title: Aripiprazole and Haloperidol Activate GSK3β-Dependent Signalling Pathway Differentially in Various Brain Regions of Rats.
abstract: Aripiprazole, a dopamine D₂ receptor (D₂R) partial agonist, possesses a unique clinical profile. Glycogen synthase kinase 3β (GSK3β)-dependent signalling pathways have been implicated in the pathophysiology of schizophrenia and antipsychotic drug actions. The present study examined whether aripiprazole differentially affects the GSK3β-dependent signalling pathways in the prefrontal cortex (PFC), nucleus accumbens (NAc), and caudate putamen (CPu), in comparison with haloperidol (a D₂R antagonist) and bifeprunox (a D₂R partial agonist). Rats were orally administrated aripiprazole (0.75 mg/kg), bifeprunox (0.8 mg/kg), haloperidol (0.1 mg/kg) or vehicle three times per day for one week. The levels of protein kinase B (Akt), p-Akt, GSK3β, p-GSK3β, dishevelled (Dvl)-3, and β-catenin were measured by Western Blots. Aripiprazole increased GSK3β phosphorylation in the PFC and NAc, respectively, while haloperidol elevated it in the NAc only. However, Akt activity was not changed by any of these drugs. Additionally, both aripiprazole and haloperidol, but not bifeprunox, increased the expression of Dvl-3 and β-catenin in the NAc. The present study suggests that activation of GSK3β phosphorylation in the PFC and NAc may be involved in the clinical profile of aripiprazole; additionally, aripiprazole can increase GSK3β phosphorylation via the Dvl-GSK3β-β-catenin signalling pathway in the NAc, probably due to its relatively low intrinsic activity at D₂Rs.
authors.affiliation: Illawarra Health and Medical Research Institute, Wollongong 2522, Australia. bp355@uowmail.edu.au.|School of Medicine, University of Wollongong, Wollongong 2522, Australia. bp355@uowmail.edu.au.
authors.forename: Bo
authors.initials: B
authors.lastname: Pan
authors.affiliation: Illawarra Health and Medical Research Institute, Wollongong 2522, Australia. xhuang@uow.edu.au.|School of Medicine, University of Wollongong, Wollongong 2522, Australia. xhuang@uow.edu.au.
authors.forename: Xu-Feng
authors.initials: XF
authors.lastname: Huang
authors.affiliation: Illawarra Health and Medical Research Institute, Wollongong 2522, Australia. chao@uow.edu.au.|School of Medicine, University of Wollongong, Wollongong 2522, Australia. chao@uow.edu.au.
authors.forename: Chao
authors.initials: C
authors.lastname: Deng
mesh_terms: D000284:Administration, Oral; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D000068180:Aripiprazole / Q000494:pharmacology*; D001583:Benzoxazoles / Q000494:pharmacology; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D000072261:Dishevelled Proteins / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism*; D006220:Haloperidol / Q000494:pharmacology*; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D001583:Benzoxazoles; D000072261:Dishevelled Proteins; D010879:Piperazines; D017448:Receptors, Dopamine D2; D051176:beta Catenin; D000068180:Aripiprazole; C509981:bifeprunox; D000071679:Glycogen Synthase Kinase 3 beta; D006220:Haloperidol
keywords: Dvl-3; GSK3β; antipsychotics; aripiprazole; bifeprunox; haloperidol; β-catenin