Effects of the antipsychotics haloperidol, clozapine, and aripiprazole on the dendritic spine

Takaki, Manabu; Kodama, Masafumi; Mizuki, Yutaka; Kawai, Hiroki; Yoshimura, Bunta; Kishimoto, Makiko; Okahisa, Yuko; Yamada, Norihito

doi:10.1016/j.euroneuro.2018.03.004

Cited by 20 publications

(23 citation statements)

References 66 publications

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“…In this study, chronic haloperidol was the only one exerting an effect over GSK3b, triggering a significant increase in total GSK3b expression in rat cortex. Although the literature is scarce, both acute haloperidol and clozapine seem to decrease the phosphorylation of GSK3b at Ser9 in vitro (Takaki et al, 2018). On the contrary, a study carried out in mice reported an increased in the phosphorylation status after acute clozapine and risperidone, with no changes with haloperidol (Li et al, 2007).…”

Section: Discussionmentioning

confidence: 96%

Ribosomal Protein S6 Hypofunction in Postmortem Human Brain Links mTORC1-Dependent Signaling and Schizophrenia

et al. 2020

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The mechanistic target of rapamycin (also known as mammalian target of rapamycin) (mTOR)-dependent signaling pathway plays an important role in protein synthesis, cell growth, and proliferation, and has been linked to the development of the central nervous system. Recent studies suggest that mTOR signaling pathway dysfunction could be involved in the etiopathogenesis of schizophrenia. The main goal of this study was to evaluate the status of mTOR signaling pathway in postmortem prefrontal cortex (PFC) samples of subjects with schizophrenia. For this purpose, we quantified the protein expression and phosphorylation status of the mTOR downstream effector ribosomal protein S6 as well as other pathway interactors such as Akt and GSK3b. Furthermore, we quantified the status of these proteins in the brain cortex of rats chronically treated with the antipsychotics haloperidol, clozapine, or risperidone. We found a striking decrease in the expression of total S6 and in its active phosphorylated form phospho-S6 (Ser235/236) in the brain of subjects with schizophrenia compared to matched controls. The chronic treatment with the antipsychotics haloperidol and clozapine affected both the expression of GSK3b and the activation of Akt [phospho-Akt (Ser473)] in rat brain cortex, while no changes were observed in S6 and phospho-S6 (Ser235/236) protein expression with any antipsychotic treatment. These findings provide further evidence for the involvement of the mTOR-dependent signaling pathway in schizophrenia and suggest that a hypofunctional S6 may have a role in the etiopathogenesis of this disorder.

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Section: Discussionmentioning

confidence: 96%

Ribosomal Protein S6 Hypofunction in Postmortem Human Brain Links mTORC1-Dependent Signaling and Schizophrenia

et al. 2020

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“…Thus, treatment with this drug could be considered in cases of schizophrenia patients who have specific MMP-9 gene variations. The exact mechanism of action of clozapine remains to be elucidated- whether by targeting different pathways that are influenced by low MMP-9 levels, such as brain-derived neurotrophic factor (Huang, 2013) and glycogen synthase kinase 3β (Kang et al, 2004), or by directly affecting dendritic spine formation (Critchlow et al, 2006; Takaki et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Psychosocial Stress Induces Schizophrenia-Like Behavior in Mice With Reduced MMP-9 Activity

Vafadari

Mitra²,

Stefaniuk³

et al. 2019

Front. Behav. Neurosci.

