ArticleNeuropsychopharmacology : official publication of the American College of Neuropsychopharmacology2009
Clozapine interaction with phosphatidyl inositol 3-kinase (PI3K)/insulin-signaling pathway in Caenorhabditis elegans.
Article in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 37 citations in OpenAlex.
- No effect of adjunctive, repeated-dose intranasal insulin treatment on psychopathology and cognition in patients with schizophrenia.Journal of clinical psychopharmacology · 2013Trial
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- Converging evidence for functional connections between the lithium response and PI3K-Akt signaling.Translational psychiatry · 2024Article
- Evolutionary conservation of putative suicidality-related risk genes that produce diminished motivation corrected by clozapine, lithium and antidepressants.Frontiers in psychiatry · 2024Article
- Morphological and transcriptomic analyses of stem cell-derived cortical neurons reveal mechanisms underlying synaptic dysfunction in schizophrenia.Genome medicine · 2023Article
- Review
- Metabolic and behavioral effects of olanzapine and fluoxetine on the model organismSaudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society · 2021Article
- Acyl-CoA-binding protein (ACBP): a phylogenetically conserved appetite stimulator.Cell death & disease · 2020Article
- Review
- Overexpression of BmFoxO inhibited larval growth and promoted glucose synthesis and lipolysis in silkworm.Molecular genetics and genomics : MGG · 2019Article
- HDAC6 Modulates Signaling Pathways Relevant to Synaptic Biology and Neuronal Differentiation in Human Stem-Cell-Derived Neurons.International journal of molecular sciences · 2019Review
- Pharming for Genes in Neurotransmission: Combining Chemical and Genetic Approaches in Caenorhabditis elegans.ACS chemical neuroscience · 2018Review
- Crossing the Worm-Brain Barrier by UsingMolecular neuropsychiatry · 2018Review
- Lysine Deacetylation by HDAC6 Regulates the Kinase Activity of AKT in Human Neural Progenitor Cells.ACS chemical biology · 2017Article
- The Atypical Antipsychotic Agent, Clozapine, Protects Against Corticosterone-Induced Death of PC12 Cells by Regulating the Akt/FoxO3a Signaling Pathway.Molecular neurobiology · 2017Article
- Clozapine Modulates Glucosylceramide, Clears Aggregated Proteins, and Enhances ATG8/LC3 in Caenorhabditis elegans.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2017Article
- Forward Genetic Screen inFrontiers in molecular neuroscience · 2016Article
- Methods for studying the mechanisms of action of antipsychotic drugs in Caenorhabditis elegans.Journal of visualized experiments : JoVE · 2014Article
- Drug elucidation: invertebrate genetics sheds new light on the molecular targets of CNS drugs.Frontiers in pharmacology · 2014Review
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Authors and funding
6 authors at 3 institutions in 1 country.
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Abstract
Clozapine has superior and unique effects as an antipsychotic agent, but the mediators of these effects are not known. We studied behavioral and developmental effects of clozapine in Caenorhabditis elegans, as a model system to identify previously undiscovered mechanisms of drug action. Clozapine induced early larval arrest, a phenotype that was also seen with the clozapine metabolite N-desmethyl clozapine but not with any other typical or atypical antipsychotic drug tested. Mutations in the insulin receptor/daf-2 and phosphatidyl inositol 3-kinase (PI3K)/age-1 suppressed clozapine-induced larval arrest, suggesting that clozapine may activate the insulin-signaling pathway. Consistent with this notion, clozapine also increased the expression of an age-1::GFP reporter. Activation of the insulin-signaling pathway leads to cytoplasmic localization of the fork head transcription factor FOXO/daf-16. Clozapine produced cytoplasmic localization of DAF-16::GFP in arrested L1 larvae, in contrast to stressors such as starvation or high temperature, which produce nuclear localization of DAF-16::GFP in arrested L1 larvae. Clozapine also inhibited pharyngeal pumping in C. elegans, an effect that may contribute to, but did not explain, clozapine-induced larval arrest. Our findings demonstrate a drug-specific interaction between clozapine and the PI3K/insulin-signaling pathway in C. elegans. As this pathway is conserved across species, the results may have implications for understanding the unique effects of clozapine in humans.
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