Alterations in the endocannabinoid system in the rat valproic acid model of autism
Alterations in the endocannabinoid system in the rat valproic acid model of autism
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DOI：
10.1016/j.bbr.2013.04.043
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发表时间：
2013-07-15
影响因子：
2.7
通讯作者：
Roche, M.
中科院分区：
文献类型：
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作者：
Kerr, D. M.;Downey, L.;Roche, M.
内源性大麻素系统在调节情绪和社会行为中起着至关重要的作用，然而，该系统是否在自闭症谱系障碍相关症状中起作用尚不清楚。目前的研究评估了内源性大麻素系统的改变是否伴随丙戊酸（VPA）自闭症大鼠模型的行为改变。暴露于VPA的青春期大鼠在暴露于新的厌恶场所时表现出社会调查行为受损，痛觉减退和局部运动活动减少。内源性大麻素、大麻酰胺（AEA）和2-花生四烯酰基甘油（2-AG）在海马、额叶皮层和小脑中的水平与暴露于VPA的动物相比没有改变。然而，在暴露于vpa的大鼠小脑中，主要负责2-AG合成的酶二酰基甘油脂肪酶α的mRNA表达减少。此外，虽然暴露于vpa的动物海马中2- ag分解代谢酶单酰基甘油脂肪酶的mRNA表达减少，但该酶的活性却增加。CB1或CB2受体的表达在任何被检测的区域都没有改变，但是暴露于vpa的大鼠表现出额叶皮层PPAR α和GPR55的表达减少，海马体PPAR γ和GPR55的表达减少，这是内源性大麻素的额外受体靶点。此外，脂肪酸酰胺水解酶底物AEA、油基乙醇酰胺和棕榈基乙醇酰胺的组织水平在社会暴露后立即在vpa暴露大鼠的海马中升高。这些数据表明，产前VPA暴露与大脑内源性大麻素系统的改变有关，并支持了内源性大麻素功能障碍可能是自闭症谱系障碍中观察到的行为异常的基础的假设。(c) 2013 Elsevier B.V.版权所有
The endocannabinoid system plays a crucial role in regulating emotionality and social behaviour, however it is unknown whether this system plays a role in symptoms associated with autism spectrum disorders. The current study evaluated if alterations in the endocannabinoid system accompany behavioural changes in the valproic acid (VPA) rat model of autism. Adolescent rats prenatally exposed to VPA exhibited impaired social investigatory behaviour, hypoalgesia and reduced lococmotor activity on exposure to a novel aversive arena. Levels of the endocananbinoids, anandamide (AEA) and 2-arachidonylglycerol (2-AG) in the hippocampus, frontal cortex or cerebellum were not altered in VPA- versus saline-exposed animals. However, the expression of mRNA for diacylglycerol lipase alpha, the enzyme primarily responsible for the synthesis of 2-AG, was reduced in the cerebellum of VPA-exposed rats. Furthermore, while the expression of mRNA for the 2-AG-catabolising enzyme monoacylglycerol lipase was reduced, the activity of this enzyme was increased, in the hippocampus of VPA-exposed animals. CB1 or CB2 receptor expression was not altered in any of the regions examined, however VPA-exposed rats exhibited reduced PPAR alpha and GPR55 expression in the frontal cortex and PPAR gamma and GPR55 expression in the hippocampus, additional receptor targets of the endocannabinoids. Furthermore, tissue levels of the fatty acid amide hydrolase substrates, AEA, oleoylethanolamide and palmitoylethanolamide, were higher in the hippocampus of VPA-exposed rats immediately following social exposure. These data indicate that prenatal VPA exposure is associated with alterations in the brain's endocannabinoid system and support the hypothesis that endocannabinoid dysfunction may underlie behavioural abnormalities observed in autism spectrum disorders. (c) 2013 Elsevier B.V. All rights reserved.