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Understanding gene-environment interactions in the pathogenesis of schizophrenia remains a major research challenge. Matrix metalloproteinase-9 (MMP-9) has been previously implicated in the pathophysiology of schizophrenia. In the present study, adolescent Mmp-9 heterozygous mice, with a genetically lower level of MMP-9, were subjected to resident-intruder psychosocial stress for 3 weeks and then examined in behavioral tests that evaluated cognitive deficits and positive- and negative-like symptoms of schizophrenia. Cognitive and positive symptoms in unstressed Mmp-9 heterozygous mice were unaffected by stress exposure, whereas negative symptoms were manifested only after stress exposure. Interestingly, negative symptoms were ameliorated by treatment with the antipsychotic drug clozapine. We describe a novel gene × environment interaction mouse model of schizophrenia. Lower MMP-9 levels in the brain might be a risk factor for schizophrenia that, in combination with environmental factors (e.g., psychosocial stress), may evoke schizophrenia-like symptoms that are sensitive to antipsychotic treatment.

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“…We also attempted to illustrate the paradoxical positive and negative actions of clozapine on ErbB phosphorylation and signaling 18,22,27 . When ErbB1 was stimulated by its full ligand EGF, clozapine works as an inhibitor for the kinase in the present study, while clozapine itself is reported to stimulate ErbB1 kinase or Erk/Akt signaling in vivo 26,28,49 . Smith et al 27 proposed that the clozapine-triggered activation of Akt signaling involves insulin secretion in vivo while Pereira et al 22 suggest that the clozapine-triggered activation of Erk signaling in vivo is mediated by ErbB1 (EGFR) transactivation.…”

Section: Discussionmentioning

confidence: 47%

“…Haloperidol and clozapine act on neurons to induce neurite extension, stimulating Ras-MAP kinase signaling 22–24 . Treatment with several antipsychotics results in the increases in Akt signaling in the brain 25–28 . These reports propose the possibility that several antipsychotic compounds such as clozapine carry unrevealed biological activities on various protein kinases.…”

Section: Introductionmentioning

confidence: 99%

Clozapine-dependent inhibition of EGF/neuregulin receptor (ErbB) kinases

et al. 2019

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Clozapine is an antipsychotic agent prescribed to psychotic patients exhibiting tolerance and/or resistance to the conventional antipsychotic medications that mainly drive monoamine antagonism. As the pharmacological fundamentals of its unique antipsychotic profile have been unrevealed, here, we attempted to obtain hints at this question. Here, we found that clozapine directly acts on ErbB kinases to downregulate epidermal growth factor (EGF)/neuregulin signaling. In cultured cell lines and cortical neurons, EGF-triggered ErbB1 phosphorylation was diminished by 30 μM clozapine, but not haloperidol, risperidone, or olanzapine. The neuregulin-1-triggered ErbB4 phosphorylation was attenuated by 10 μM clozapine and 30 μM haloperidol. We assumed that clozapine may directly interact with the ErbB tyrosine kinases and affect their enzyme activity. To test this assumption, we performed in vitro kinase assays using recombinant truncated ErbB kinases. Clozapine (3–30 μM) significantly decreased the enzyme activity of the truncated ErbB1, B2, and B4 kinases. Acute in vivo administration of clozapine (20 mg/kg) to adult rats significantly suppressed the basal phosphorylation levels of ErbB4 in the brain, although we failed to detect effects on basal ErbB1 phosphorylation. Altogether with the previous findings that quinazoline inhibitors for ErbB kinases harbor antipsychotic potential in animal models for schizophrenia, our present observations suggest the possibility that the micromolar concentrations of clozapine can attenuate the activity of ErbB receptor kinases, which might illustrate a part of its unique antipsychotic psychopharmacology.

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Effects of the antipsychotics haloperidol, clozapine, and aripiprazole on the dendritic spine

Cited by 20 publications

References 66 publications

Ribosomal Protein S6 Hypofunction in Postmortem Human Brain Links mTORC1-Dependent Signaling and Schizophrenia

Ribosomal Protein S6 Hypofunction in Postmortem Human Brain Links mTORC1-Dependent Signaling and Schizophrenia

Psychosocial Stress Induces Schizophrenia-Like Behavior in Mice With Reduced MMP-9 Activity

Clozapine-dependent inhibition of EGF/neuregulin receptor (ErbB) kinases

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