Physiology, School of Medicine, National University of Ireland Galway, Ireland.
Behav Brain Res. 2013 Jul 15;249:124-32. doi: 10.1016/j.bbr.2013.04.043. Epub 2013 May 1.
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 α, 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 PPARα and GPR55 expression in the frontal cortex and PPARγ 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.
内源性大麻素系统在调节情绪和社交行为方面起着至关重要的作用，但目前尚不清楚该系统是否在与自闭症谱系障碍相关的症状中发挥作用。本研究评估了内源性大麻素系统的改变是否伴随着丙戊酸（VPA）自闭症大鼠模型中的行为变化。产前暴露于 VPA 的青春期大鼠表现出社交探究行为受损、痛觉减退和在暴露于新的厌恶环境时运动活动减少。VPA 暴露动物与生理盐水暴露动物相比，海马体、额叶皮层或小脑内的内源性大麻素，即大麻素（AEA）和 2-花生四烯酰甘油（2-AG）的水平没有改变。然而，VPA 暴露大鼠小脑内二酰基甘油脂肪酶 α（主要负责 2-AG 合成的酶）的 mRNA 表达减少。此外，虽然 2-AG 分解代谢酶单酰基甘油脂肪酶的 mRNA 表达减少，但该酶的活性在 VPA 暴露动物的海马体中增加。在研究的任何区域，CB1 或 CB2 受体表达均未改变，但 VPA 暴露的大鼠在前额叶皮层中表现出 PPARα 和 GPR55 表达减少，在海马体中表现出 PPARγ 和 GPR55 表达减少，这些都是内源性大麻素的额外受体靶标。此外，VPA 暴露大鼠海马体中脂肪酸酰胺水解酶底物 AEA、油酰乙醇酰胺和棕榈酰乙醇酰胺的组织水平在社交暴露后立即升高。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假说。
