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KMID : 0620920070390030353
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Experimental & Molecular Medicine
2007 Volume.39 No. 3 p.353 ~ p.360
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Haloperidol and clozapine differentially regulate signals upstream of glycogen synthase kinase 3 in the rat frontal cortex
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Roh Myoung-Sun
Seo Moung-Seock
Kim Ye-Ni
Kim Se-Hyun
Jeon Won-Je
Ahn Yong-Min
Kang Ung-Gu
Juhnn Yong-Sung
Kim Yong-Sik
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Abstract
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Glycogen synthase kinase 3 (GSK3) was recently suggested to be a potential target of psychotropics used in psychiatric illnesses such as schizophrenia and bipolar disorder. Relevant studies have found that antipsychotic drugs regulate GSK3 activity via an increase in either inhibitory serine phosphorylation or amount of GSK3 after acute or subchronic treatment. Recent evidence shows that GSK3 is regulated by dopaminergic or serotonergic systems implicated in the pathophysiology and treatment mechanisms of schizophrenia and bipolar disorder. Therefore, antipsychotics may regulate GSK3 via antagonizing dopaminergic or serotonergic activity. However, the signaling pathway that is involved in GSK3 regulation by dopaminergic or serotonergic systems has not been well established. Haloperidol is a typical antipsychotic with potent dopamine D2 receptor antagonism. Clozapine is an atypical antipsychotic with potent serotonin 5HT2 receptor antagonism. We injected rats with haloperidol or clozapine and examined the phosphorylation and amount of GSK3a/b and its well-known upstream regulators Akt and Dvl in the rat frontal cortex by Western blotting. Both haloperidol and clozapine induced Ser21/9 phosphorylation of GSK3a/b. Haloperidol increased the Ser473 phosphorylation of Akt transiently, whereas clozapine maintained the increase for 1 h. Haloperidol did not affect the phosphorylation and amount of Dvl, whereas clozapine increased both phosphorylation and the amount of Dvl. Our results suggest that GSK3 activity may be regulated by both typical and atypical antipsychotics and that Akt or Dvl, depending on the D2- or 5HT2- receptor antagonism properties of typical and atypical antipsychotics, mediate the regulation differently.
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KEYWORD
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antipsychotic agents, clozapine, dishevelled protein, glycogen synthase kinase-3, haloperidol, proto-oncogene proteins c-akt
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