The effects of antipsychotics on beta-catenin, glycogen synthase kinase-3 and dishevelled in the ventral midbrain of rats.
Protein kinase B and glycogen synthase kinase-3 have been identified as susceptibility genes for schizophrenia and altered protein and mRNA levels have been detected in the brains of schizophrenics post-mortem. Recently, we reported that haloperidol, clozapine and risperidone alter glycogen synthase kinase-3 and beta-catenin protein expression and glycogen synthase kinase-3 phosphorylation levels in the rat prefrontal cortex and striatum. In the current study, beta-catenin, adenomatous polyposis coli, Wnt1, dishevelled and glycogen synthase kinase-3 were examined in the ventral midbrain and hippocampus using western blotting. In addition, beta-catenin and GSK-3 were examined in the substantia nigra and ventral tegmental area using confocal and fluorescence microscopy. The results indicate that repeated antipsychotic administration results in significant elevations in glycogen synthase kinase-3, beta-catenin and dishevelled-3 protein levels in the ventral midbrain and hippocampus. Raclopride causes similar changes in beta-catenin and GSK-3 in the ventral midbrain, suggesting that D2 dopamine receptor antagonism mediated the changes observed following antipsychotic administration. In contrast, amphetamine, a drug capable of inducing psychotic episodes, had the opposite effect on beta-catenin and GSK-3 in the ventral midbrain. Collectively, the results suggest that antipsychotics may exert their beneficial effects through modifications to proteins that are associated with the canonical Wnt pathway.
Alimohamad
H
H
Department of Anatomy and Cell Biology, The University of Western Ontario and The London Health Sciences Centre, London, Ontario, Canada.
Sutton
L
L
Mouyal
J
J
Rajakumar
N
N
Rushlow
W J
WJ
D048868:Adaptor Proteins, Signal Transducing; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001552:Benzazepines / Q000494:pharmacology; D015153:Blotting, Western; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003024:Clozapine / Q000494:pharmacology; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D000072261:Dishevelled Proteins; D018491:Dopamine Agonists / Q000494:pharmacology; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D006220:Haloperidol / Q000494:pharmacology; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D019257:Quinpirole / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018967:Risperidone / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000378:metabolism*; D051153:Wnt Proteins; D051155:Wnt1 Protein; D051176:beta Catenin
D048868:Adaptor Proteins, Signal Transducing; D014150:Antipsychotic Agents; D001552:Benzazepines; D000697:Central Nervous System Stimulants; C495268:Ctnnb1 protein, rat; D003598:Cytoskeletal Proteins; D000072261:Dishevelled Proteins; D018491:Dopamine Agonists; D036341:Intercellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D015534:Trans-Activators; D051153:Wnt Proteins; D051155:Wnt1 Protein; D051176:beta Catenin; D019257:Quinpirole; C071262:SK&F 82958; D000661:Amphetamine; D038362:Glycogen Synthase Kinase 3; D003024:Clozapine; D006220:Haloperidol; D018967:Risperidone