Abstract
Aripiprazole is a D2-like receptor (D2R) partial agonist with a favourable clinical profile. Previous investigations indicated that acute and short-term administration of aripiprazole had effects on PKA activity, GSK3β-dependent pathways, GABAA receptors, NMDA receptor and CREB1 in the brain. Since antipsychotics are used chronically in clinics, the present study investigated the long-term effects of chronic oral aripiprazole treatment on these cellular signalling pathways, in comparison with haloperidol (a D2R antagonist) and bifeprunox (a potent D2R partial agonist). We found that the Akt-GSK3β pathway was activated by aripiprazole and bifeprunox in the prefrontal cortex; NMDA NR2A levels were reduced by aripiprazole and haloperidol. In the nucleus accumbens, all three drugs increased Akt-GSK3β signalling; in addition, both aripiprazole and haloperidol, but not bifeprunox, increased the expression of Dvl-3, β-catenin and GABAA receptors, NMDA receptor subunits, as well as CREB1 phosphorylation levels. The results suggest that chronic oral administration of aripiprazole affects schizophrenia-related cellular signalling pathways and markers (including Akt-GSK3β signalling, Dvl-GSK3β-β-catenin signalling, GABAA receptor, NMDA receptor and CREB1) in a brain-region-dependent manner; the selective effects of aripiprazole on these signalling pathways might be associated with its unique clinical effects.
Highlights
The G protein-dependent protein kinase A (PKA) pathway is another downstream signalling pathway of D2-like receptors
An in vivo study has indicated that acute administration of haloperidol and olanzapine increased the expression of PKA catalytic subunits in the rat caudate putamen (CPu)[14]; PKA signalling has been elevated by acute administration of haloperidol in the striatum[15]; and the activity of the PKA pathway and expression of PKA regulatory subunits in the striatum were elevated after a 3-week administration of haloperidol in various brain regions, but decreased by clozapine administration[16]
The present study investigated the chronic effects of aripiprazole on Akt-GSK3βand Dvl-GSK3β-β-catenin signalling, PKA activity, GABAA receptor expression, N-methyl-D-aspartate receptors (NMDARs) subunits expression and cAMP-responsive element-binding protein 1 (CREB1) activity in three brain regions, compared with haloperidol and bifeprunox
Summary
The G protein-dependent PKA pathway is another downstream signalling pathway of D2-like receptors. A recent study has shown that 1-week administration of aripiprazole increased PKA phosphorylation in the nucleus accumbens (NAc), but reduced it in the CPu, while haloperidol decreased it in both the NAc and CPu17. It has been reported that 1-week treatment with both haloperidol and olanzapine increased the binding density of [3H]-Muscimol labelled GABAA receptors[24] in the PFC. Recent data suggested that expression of GABAA receptors in the rat NAc was elevated by 1-week aripiprazole administration, probably by activation of the PKA pathway[17]. A recent short-term study has reported that aripiprazole increased the gene and protein expression of CREB1, probably through the PKA pathway, in the NAc of rats[17]. The present study investigated the effects of 10-week oral administration of aripiprazole by examining PKA signalling, Akt-GSK3βand Dvl-GSK3β-β-catenin pathways, GABAA receptors and CREB1 activity, in comparison with haloperidol and bifeprunox
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