Biomol Ther.
2014 Sep;22(5):406-413. 10.4062/biomolther.2014.027.
Effects of Atomoxetine on Hyper-Locomotive Activity of the Prenatally Valproate-Exposed Rat Offspring
- Affiliations
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- 1Department of Neuroscience and Center for Neuroscience Research, SMART Institute of Advanced Biomedical Sciences, Seoul 143-701, Republic of Korea.
- 2Department of Advanced Translational Medical Science, School of Medicine, Konkuk University, Seoul 143-701, Republic of Korea.
- 3Department of Pharmacology, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
- 4Department of Psychiatry, School of Medicine, Dankook University Hospital, Cheonan 330-715, Republic of Korea.
- 5Department of Neuropsychiatry, School of Medicine, Kyung Hee University, Seoul 130-702, Republic of Korea. mompeian@khu.ac.kr
- KMID: 2380317
- DOI: http://doi.org/10.4062/biomolther.2014.027
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.
MeSH Terms
-
Acetylation
Animals
Autistic Disorder
Child
Autism Spectrum Disorder
Chromatin Immunoprecipitation
Dopamine
Epigenomics
Histone Deacetylase Inhibitors
Histones
Humans
Methylphenidate
Models, Animal
Norepinephrine
Norepinephrine Plasma Membrane Transport Proteins
Phenotype
Prefrontal Cortex
Pregnancy
Rats*
RNA, Messenger
Valproic Acid
Atomoxetine Hydrochloride
Dopamine
Histone Deacetylase Inhibitors
Histones
Methylphenidate
Norepinephrine
Norepinephrine Plasma Membrane Transport Proteins
RNA, Messenger
Valproic Acid
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