Clozapine induces chloride channel-4 expression through PKA activation and modulates CDK5 expression in SH-SY5Y and U87 cells

Jeon, Songhee; Kim, Yeni; Chung, In Won; Kim, Yong Sik

doi:10.1016/j.pnpbp.2014.09.002

Cited by 15 publications

(20 citation statements)

References 36 publications

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“…Previously, haloperidol was able to increase phosphorylation levels of CREB1 in the striatum and hippocampal neuron culture 28 29 30 . In addition, amisulpride, clozapine and olanzapine were also able to induce CREB1 phosphorylation in in vitro studies 31 32 33 . A 1-week in vivo study has shown that a 1-week administration of aripiprazole increased the expression of CREB1 in the NAc 17 .…”

Section: Discussionmentioning

confidence: 91%

“…Previous in vivo and in vitro studies have shown that haloperidol increased phosphorylation levels of CREB1 28 29 30 . Additionally, amisulpride, clozapine and olanzapine also elevated phosphorylation levels of CREB1 in vitro 31 32 33 . Furthermore, a 3-week injection of aripiprazole changed the phosphorylation levels of CREB1 in the PFC and striatum of rats, probably through NMDA receptors 34 .…”

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confidence: 93%

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Chronic administration of aripiprazole activates GSK3β-dependent signalling pathways and up-regulates GABAA receptor expression and CREB1 activity in rats

Pan

Huang

Deng

2016

Sci Rep

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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.

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Section: Discussionmentioning

confidence: 91%

mentioning

confidence: 93%

Chronic administration of aripiprazole activates GSK3β-dependent signalling pathways and up-regulates GABAA receptor expression and CREB1 activity in rats

Pan

Huang

Deng

2016

Sci Rep

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“…Previous studies revealed that haloperidol increased phosphorylation levels of CREB in both in vivo and in vitro studies (Konradi and Heckers, 1995, Pozzi et al, 2003, Yang et al, 2004. Both amisulpride and clozapine can also induce the phosphorylation of CREB in vitro (Jeon et al, 2015, Park et al, 2011. Therefore, we proposed that antipsychotic drugs may modulate GABA A receptors and CREB1 activity through the PKA signalling pathway.…”

Section: Introductionmentioning

confidence: 84%

Aripiprazole Increases the PKA Signalling and Expression of the GABAA Receptor and CREB1 in the Nucleus Accumbens of Rats

et al. 2016

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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.

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“…Although these concentrations may seem high compared to the therapeutic plasma levels, they are similar to the concentrations of antipsychotic drugs (1–25 µM) that cause GDNF release from C6 cells [25] and to the concentrations of antidepressants (1–10 µM) that alter PACAP mRNA receptors in rat primary cortical neurons [30]. Human glioblastoma cells are used as an example of glial cells in in vitro studies because of their functional similarity to normal astrocytes [7, 33, 34]. Our findings indicate that PACAP38 dose-dependently increased AC activity in both T98G cell membranes and astrocytes (Fig.…”

Section: Discussionmentioning

confidence: 99%

Neuroleptic Drugs and PACAP Differentially Affect the mRNA Expression of Genes Encoding PAC1/VPAC Type Receptors

Jóźwiak-Bębenista

Kowalczyk

2016

Neurochem Res

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Several lines of evidence suggest that pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide playing an important role as a neuromodulator. It has been indicated that PACAP is associated with mental diseases, and that regulation of the PACAPergic signals could be a potential target for the treatment of such psychiatric states as schizophrenia. Recent studies have suggested that action of neuroleptic drugs is mediated not only by dopaminergic and serotonergic neurotransmission, but also via neuropeptides which may act both as neurotransmitters and as neuromodulators. The present study examines whether currently-used neuroleptics influence the action of PACAP receptors, whose expression is altered in a schizophrenic patient. Real-time polymerase chain reaction (PCR) was used to examine the effects of haloperidol, olanzapine and amisulpride on the expression of genes coding PAC1/VPAC type receptors in the T98G glioblastoma cell line, as an example of an in vitro model of glial cells. PAC1 mRNA expression fell after 24-h incubation with haloperidol or olanzapine; however the effect was not maintained after 72 h, and haloperidol even up-regulated PAC1 mRNA expression in a dose-dependent manner. All the examined drugs decreased VPAC2 mRNA expression, especially after 72-h incubation. Haloperidol (typical neuroleptic) was distinctly more potent than atypical neuroleptic drugs (olanzapine and amisulpride). In addition, PACAP increased PAC1 and VPAC2 mRNA expression. In conclusion, our findings suggest PACAP receptors may be involved in the mechanism of typical and atypical neuroleptic drugs.

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Clozapine induces chloride channel-4 expression through PKA activation and modulates CDK5 expression in SH-SY5Y and U87 cells

Cited by 15 publications

References 36 publications

Chronic administration of aripiprazole activates GSK3β-dependent signalling pathways and up-regulates GABAA receptor expression and CREB1 activity in rats

Chronic administration of aripiprazole activates GSK3β-dependent signalling pathways and up-regulates GABAA receptor expression and CREB1 activity in rats

Aripiprazole Increases the PKA Signalling and Expression of the GABAA Receptor and CREB1 in the Nucleus Accumbens of Rats

Neuroleptic Drugs and PACAP Differentially Affect the mRNA Expression of Genes Encoding PAC1/VPAC Type Receptors

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