Effects of Atomoxetine on Hyper-Locomotive Activity of the Prenatally Valproate-Exposed Rat Offspring.
10.4062/biomolther.2014.027
- Author:
Chang Soon CHOI
1
;
Minha HONG
;
Ki Chan KIM
;
Ji Woon KIM
;
Sung Min YANG
;
Hana SEUNG
;
Mee Jung KO
;
Dong Hee CHOI
;
Jueng Soo YOU
;
Chan Young SHIN
;
Geon Ho BAHN
Author Information
1. Department of Neuroscience and Center for Neuroscience Research, SMART Institute of Advanced Biomedical Sciences, Seoul 143-701, Republic of Korea.
- Publication Type:Original Article
- Keywords:
Valproic acid;
Autism;
Hyperactivity;
Norepinephrine transporter;
Atomoxetine
- MeSH:
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
- From:Biomolecules & Therapeutics
2014;22(5):406-413
- CountryRepublic of Korea
- Language:English
-
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.
