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

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.

• Authors: Xiaohua Li, Kelley M Rosborough, Ari B Friedman, Wawa Zhu, Kevin A Roth
• Journal: The international journal of neuropsychopharmacology (Int J Neuropsychopharmacol) Vol. 10 Issue 1 Pg. 7-19 (Feb 2007) ISSN: 1461-1457 [Print] England
• PMID: 16672106 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adrenergic Uptake Inhibitors
• Antidepressive Agents
• Antipsychotic Agents
• Dibenzothiazepines
• Enzyme Inhibitors
• Piperazines
• Serotonin Uptake Inhibitors
• Thiazoles
• Benzodiazepines
• Quetiapine Fumarate
• Serine
• ziprasidone
• Glycogen Synthase Kinase 3
• Clozapine
• Risperidone
• Olanzapine

Topics

• Adrenergic Uptake Inhibitors (pharmacology)
• Animals
• Antidepressive Agents (pharmacology)
• Antipsychotic Agents (pharmacology)
• Benzodiazepines (pharmacology)
• Brain (drug effects, enzymology)
• Clozapine (pharmacology)
• Dibenzothiazepines (pharmacology)
• Dose-Response Relationship, Drug
• Drug Synergism
• Enzyme Inhibitors (pharmacology)
• Glycogen Synthase Kinase 3 (antagonists & inhibitors, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Olanzapine
• Phosphorylation (drug effects)
• Piperazines (pharmacology)
• Quetiapine Fumarate
• Risperidone (pharmacology)
• Serine (metabolism)
• Selective Serotonin Reuptake Inhibitors (pharmacology)
• Thiazoles (pharmacology)
• Time Factors