title: Chronic administration of aripiprazole activates GSK3β-dependent signalling pathways, and up-regulates GABAA receptor expression and CREB1 activity in rats.
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.
authors.affiliation: Antipsychotic Research Laboratory, Illawarra Health and Medical Research Institute, Wollongong, 2522, NSW, Australia.|Centre for Translational Neuroscience, School of Medicine, University of Wollongong, Wollongong, 2522, NSW, Australia.
authors.forename: Bo
authors.initials: B
authors.lastname: Pan
authors.affiliation: Centre for Translational Neuroscience, School of Medicine, University of Wollongong, Wollongong, 2522, NSW, Australia.
authors.forename: Xu-Feng
authors.initials: XF
authors.lastname: Huang
authors.affiliation: Antipsychotic Research Laboratory, Illawarra Health and Medical Research Institute, Wollongong, 2522, NSW, Australia.|Centre for Translational Neuroscience, School of Medicine, University of Wollongong, Wollongong, 2522, NSW, Australia.
authors.forename: Chao
authors.initials: C
authors.lastname: Deng
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage*; D000068180:Aripiprazole / Q000008:administration & dosage*; D001583:Benzoxazoles / Q000008:administration & dosage; D017362:Cyclic AMP Response Element-Binding Protein / Q000032:analysis*; D000071679:Glycogen Synthase Kinase 3 beta / Q000032:analysis*; D006220:Haloperidol / Q000008:administration & dosage; D010879:Piperazines / Q000008:administration & dosage; D017397:Prefrontal Cortex / Q000187:drug effects; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation
chemical_list: D014150:Antipsychotic Agents; D001583:Benzoxazoles; C508137:Creb1 protein, rat; D017362:Cyclic AMP Response Element-Binding Protein; D010879:Piperazines; D000068180:Aripiprazole; C509981:bifeprunox; D000071679:Glycogen Synthase Kinase 3 beta; D006220:Haloperidol