- 學位論文
以思覺失調症候選基因Akt1缺損小鼠為模型探討Akt1調控多巴胺二型受體之活性與鋰鹽對於Akt1相關行為缺損之治療效果
The Involvement of Akt1 in the Regulation of Striatal Dopamine D2 Receptor Activity and the Rescue Effect of Lithium on Akt1-Related Behavioral Deficits in Akt1 Mutant Mice Model of Schizophrenia
摘要
思覺失調症是一複雜的神經精神疾患，其疾病好發年紀在青少年晚期以及成年早期。過去的證據指出思覺失調症的候選基因之ㄧ-AKT1同時也是亞基安非他命濫用的候選基因。除此之外，越來越多的案例指出思覺失調症共病物質濫用的普遍性以及物質(藥物)濫用如何加重思覺失調症相關症狀。近來，越來越多的研究著墨於Akt1基因缺損如何受到性別差異的影響導致出不同的行為異常或神經傳導物上的改變。本研究利用Akt1缺損小鼠，欲配合長期甲基安非他命的施打，觀察其行為，神經傳導物質活性與表現量以及藥物治療操弄，來深入探討思覺失調症的成病因子以及尋找有潛力的治療藥物。實驗ㄧ，欲分析不同年齡層是否影響Akt1對於多巴胺二型受體的活性及其差異，使用放射性同位素配合正子斷層掃描以利觀察。實驗發現，只有成年公鼠的多巴胺二型受體活性受到影響，且根據不同的基因型或是環境因子操控的有無，其活性產生不同的改變。除此之外也發覺這影響並非來自多巴胺或是多巴胺二型受體本身表現量的改變，推測應該是來自於Akt1缺損導致的結果。實驗二使用GSK3相關抗憂鬱藥物-鋰鹽，成功治療或減輕Akt1基因缺損母鼠的異常行為，以期提供病患ㄧ有效的治療方向與發展。本研究闡釋了多巴胺受體本身活性的重要性來推測思覺失調症可能的致病因子之ㄧ，也展示鋰鹽對於思覺失調症相關行為缺陷的治療潛力。
並列摘要
Schizophrenia is a complex neuropsychiatric disorder and its onset generally occurs in late adolescence or early adulthood. Accumulating evidence from human genetic and animal studies suggests that AKT1 is a susceptibility gene for both schizophrenia and methamphetamine (Meth) use disorder. Comorbid substance abuse in schizophrenia has been consistently reported and substance abuse may also exacerbate schizophrenia-related symptoms. Recently, the sex-specific role of Akt1 had been reported that the modulation of Meth-induced hyperlocomotion and striatal neuronal activity in male mice, whereas the behavior deficits such as depression-like behavior and sensorimotor gating function in female mice. Otherwise, recent study also revealed that Akt1-deficit mice were insensitive to antipsychotic drugs, but GSK3 (a key downstream kinase for Akt1) inhibitor could have therapeutic potential. To further investigate the impact of Akt1 deficiency on the regulation of dopamine D2 receptor (DRD2) activity and the therapeutic potential of lithium, which is a GSK3 inhibitor, on the alleviation of Akt1-related deficits, a series of 2 studies was conducted. In the study1, microPET imaging with 18F-fallypride revealed the striatal DRD2 activity in male Akt1 heterozygous (Akt1+/-) mice and their wild-type (WT) littermate controls during the periods of adolescence, adulthood, and aging. In the study 2, WT and Akt1+/- females received chronic lithium administration for treating a set of 3 behavioral tasks. In the study 1, our data indicated that alterations of DRD2 activity were found in the striatum of adult but not adolescent or aged mice. And the findings did not result from the dopamine level or DRD2 expression. In the study 2, chronic treatment of lithium alleviated behavioral impairments in the acoustic PPI and tail suspension task in Akt1+/- mice and dampened the Meth-induced stereotypic behaviors in both WT and Akt1+/- females. Collectively, these findings support that Akt1 deficiency predisposes to abnormalities of striatal DRD2 activity contributing to the pathogenesis of comorbid schizophrenia and the therapeutic potential of lithium struggles against the behavioral deficits using Akt1+/- mouse model of schizophrenia.
並列關鍵字
Schizophrenia ； Akt1 ； Dopamine D2 receptor ； Methamphetamine ； Behavioral sensitization ； MicroPET ； 18F-fallypride ； Lithium參考文獻
延伸閱讀
- Chen, Y. S. (2012). 評估精神分裂症動物模式之Akt1基因缺損小鼠在五擇一序列反應時程作業的注意力功能 [master's thesis, National Taiwan University]. Airiti Library. https://doi.org/10.6342/NTU.2012.02909
- Wong, W. R. (2014). 以思覺失調症候選基因Akt1缺陷小鼠探討新生期聚肌胞苷酸刺激對新生期免疫反應與成鼠行為之影響 [master's thesis, National Taiwan University]. Airiti Library. https://doi.org/10.6342/NTU.2014.01735
- 李明儀（2007）。The Association Study of AKT1 Genotype, Lymphocyte AKT1 Expression Level, and Neuropsychological Performance Deficit in Schizophrenic Patients〔碩士論文，國立臺灣大學〕。華藝線上圖書館。https://doi.org/10.6342/NTU.2007.00317