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.
Highlights
Aripiprazole is an atypical antipsychotic drug with therapeutic effects on both positive and negative symptoms of schizophrenia, but reduced extrapyramidal side-effects (EPS) compared with typical antipsychotics [1]
Our results have demonstrated that administration of both aripiprazole and haloperidol, but not bifeprunox, had significant effects on altering the expression of Dvl-3 and β-catenin in the nucleus accumbens (NAc)
Our study suggests that a relatively low intrinsic activity at D2 receptor (D2R) might be essential for a D2R partial agonist to achieve meaningful effects via affecting the Dvl-Glycogen synthase kinase 3β (GSK3β)-β-catenin signalling pathway
Summary
Aripiprazole is an atypical antipsychotic drug with therapeutic effects on both positive and negative symptoms of schizophrenia, but reduced extrapyramidal side-effects (EPS) compared with typical antipsychotics (e.g., haloperidol) [1]. Glycogen synthase kinase 3β (GSK3β) has been implicated in the pathophysiology of schizophrenia and the actions of antipsychotic drugs [2]. GSK3β is a major downstream regulator of dopamine D2 receptors (D2Rs), which is targeted by most antipsychotics (including aripiprazole) [3]. Aripiprazole has been shown to have effects on regulating the Akt-GSK3β signalling pathway [2]. Whether aripiprazole can affect GSK3β activity in other schizophrenia-related brain regions has not yet been studied. Our previous acute study [8] has found that acute administration of aripiprazole increased the phosphorylation levels of GSK3β in. NToot icnlevaers.tiTgoatienvtehsistigisastue et,hiws eisscuheo,swe eacphootseenat pDo2tRenptaDrt2iRal paagrotinailsat—gobnifiestp—rubnifoexpr[u18n]oxto[1c8o]mtopacoremwpaitrhe wariitphiparraizpoipler.azTohlee.refTohreer, eftohree, ptrheesepnrtessetnutdsytudexyamexianmedinetdhethdeifdfeifrfeenrtenetfefeffcetsctsoof f oonnee--wweeeekk oorraall aaddmmiinniissttrraattiioonn ooff aarriippiipprraazzoollee oonn tthhee AAkktt--GGSSKK33ββ aanndd DDvvll--GGSSKK33ββ--ββ--ccaatteenniinn ssiiggnnaalllliinngg ppaatthhwwaayyss iinn tthhrreeee sscchhiizzoopphhrreenniiaa--rreellaatteedd bbrraaiinn rreeggiioonnss iinn ccoommppaarriissoonn wwiitthh aa DD22RR aannttaaggoonniisstt——hhaallooppeerriiddooll aanndd aa DD22RR ppaarrttiiaall aaggoonniisstt——bbiiffeepprruunnooxx RReesseeaarrcchheerrss hhaavvee aattttrriibbuutteedd tthhee uunniiqquuee cclliinniiccaall pprrooffiillee ooff aarriippiipprraazzoollee ttooitistsppaartritailalagaognoinsimsmataDt 2DR2sR[1s6[,1167,]1. 7H].owHeovwere,vtehre, rtohlee rtholaet Dth2aRt pDa2rRtiapl aargtoianlisamgopnliasyms ipnlatyhse irnegtuhleatrioegnuolafttiohne Dofvlt-hGeSKD3vβl--Gβ-ScKat3eβn-iβn-csiagtnenalilninsgigpnaatlhliwngaypbaythawriapyipbryazoarleipiisprnaoztocleleaisr. nToot icnlevaers.tiTgoatienvtehsistigisastue et,hiws eisscuheo,swe eacphootseenat pDo2tRenptaDrt2iRal paagrotinailsat—gobnifiestp—rubnifoexpr[u18n]oxto[1c8o]mtopacoremwpaitrhe wariitphiparraizpoipler.azTohlee.refTohreer, eftohree, ptrheesepnrtessetnutdsytudexyamexianmedinetdhethdeifdfeifrfeenrtenetfefeffcetsctsoof f oonnee--wweeeekk oorraall aaddmmiinniissttrraattiioonn ooff aarriippiipprraazzoollee oonn tthhee AAkktt--GGSSKK33ββ aanndd DDvvll--GGSSKK33ββ--ββ--ccaatteenniinn ssiiggnnaalllliinngg ppaatthhwwaayyss iinn tthhrreeee sscchhiizzoopphhrreenniiaa--rreellaatteedd bbrraaiinn rreeggiioonnss iinn ccoommppaarriissoonn wwiitthh aa DD22RR aannttaaggoonniisstt——hhaallooppeerriiddooll aanndd aa DD22RR ppaarrttiiaall aaggoonniisstt——bbiiffeepprruunnooxx
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