The effects of neuropsychiatric drugs on glycogen synthase kinase-3 signaling.

Glycogen synthase kinase-3 (GSK-3) has been implicated in the action of antipsychotics, mood stabilizers, and antidepressants. Given that only antipsychotics are able to alleviate the positive symptoms of schizophrenia, the regulation of GSK-3 by antipsychotics would be expected to differ from other neuropsychiatric drugs if GSK-3 is involved in the alleviation of psychosis. Consequently, the current study examined the effects of antipsychotics (haloperidol and clozapine), mood stabilizers (lithium and valproic acid), and antidepressants (imipramine and fluoxetine) on GSK-3, as well as Akt and Wnt in the prefrontal cortex and striatum. Western blotting and co-immunoprecipitation experiments showed that only antipsychotic treatment increased Dvl-3, GSK-3, and β-catenin levels and enhanced the association of GSK-3 at the dopamine D2 receptor (D₂DR) complex in the rat prefrontal cortex. In the striatum, haloperidol had the same effect on Wnt signaling as observed in the prefrontal cortex, whereas clozapine did not affect Dvl-3, GSK-3 or β-catenin levels. All three classes of drugs were able to activate Akt signaling as shown by the increased phosphorylated Akt and phosphorylated GSK-3 protein levels in the prefrontal cortex and/or striatum. In conclusion, regulation of the Wnt pathway is specific to antipsychotics, whereas antipsychotics, mood stabilizers, and antidepressants all affect Akt.