The International Journal of Neuropsychopharmacology

Table of Contents - 2007 - Volume 10, Issue 01  


Regulation of mouse brain glycogen synthase kinase-3 by atypical antipsychotics

Xiaohua Li a1c1, Kelley M. Rosborough a1, Ari B. Friedman a1, Wawa Zhu a1 and Kevin A. Roth a2
a1 Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA
a2 Department of Neuropathology, University of Alabama at Birmingham, Birmingham, AL, USA

Article author query
li x   [PubMed][Google Scholar] 
rosborough km   [PubMed][Google Scholar] 
friedman ab   [PubMed][Google Scholar] 
zhu w   [PubMed][Google Scholar] 
roth ka   [PubMed][Google Scholar] 

Abstract

Glycogen synthase kinase-3 (GSK3) has been recognized as an important enzyme that modulates many aspects of neuronal function. Accumulating evidence implicates abnormal activity of GSK3 in mood disorders and schizophrenia, and GSK3 is a potential protein kinase target for psychotropics used in these disorders. We previously reported that serotonin, a major neurotransmitter involved in mood disorders, regulates GSK3 by acutely increasing its N-terminal serine phosphorylation. The present study was undertaken to further determine if atypical antipsychotics, which have therapeutic effects in both mood disorders and schizophrenia, can regulate phospho-Ser-GSK3 and inhibit its activity. The results showed that acute treatment of mice with risperidone rapidly increased the level of brain phospho-Ser-GSK3 in the cortex, hippocampus, striatum, and cerebellum in a dose-dependent manner. Regulation of phospho-Ser-GSK3 was a shared effect among several atypical antipsychotics, including olanzapine, clozapine, quetiapine, and ziprasidone. In addition, combination treatment of mice with risperidone and a monoamine reuptake inhibitor antidepressant imipramine or fluoxetine elicited larger increases in brain phospho-Ser-GSK3 than each agent alone. Taken together, these results provide new information suggesting that atypical antipsychotics, in addition to mood stabilizers and antidepressants, can inhibit the activity of GSK3. These findings may support the pharmacological mechanisms of atypical antipsychotics in the treatment of mood disorders.

(Received December 11 2005)
(Reviewed January 5 2006)
(Revised January 18 2006)
(Accepted January 23 2006)
(Published Online May 4 2006)


Key Words: Antidepressants; antipsychotics; Glycogen synthase kinase-3; serotonin.

Correspondence:
c1 Department of Psychiatry and Behavioral Neurobiology, 1720 7th Ave South, Sparks Center 1075, University of Alabama at Birmingham, Birmingham, AL 35294-0017, USA. Tel.: (205) 934-1169 Fax: (205) 934-2500 E-mail: xili@uab.edu

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