Psychotropic drugs affect Ser9-phosphorylated GSK-3β protein levels in rodent frontal cortex

Glycogen synthase kinase (GSK)-3β, a serine/threonine kinase highly abundant in brain is a negative regulator of signal transduction cascades including the phosphatidylinositol-3-kinase (PI3-K)/Akt and the Wnt. GSK-3β has recently been suggested to be an intracellular target of the mood stabilizers lithium and valproate and of the typical and atypical antipsychotic agents haloperidol and clozapine. We have previously shown that these agents do not alter frontal cortex GSK-3β protein levels or activity. The current study was conducted to assess the effect of psychotropic drugs on phospho-Ser9-GSK-3β levels in rodents. Chronic administration of haloperidol to rats resulted in a significant reduction in frontal cortex phospho-Ser9-GSK-3β protein levels and no change in those of GSK-3α, while chronic administration of clozapine or subchronic administration of valproate caused significant elevation of GSK-3β protein levels. Mice treated chronically with lithium exhibited the most prominent elevation in phosphoSer9-GSK-3β. The results support the notion that GSK-3β may be a common target for mood stabilizers and neuroleptics.