title: Aripiprazole Increases the PKA Signalling and Expression of the GABAA Receptor and CREB1 in the Nucleus Accumbens of Rats.
abstract: The GABAA receptor is implicated in the pathophysiology of schizophrenia and regulated by PKA signalling. Current antipsychotics bind with D2-like receptors, but not the GABAA receptor. The cAMP-responsive element-binding protein 1 (CREB1) is also associated with PKA signalling and may be related to the positive symptoms of schizophrenia. This study investigated the effects of antipsychotics in modulating D2-mediated PKA signalling and its downstream GABAA receptors and CREB1. Rats were treated orally with aripiprazole (0.75 mg/kg, ter in die (t.i.d.)), bifeprunox (0.8 mg/kg, t.i.d.), haloperidol (0.1 mg/kg, t.i.d.) or vehicle for 1 week. The levels of PKA-Cα and p-PKA in the prefrontal cortex (PFC), nucleus accumbens (NAc) and caudate putamen (CPu) were detected by Western blots. The mRNA levels of Gabrb1, Gabrb2, Gabrb3 and Creb1, and their protein expression were measured by qRT-PCR and Western blots, respectively. Aripiprazole elevated the levels of p-PKA and the ratio of p-PKA/PKA in the NAc, but not the PFC and CPu. Correlated with this elevated PKA signalling, aripiprazole elevated the mRNA and protein expression of the GABAA (β-1) receptor and CREB1 in the NAc. While haloperidol elevated the levels of p-PKA and the ratio of p-PKA/PKA in both NAc and CPu, it only tended to increase the expression of the GABAA (β-1) receptor and CREB1 in the NAc, but not the CPu. Bifeprunox had no effects on PKA signalling in these brain regions. These results suggest that aripiprazole has selective effects on upregulating the GABAA (β-1) receptor and CREB1 in the NAc, probably via activating PKA signalling.
authors.affiliation: Antipsychotic Research Laboratory, Illawarra Health and Medical Research Institute, Wollongong, NSW, 2522, Australia.|Centre for Translational Neuroscience, School of Medicine, University of Wollongong, Wollongong, NSW, 2522, Australia.
authors.forename: Bo
authors.initials: B
authors.lastname: Pan
authors.affiliation: Antipsychotic Research Laboratory, Illawarra Health and Medical Research Institute, Wollongong, NSW, 2522, Australia.|Centre for Translational Neuroscience, School of Medicine, University of Wollongong, Wollongong, NSW, 2522, Australia.
authors.forename: Jiamei
authors.initials: J
authors.lastname: Lian
authors.affiliation: Centre for Translational Neuroscience, School of Medicine, University of Wollongong, Wollongong, NSW, 2522, Australia.
authors.forename: Xu-Feng
authors.initials: XF
authors.lastname: Huang
authors.affiliation: Antipsychotic Research Laboratory, Illawarra Health and Medical Research Institute, Wollongong, NSW, 2522, Australia. chao@uow.edu.au.|Centre for Translational Neuroscience, School of Medicine, University of Wollongong, Wollongong, NSW, 2522, Australia. chao@uow.edu.au.
authors.forename: Chao
authors.identifier: http://orcid.org/0000-0003-1147-5741
authors.initials: C
authors.lastname: Deng
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D000068180:Aripiprazole / Q000494:pharmacology*; D001583:Benzoxazoles / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D014150:Antipsychotic Agents; D001583:Benzoxazoles; C508137:Creb1 protein, rat; D017362:Cyclic AMP Response Element-Binding Protein; D010879:Piperazines; D011963:Receptors, GABA-A; D000068180:Aripiprazole; C509981:bifeprunox; D017868:Cyclic AMP-Dependent Protein Kinases; D006220:Haloperidol
keywords: Antipsychotics; Aripiprazole; Bifeprunox; CREB1; GABAA receptors; Haloperidol; PKA