Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 17, Issue 4, Pages -Publisher
MDPI
DOI: 10.3390/ijms17040459
Keywords
antipsychotics; aripiprazole; beta-catenin; bifeprunox; Dv1-3; GSK3 beta; haloperidol
Funding
- Australian National Health and Medical Research Council [APP1008473]
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Aripiprazole, a dopamine D-2 receptor (D2R) partial agonist, possesses a unique clinical profile. Glycogen synthase kinase 3 beta (GSK3 beta)-dependent signalling pathways have been implicated in the pathophysiology of schizophrenia and antipsychotic drug actions. The present study examined whether aripiprazole differentially affects the GSK3 beta-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, GSK3(3, p-GSK3 beta, dishevelled (Dvl)-3, and beta-catenin were measured by Western Blots. Aripiprazole increased GSK3 beta 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 beta-catenin in the NAc. The present study suggests that activation of GSK3 beta phosphorylation in the PFC and NAc may be involved in the clinical profile of aripiprazole; additionally, aripiprazole can increase GSK3 beta phosphorylation via the Dvl-GSK3 beta-beta-catenin signalling pathway in the NAc, probably due to its relatively low intrinsic activity at D(2)Rs.
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