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Abstract
Aripiprazole is a wide-used antipsychotic drug with therapeutic effects on both positive and negative symptoms of schizophrenia, and reduced side-effects. Although aripiprazole was developed as a dopamine D2 receptor (D2R) partial agonist, all other D2R partial agonists that aimed to mimic aripiprazole failed to exert therapeutic effects in clinic. The present in vivo study aimed to investigate the effects of aripiprazole on the D2R downstream cAMP-PKA and Akt-GSK3β signalling pathways in comparison with a D2R antagonist – haloperidol and a D2R partial agonist – bifeprunox. Rats were injected once with aripiprazole (0.75mg/kg, i.p.), bifeprunox (0.8mg/kg, i.p.), haloperidol (0.1mg/kg, i.p.) or vehicle. Five brain regions – the prefrontal cortex (PFC), nucleus accumbens (NAc), caudate putamen (CPu), ventral tegmental area (VTA) and substantia nigra (SN) were collected. The protein levels of PKA, Akt and GSK3β were measured by Western Blotting; the cAMP levels were examined by ELISA tests. The results showed that aripiprazole presented similar acute effects on PKA expression to haloperidol, but not bifeprunox, in the CPU and VTA. Additionally, aripiprazole was able to increase the phosphorylation of GSK3β in the PFC, NAc, CPu and SN, respectively, which cannot be achieved by bifeprunox and haloperidol. These results suggested that acute treatment of aripiprazole had differential effects on the cAMP-PKA and Akt-GSK3β signalling pathways from haloperidol and bifeprunox in these brain areas. This study further indicated that, by comparison with bifeprunox, the unique pharmacological profile of aripiprazole may be attributed to the relatively lower intrinsic activity at D2R.
Highlights
Aripiprazole has therapeutic effects on both positive and negative symptoms of schizophrenia, with improved extrapyramidal side-effects (EPS) compared with first-generation antipsychoticPLOS ONE | DOI:10.1371/journal.pone.0132722 July 10, 2015Unique Effects of Aripiprazole on protein kinase A (PKA) and Akt-GSK3β Signalling drugs and reduced metabolic side-effects compared with second-generation antipsychotic drugs; aripiprazole is regarded as the third-generation antipsychotic drug [1, 2]
The results of the current study showed that aripiprazole had similar effects on PKA subunits to haloperidol, but not bifeprunox in the caudate putamen (CPu) and ventral tegmental area (VTA), indicating that relatively lower intrinsic activity of aripiprazole on D2 receptor (D2R) might be the mechanism of aripiprazole to exert its therapeutic effects on treating positive symptoms of schizophrenia; on the other hand, aripiprazole displayed a very different action mode on the GSK3β activity from the other two chemicals, probably explaining its therapeutic effects on both positive and negative symptoms of schizophrenia, with reduced EPS
The present study demonstrated that acute treatment with aripiprazole increased the levels of p-GSK3β, as well as the ratio of p-GSK3β/GSK3β in the prefrontal cortex (PFC), CPu, nucleus accumbens (NAc), respectively, which indicates the inhibition of the functions of GSK3β in these brain areas
Summary
Aripiprazole has therapeutic effects on both positive and negative symptoms of schizophrenia, with improved extrapyramidal side-effects (EPS) compared with first-generation antipsychoticPLOS ONE | DOI:10.1371/journal.pone.0132722 July 10, 2015Unique Effects of Aripiprazole on PKA and Akt-GSK3β Signalling drugs (e.g. haloperidol) and reduced metabolic side-effects compared with second-generation antipsychotic drugs (e.g. olanzapine); aripiprazole is regarded as the third-generation antipsychotic drug [1, 2]. Several studies suggested that the potent partial agonism of aripiprazole for the dopamine D2 receptor (D2R) stabilises the dopamine D2 system, playing a critical role in its unique clinical actions [3, 4]. This hypothesis has been questioned because there are no other D2R partial agonists that are widely accepted and used after aripiprazole. An in vivo study from our group found selective effects of aripiprazole on the mesolimbic vs the nigrostriatal dopaminergic pathways compared with haloperidol, which could be explained by the functional selectivity of aripiprazole [11]. How aripiprazole differentially affects the downstream signalling pathways of the D2R in various dopaminergic pathways in vivo has not been well studied
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