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
Date Issued
2014
Date
2014
Author(s)
Luo, Da-Zhong
Abstract
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.
Subjects
思覺失調症
Akt1
多巴胺二型受體
甲基安非他命
行為敏感化
微正子斷層掃描
18F-fallypride
鋰鹽
SDGs
Type
thesis
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