title: Effects of atomoxetine on hyper-locomotive activity of the prenatally valproate-exposed rat offspring.
abstract: A substantial proportion of patients with autism spectrum disorder (ASD) display hyperactivity as a comorbid symptom. Exposure to valproic acid (VPA) during pregnancy produces ASD-like core behavioral phenotypes as well as hyperactivity in offspring both in human and experimental animals, which makes it a plausible model to study ASD-related neurobiological processes. In this study, we examined the effects of two of currently available attention defecit hyperactivity disorder (ADHD) medications, methylphenidate (MPH) and atomoxetine (ATX) targeting dopamine and norepinephrine transporters (DAT and NET), respectively, on hyperactive behavior of prenatally VPA-exposed rat offspring. In the prefrontal cortex of VPA exposed rat offspring, both mRNA and protein expression of DAT was increased as compared with control. VPA function as a histone deacetylase inhibitor (HDACi) and chromatin immunoprecipitation experiments demonstrated that the acetylation of histone bound to DAT gene promoter was increased in VPA-exposed rat offspring suggesting epigenetic mechanism of DAT regulation. Similarly, the expression of NET was increased, possibly via increased histone acetylation in prefrontal cortex of VPA-exposed rat offspring. When we treated the VPA-exposed rat offspring with ATX, a NET selective inhibitor, hyperactivity was reversed to control level. In contrast, MPH that inhibits both DAT and NET, did not produce inhibitory effects against hyperactivity. The results suggest that NET abnormalities may underlie the hyperactive phenotype in VPA animal model of ASD. Profiling the pharmacological responsiveness as well as investigating underlying mechanism in multiple models of ASD and ADHD may provide more insights into the neurobiological correlates regulating the behavioral abnormalities.
authors.affiliation: Department of Neuroscience and Center for Neuroscience Research, SMART Institute of Advanced Biomedical Sciences, Seoul 143-701 ; Department of Advanced Translational Medical Science, School of Medicine, Konkuk University, Seoul 143-701.
authors.forename: Chang Soon
authors.initials: CS
authors.lastname: Choi
authors.affiliation: Department of Psychiatry, School of Medicine, Dankook University Hospital, Cheonan 330-715 ; Department of Neuropsychiatry, School of Medicine, Kyung Hee University, Seoul 130-702, Republic of Korea.
authors.forename: Minha
authors.initials: M
authors.lastname: Hong
authors.affiliation: Department of Neuroscience and Center for Neuroscience Research, SMART Institute of Advanced Biomedical Sciences, Seoul 143-701 ; Department of Pharmacology, College of Pharmacy, Seoul National University, Seoul 151-742.
authors.forename: Ki Chan
authors.initials: KC
authors.lastname: Kim
authors.affiliation: Department of Neuroscience and Center for Neuroscience Research, SMART Institute of Advanced Biomedical Sciences, Seoul 143-701 ; Department of Advanced Translational Medical Science, School of Medicine, Konkuk University, Seoul 143-701.
authors.forename: Ji-Woon
authors.initials: JW
authors.lastname: Kim
authors.affiliation: Department of Neuroscience and Center for Neuroscience Research, SMART Institute of Advanced Biomedical Sciences, Seoul 143-701 ; Department of Advanced Translational Medical Science, School of Medicine, Konkuk University, Seoul 143-701.
authors.forename: Sung Min
authors.initials: SM
authors.lastname: Yang
authors.affiliation: Department of Neuroscience and Center for Neuroscience Research, SMART Institute of Advanced Biomedical Sciences, Seoul 143-701 ; Department of Advanced Translational Medical Science, School of Medicine, Konkuk University, Seoul 143-701.
authors.forename: Hana
authors.initials: H
authors.lastname: Seung
authors.affiliation: Department of Neuroscience and Center for Neuroscience Research, SMART Institute of Advanced Biomedical Sciences, Seoul 143-701 ; Department of Advanced Translational Medical Science, School of Medicine, Konkuk University, Seoul 143-701.
authors.forename: Mee Jung
authors.initials: MJ
authors.lastname: Ko
authors.affiliation: Department of Neuroscience and Center for Neuroscience Research, SMART Institute of Advanced Biomedical Sciences, Seoul 143-701.
authors.forename: Dong-Hee
authors.initials: DH
authors.lastname: Choi
authors.affiliation: Department of Neuroscience and Center for Neuroscience Research, SMART Institute of Advanced Biomedical Sciences, Seoul 143-701.
authors.forename: Jueng Soo
authors.initials: JS
authors.lastname: You
authors.affiliation: Department of Neuroscience and Center for Neuroscience Research, SMART Institute of Advanced Biomedical Sciences, Seoul 143-701 ; Department of Advanced Translational Medical Science, School of Medicine, Konkuk University, Seoul 143-701.
authors.forename: Chan Young
authors.initials: CY
authors.lastname: Shin
authors.affiliation: Department of Neuropsychiatry, School of Medicine, Kyung Hee University, Seoul 130-702, Republic of Korea.
authors.forename: Geon Ho
authors.initials: GH
authors.lastname: Bahn
keywords: Atomoxetine; Autism; Hyperactivity; Norepinephrine transporter; Valproic acid