda University School of Pharmacy, Loma Linda, CA, 92350, USA. idelapena@llu.edu.
3
Department of Pharmaceutical and Administrative Sciences, Loma Linda University School of Pharmacy, Loma Linda, CA, 92350, USA.
4
Department of Neuroscience, School of Medicine, Konkuk University, Seoul, 143-701, Republic of Korea.
5
Department of Psychiatry, Chung-Ang University Medical School, 102 Heukseok-ro, Dongjak-gu, Seoul, 156-755, Republic of Korea.
6
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.
7
Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, 130-701, Republic of Korea.
8
Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, 130-701, Republic of Korea.
9
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. cheongjh@syu.ac.kr.

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.

KEYWORDS:

Atomoxetine; Genes; Impulsivity; Methylphenidate; Prefrontal cortex; SHR/NCrl; Wistar rats

PMID:
28744604
DOI:
10.1007/s10519-017-9861-3
[Indexed for MEDLINE]

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