ArticleNeuropsychopharmacology : official publication of the American College of Neuropsychopharmacology2014
Clozapine acts as an agonist at serotonin 2A receptors to counter MK-801-induced behaviors through a βarrestin2-independent activation of Akt.
Article in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 65 citations in OpenAlex.
- Randomised controlled trial of clozapine in resistant schizophrenia and schizoaffective disorder.Journal of psychopharmacology (Oxford, England) · 2025Trial
- Differential Neuronal Development in iPSC-Derived Neural Stem Cells From Monozygotic Twin Cases With Treatment-Resistant Schizophrenia and Discordant Responses to Clozapine.Neuropsychopharmacology reports · 2026Article
- A structural overview of G-protein-coupled receptors in neurological disorders.Acta pharmacologica Sinica · 2026Review
- Assessment of clozapine taste in healthy volunteers: evidence for non-aversive sensory profile.Therapeutic advances in psychopharmacology · 2026Article
- 5-HTPharmacological reviews · 2025Review
- Discovery of a Novel, Potent, and Selective 5‑Hydroxytryptamine 2B Receptor Antagonist that Induces Mitochondrial Biogenesis in the Kidney.ACS pharmacology & translational science · 2025Article
- AiGPro: a multi-tasks model for profiling of GPCRs for agonist and antagonist.Journal of cheminformatics · 2025Article
- Predictors of clozapine concentration and psychiatric symptoms in patients with schizophrenia.PloS one · 2025Article
- Psychotomimetic compensation versus sensitization.Pharmacology research & perspectives · 2024Review
- Impact of Pharmacogenetic Testing on Clozapine Treatment Efficacy in Patients with Treatment-Resistant Schizophrenia.Biomedicines · 2024Article
- Profiling of ERBB receptors and downstream pathways reveals selectivity and hidden properties of ERBB4 antagonists.iScience · 2024Article
- Mechanisms and molecular targets surrounding the potential therapeutic effects of psychedelics.Molecular psychiatry · 2023Review
- Antipsychotic drugs may contribute to venous thromboembolism - a case report and review literature.JRSM open · 2023Article
- The role of serotonin neurotransmission in rapid antidepressant actions.Psychopharmacology · 2022Review
- Pharmacological effects and therapeutic potential of natural compounds in neuropsychiatric disorders: An update.Frontiers in pharmacology · 2022Review
- Repurposing Antipsychotics for Cancer Treatment.Biomedicines · 2021Review
- Chemogenetics drives paradigm change in the investigation of behavioral circuits and neural mechanisms underlying drug action.Behavioural brain research · 2021Review
- Pivotal mental states.Journal of psychopharmacology (Oxford, England) · 2021Review
- Atypical Antipsychotics and Metabolic Syndrome: From Molecular Mechanisms to Clinical Differences.Pharmaceuticals (Basel, Switzerland) · 2021Review
- Is Adult Hippocampal Neurogenesis Really Relevant for the Treatment of Psychiatric Disorders?Current neuropharmacology · 2021Review
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
The G protein-coupled serotonin 2A receptor (5-HT2AR) is a prominent target for atypical antipsychotic drugs, such as clozapine. Although clozapine is known to inhibit 5-HT2AR signaling through G protein-dependent mechanisms, it differs from classic GPCR antagonists, in that it also induces 5-HT2AR internalization and activates Akt signaling via a 5-HT2AR-mediated event. In this regard, clozapine may also be considered a functionally selective agonist. The cognate neurotransmitter at the 5-HT2AR, serotonin, also induces 5-HT2AR internalization and Akt phosphorylation. Serotonin promotes interactions with the scaffolding and regulatory protein, βarrestin2, which results in the recruitment and activation of Akt. These interactions prove to be critical for serotonin-induced, 5-HT2AR-mediated behavioral responses in mice. Herein, we sought to determine whether clozapine also utilizes βarrestin2-mediated mechanisms to induce 5-HT2AR signaling, and whether this interaction contributes to its behavioral effects in mice. We demonstrate that unlike serotonin, clozapine-mediated 5-HT2AR internalization and Akt phosphorylation is independent of receptor interactions with βarrestin2. Moreover, clozapine-mediated suppression of MK-801 and phencyclidine (PCP)-induced hyperlocomotion is βarrestin2 independent, although it is dependent upon Akt. These results demonstrate that pharmacologically oppositional ligands, serotonin and clozapine, utilize differential mechanisms to achieve the same 5-HT2AR-meadiated downstream events: Akt phosphorylation and receptor internalization. Although βarrestin2 has no effect on clozapine's actions in vivo, Akt phosphorylation is required for clozapine's efficacy in blocking MK-801- and PCP-induced models of schizophrenic behaviors in mice.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.