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.

Early antipsychotic exposure affects NMDA and GABAA receptor binding in the brains of juvenile rats

“…Our results showed that aripiprazole upregulated the [ 3 H]muscimol binding level in the PFC, NAcC and CPu of juvenile rats. The results were consistent with the previous papers from our group that both short-term and chronic treatment of aripiprazole increased the expression of GABA A receptor (β-1 subunit) in the NAc of male adult and adolescent rats (Pan et al, 2016a;Pan et al, 2016b). Previously, it has been reported that 1…”

“…Therefore, aripiprazole-induced alteration of NMDA receptor expression may be regulated via acting on dopaminergic D2, such as through D2 receptor downstream protein kinase B (Akt)-glycogen synthase kinase 3 beta (GSK3β) and protein kinase A (PKA) signalling pathways (Beaulieu and Gainetdinov, 2011;Pan et al, 2016a). It has also been reported that the GABA A receptor could be regulated by aripiprazole via D2 receptor downstream PKA signalling (Connelly et al, 2013;Pan et al, 2016b). On the other hand, risperidone is a potent D2 antagonist and also 5-HT2A/C antagonist (Correll, 2010).…”

“…Another study illustrated that, after 3 weeks' of risperidone administration to juvenile male rats, risperidone significantly reduced NMDA receptor bindings in the NAc and caudate putamen (CPu), while it elevated the AMPA receptor bindings in the medial prefrontal cortex (PFC) and CPu of male juvenile rats (Choi et al, 2009). Recent studies in our group have reported that aripiprazole and haloperidol could up-regulate the levels of NMDA NR1 and NR2A subunits via the D 2 receptor downstream protein kinase B (Akt)glycogen synthase kinase 3β (GSK3β) pathway in the NAc of adult rats, while these antipsychotics mediate GABA A receptors via the cyclic adenosine monophosphate (cAMP)protein kinase A (PKA) pathway (Pan et al, 2016a;Pan et al, 2016b). However, limited studies have examined the effects of early antipsychotic treatment on NMDA and GABA receptor neurotransmission in children and adolescents.…”

GPR30 receptor promotes preoperative anxiety-induced postoperative hyperalgesia by up-regulating GABAA-α4β1δ subunits in periaqueductal gray in female rats

“…Moreover, ethanol modulation of extrasynaptic GABA A α4 and δ subunits is PKAdependent, and PKA directly affects the expression and function of these receptors, which increase the tonic current in cortical neurons after exposure to a PKA activator, but PKC activation exerts no influence in the tonic current [37]. Aripiprazole increases the expression of GABA A (containing β-1 subunit) receptor in the nucleus accumbens of rats, which is significantly correlated with the enhanced PKA signaling [38]. In addition to hyperalgesia in behavioral tests, we found that the expression (based on western blotting) of GABA A α4, β1, and δ subunits significantly increased in the PAG of Group S + I and Group G1 + I, and the neurons of the PAG also appeared simultaneously immunopositive for GPR30 and GABA A α4, β1, and δ subunits.…”

Novel Antipsychotic Drugs Approved in 2015: Brexpiprazole, Cariprazine, Aripiprazole Lauroxil

“…Many have similar 3D structures so that it is not easy to rationalize their differing relative potency in different clinical settings. However, significantly SAR for different degrees of internal mobility suggests that molecular dynamics should be an additional factor considered when trying to understand the mode of action of this clinically important family of molecules [36].…”