Activation of the canonical Wnt pathway by the antipsychotics haloperidol and clozapine involves dishevelled-3

Area of Science:

• Neuroscience
• Molecular Biology
• Pharmacology

Background:

• Schizophrenia is associated with alterations in protein kinase B (Akt), glycogen synthase kinase-3 (GSK-3), and Wnt signaling pathways.
• These pathways are known targets for antipsychotic drug action.

Purpose of the Study:

• To investigate the effects of antipsychotics clozapine and haloperidol on Wnt signaling proteins in the rat prefrontal cortex.
• To elucidate the cellular mechanisms underlying antipsychotic-induced Wnt pathway modulation using PC12 and SH-SY5Y cell lines.

Main Methods:

• Western blotting (WB) was used to quantify protein levels in rat prefrontal cortex and cell lines.
• Pharmacological agents and protein overexpression were employed in cell-based assays.
• Immunoprecipitation (IP) was performed to assess protein-protein interactions in brain tissue.

Main Results:

• Clozapine and haloperidol treatment led to increased levels of Wnt-5a, dishevelled-3, Axin, GSK-3, and beta-catenin in the rat prefrontal cortex.
• Overexpression of dishevelled-3 in cell lines mimicked the in vivo changes induced by antipsychotics.
• Immunoprecipitation revealed an association between dishevelled-3 and the D2 dopamine receptor.

Conclusions:

• Antipsychotics may modulate Wnt signaling, specifically dishevelled-3, through D2 dopamine receptors.
• This interaction initiates downstream changes in Axin, GSK-3, and beta-catenin, potentially contributing to the therapeutic effects of antipsychotics in schizophrenia.