Journal
AUTISM RESEARCH
Volume 9, Issue 9, Pages 926-939Publisher
WILEY
DOI: 10.1002/aur.1596
Keywords
valproic acid; methylphenidate; atomoxetine; behavioral analysis; animal model
Categories
Funding
- Japan Society for the Promotion of Science [KAKENHI 25460099, KAKENHI 26293020, KAKENHI 26670122, KAKENHI 15H01288, KAKENHI 15K18874]
- Japan Society for the Promotion of Science
- Dainippon Sumitomo Pharma Co., Ltd. (Japan)
- Neuropsychiatry Drug Discovery Consortium
- Takeda Science Foundation (Japan)
- Research Foundation for Pharmaceutical Sciences (Japan)
- Grants-in-Aid for Scientific Research [15K18874, 26670122, 15H01288, 26293020] Funding Source: KAKEN
Ask authors/readers for more resources
Rodents exposed prenatally to valproic acid (VPA) show autism-related behavioral abnormalities. We recently found that prenatal VPA exposure causes a reduction of dopaminergic activity in the prefrontal cortex of male, but not female, mice. This suggests that reduced prefrontal dopaminergic activity is associated with behavioral abnormalities in VPA-treated mice. In the present study, we examined whether the attention deficit/hyperactivity disorder drugs methylphenidate and atomoxetine (which increase dopamine release in the prefrontal cortex, but not striatum, in mice) could alleviate the behavioral abnormalities and changes in dendritic spine morphology induced by prenatal VPA exposure. We found that methylphenidate and atomoxetine increased prefrontal dopamine and noradrenaline release in VPA-treated mice. Acute treatment with methylphenidate or atomoxetine did not alleviate the social interaction deficits or recognition memory impairment in VPA-treated mice, while chronic treatment for 2 weeks did. Methylphenidate or atomoxetine for 2 weeks also improved the prenatal VPA-induced decrease in dendritic spine density in the prefrontal cortex. The effects of these drugs on behaviors and dendritic spine morphology were antagonized by concomitant treatment with the dopamine-D-1 receptor antagonist SCH39166 or the dopamine-D-2 receptor antagonist raclopride, but not by the alpha(2)-adrenoceptor antagonist idazoxan. These findings suggest that chronic treatment with methylphenidate or atomoxetine improves abnormal behaviors and diminishes the reduction in spine density in VPA-treated mice via a prefrontal dopaminergic system-dependent mechanism. (C) 2015 International Society for Autism Research, Wiley Periodicals, Inc.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available