Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Department of Pharmacology, Graduate School of Dentistry, Osaka University, 1-8 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Psychopharmacology (Berl). 2017 Nov;234(21):3217-3228. doi: 10.1007/s00213-017-4703-9. Epub 2017 Aug 10.
Rodents exposed prenatally to valproic acid (VPA) exhibit autism spectrum disorder (ASD)-like behavioral abnormalities. We recently found that prenatal VPA exposure causes hypofunction of the prefrontal dopaminergic system in mice. This suggests that the dopaminergic system may be a potential pharmacological target for treatment of behavioral abnormalities in ASD patients.
In the present study, we examined the effects of antipsychotic drugs, which affect the dopaminergic system, on the social interaction deficits, recognition memory impairment, and reduction in dendritic spine density in the VPA mouse model of ASD.
Both acute and chronic administrations of the atypical antipsychotic drugs risperidone and aripiprazole increased prefrontal dopamine (DA) release, while the typical antipsychotic drug haloperidol did not. Chronic risperidone and aripiprazole, but not haloperidol, increased the expression of c-Fos in the prefrontal cortex, although they all increased c-Fos expression in the striatum. Chronic, but not acute, administrations of risperidone and aripiprazole improved the VPA-induced social interaction deficits and recognition memory impairment, as well as the reduction in dendritic spine density in the prefrontal cortex and hippocampus. In contrast, chronic administration of haloperidol did not ameliorate VPA-induced abnormalities in behaviors and dendritic spine density.
These findings indicate that chronic risperidone and aripiprazole treatments improve VPA-induced abnormalities in behaviors and prefrontal dendritic spine density, which may be mediated by repeated elevation of extracellular DA in the prefrontal cortex. Our results also imply that loss of prefrontal dendritic spines may be involved in the abnormal behaviors in the VPA mouse model of ASD.
产前暴露于丙戊酸（VPA）的啮齿动物表现出自闭症谱系障碍（ASD）样行为异常。我们最近发现，产前 VPA 暴露导致小鼠前额叶多巴胺能系统功能低下。这表明多巴胺能系统可能是治疗 ASD 患者行为异常的潜在药物靶点。
在本研究中，我们研究了影响多巴胺能系统的抗精神病药物对 ASD VPA 小鼠模型的社会交往缺陷、识别记忆障碍和树突棘密度减少的影响。
急性和慢性给予非典型抗精神病药物利培酮和阿立哌唑均可增加前额叶多巴胺（DA）释放，而典型抗精神病药物氟哌啶醇则不能。慢性利培酮和阿立哌唑增加前额皮质 c-Fos 的表达，而氟哌啶醇则没有，尽管它们都增加了纹状体中的 c-Fos 表达。慢性而非急性给予利培酮和阿立哌唑可改善 VPA 引起的社会交往缺陷、识别记忆障碍以及前额叶皮质和海马中的树突棘密度减少。相比之下，慢性给予氟哌啶醇不能改善 VPA 引起的行为和树突棘密度异常。
这些发现表明，慢性利培酮和阿立哌唑治疗可改善 VPA 诱导的行为和前额叶树突棘密度异常，这可能是通过反复增加前额叶皮质细胞外 DA 介导的。我们的结果还表明，前额叶树突棘的丧失可能与 ASD VPA 小鼠模型中的异常行为有关。
