Exp Mol Med.  2007 Jun;39(3):353-360.

Haloperidol and clozapine differentially regulate signals pstream of glycogen synthase kinase 3 in the rat frontal cortex

• Roh MS
• Seo MS
• Kim Y
• Kim SH
• Jeon WJ
• Ahn YM
• Kang UG
• Juhnn YS
• Kim YS

Abstract

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 D(2) receptor antagonism. Clozapine is an atypical antipsychotic with potent serotonin 5HT(2) receptor antagonism. We injected rats with haloperidol or clozapine and examined the phosphorylation and amount of GSK3alpha/beta 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 GSK3GSK3alpha/beta. 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 D(2)- or 5HT(2)- receptor antagonism properties of typical and atypical antipsychotics, mediate the regulation differently.

Keyword

antipsychotic agents; clozapine; dishevelled protein; glycogen synthase kinase-3; haloperidol; proto-oncogene proteins c-akt

MeSH Terms

Adaptor Proteins, Signal Transducing/metabolism/*physiology
Animals
Antipsychotic Agents/*pharmacology
Clozapine/*pharmacology
Dopamine Antagonists/pharmacology
Frontal Lobe/*drug effects/enzymology
Glycogen Synthase Kinase 3/*metabolism
Haloperidol/*pharmacology
Male
Phosphoproteins/metabolism/*physiology
Phosphorylation
Proto-Oncogene Proteins c-akt/metabolism/*physiology
Rats
Rats, Sprague-Dawley
Serotonin Antagonists/pharmacology
Signal Transduction