Improvement by Methylphenidate and Atomoxetine of Social Interaction Deficits and Recognition Memory Impairment in a Mouse Model of Valproic Acid-Induced Autism
Improvement by Methylphenidate and Atomoxetine of Social Interaction Deficits and Recognition Memory Impairment in a Mouse Model of Valproic Acid-Induced Autism
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DOI：
10.1002/aur.1596
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发表时间：
2016-09-01
期刊：
影响因子：
4.7
通讯作者：
Takuma, Kazuhiro
中科院分区：
文献类型：
--
作者：
Hara, Yuta;Ago, Yukio;Takuma, Kazuhiro
出生前暴露于丙戊酸（VPA）的啮齿动物表现出自闭症相关的行为异常。我们最近发现，产前VPA暴露会导致雄性而非雌性小鼠前额叶皮质多巴胺能活性降低。这表明，减少前额多巴胺能活性与VPA治疗小鼠的行为异常。在本研究中，我们研究了注意缺陷/多动障碍药物哌甲酯和托莫西汀（增加小鼠前额叶皮质而不是纹状体的多巴胺释放）是否可以减轻产前VPA暴露诱导的行为异常和树突棘形态学变化。我们发现，哌甲酯和托莫西汀增加VPA治疗小鼠前额叶多巴胺和去甲肾上腺素的释放。哌醋甲酯或托莫西汀急性治疗没有缓解VPA治疗小鼠的社会交往缺陷或识别记忆障碍，而慢性治疗2周则有缓解作用。服用哌甲酯或托莫西汀2周还可以改善产前VPA诱导的前额叶皮质树突棘密度下降。这些药物对行为和树突棘形态的影响被多巴胺-D-1受体拮抗剂SCH 39166或多巴胺-D-2受体拮抗剂雷氯必利联合治疗所拮抗，但不能被α（2）-肾上腺素受体拮抗剂咪唑克生所拮抗。这些结果表明，哌甲酯或托莫西汀长期治疗可通过前额多巴胺能系统依赖性机制改善VPA治疗小鼠的异常行为并减少脊柱密度降低。(C)2015年国际自闭症研究学会，Wiley Periodicals，Inc。
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.