Alimohamad Heidar, Rajakumar Nagalingam, Seah Yam-Hong, Rushlow Walter
Departments of Anatomy and Cell Biology, University of Western Ontario, London, Ontario, Canada.
Biol Psychiatry. 2005 Mar 1;57(5):533-42. doi: 10.1016/j.biopsych.2004.11.036.
It has been demonstrated that schizophrenics have altered levels and/or phosphorylation states of several Wnt related proteins in the brain, including beta-catenin and GSK-3, and may represent susceptibility loci for schizophrenia. The current study was conducted to assess the effects of antipsychotics on beta-catenin and glycogen synthase kinase-3.
Western blotting and immunocytochemistry were employed to investigate the effects of antipsychotics on beta-catenin and glycogen synthase kinase-3 following acute, subchronic and chronic drug administration. Specificity of the response was tested using additional drugs such as fluoxetine, amphetamine and valproic acid.
Significant increases in the levels of beta-catenin and glycogen synthase kinase-3 total protein were identified following administration of clozapine, haloperidol or risperidone. The phosphorylation state of GSK-3 was also increased but phosphorylated beta-catenin levels were unaffected. Other drug compounds, with the exception of raclopride, had no effect on either GSK-3 or beta-catenin protein levels or distribution.
Targeting of beta-catenin and GSK-3 is a common feature of antipsychotics regardless of class and appears to be mediated by D(2) dopamine receptors. Therefore changes in beta-catenin and GSK-3 may represent one of the mechanisms through which antipsychotics are able to exert behavioral changes.
已有研究表明，精神分裂症患者大脑中几种与Wnt相关的蛋白质水平和/或磷酸化状态发生改变，包括β-连环蛋白和糖原合酶激酶-3（GSK-3），这些蛋白质可能是精神分裂症的易感基因座。本研究旨在评估抗精神病药物对β-连环蛋白和糖原合酶激酶-3的影响。
采用蛋白质免疫印迹法和免疫细胞化学法，研究急性、亚慢性和慢性给药后抗精神病药物对β-连环蛋白和糖原合酶激酶-3的影响。使用氟西汀、苯丙胺和丙戊酸等其他药物测试反应的特异性。
服用氯氮平、氟哌啶醇或利培酮后，β-连环蛋白和糖原合酶激酶-3总蛋白水平显著升高。GSK-3的磷酸化状态也增加，但磷酸化β-连环蛋白水平未受影响。除雷氯必利外，其他药物化合物对GSK-3或β-连环蛋白的蛋白水平及分布均无影响。
无论药物类别如何，靶向β-连环蛋白和GSK-3是抗精神病药物的共同特征，且似乎由D(2)多巴胺受体介导。因此，β-连环蛋白和GSK-3的变化可能是抗精神病药物能够引起行为改变的机制之一。
