ArticleBiomolecules2019
Clozapine Normalizes a Glutamatergic Transmission Abnormality Induced by an Impaired NMDA Receptor in the Thalamocortical Pathway via the Activation of a Group III Metabotropic Glutamate Receptor.
Article in Biomolecules, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers, 2 of them syntheses that pooled it.
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Who cites it
43 citing papers in PubMed, 2 syntheses or guidelines pooled it, 78 citations in OpenAlex.
- Glutamatergic neurotransmission in schizophrenia: A systematic review and quantitative synthesis of proton magnetic resonance spectroscopy studies across schizophrenia spectrum disorders.The Australian and New Zealand journal of psychiatry · 2024Pooled it
- Rational and Translational Implications of D-Amino Acids for Treatment-Resistant Schizophrenia: From Neurobiology to the Clinics.Biomolecules · 2022Pooled it
- Longitudinal brain structural changes during clozapine treatment: associations with neuroreceptor architecture and clinical response.medRxiv : the preprint server for health sciences · 2026Article
- Why Is Clozapine Uniquely Effective in Treatment-Resistant Schizophrenia? A Review and Proposal.Biological psychiatry · 2026Review
- Associations between glutamate and cerebral blood flow in treatment-resistant schizophrenia during clozapine treatment.Journal of psychopharmacology (Oxford, England) · 2026Article
- Magnetic resonance texture alterations in the caudate nucleus following 18 weeks of clozapine treatment in patients with treatment-resistant schizophrenia.Translational psychiatry · 2026Article
- Glutamate Metabotropic Receptors-Linked Postsynaptic Density Proteins: An Emergent Hub for Antipsychotics' Regulation of Synaptic Plasticity and Metaplasticity.Biomolecules · 2026Review
- The influence of social capital and evidence-based orientation on psychiatrists' attitudes toward antipsychotic polypharmacy in schizophrenia.Scientific reports · 2025Article
- The nitric oxide synthase inhibitor 7-nitroindazole attenuates social withdrawal and memory impairments induced by Blockade of the NMDA receptor in the rat.Psychopharmacology · 2025Article
- Association of astrocyte-specific gene expression in the dorsolateral prefrontal cortex with clozapine treatment in schizophrenia.Translational psychiatry · 2025Article
- Dysfunction of the NMDA Receptor in the Pathophysiology of Schizophrenia and/or the Pathomechanisms of Treatment-Resistant Schizophrenia.Biomolecules · 2024Review
- A Novel Gliotransmitter, L-β-Aminoisobutyric Acid, Contributes to Pathophysiology of Clinical Efficacies and Adverse Reactions of Clozapine.Biomolecules · 2023Review
- Enhanced L-β-Aminoisobutyric Acid Is Involved in the Pathophysiology of Effectiveness for Treatment-Resistant Schizophrenia and Adverse Reactions of Clozapine.Biomolecules · 2023Article
- Therapeutic Potential and Limitation of Serotonin Type 7 Receptor Modulation.International journal of molecular sciences · 2023Review
- Second to none: rationale, timing, and clinical management of clozapine use in schizophrenia.Therapeutic advances in psychopharmacology · 2023Review
- Emerging Materials, Wearables, and Diagnostic Advancements in Therapeutic Treatment of Brain Diseases.Biosensors · 2022Review
- New 1,2,4-oxadiazole derivatives with positive mGluJournal of enzyme inhibition and medicinal chemistry · 2022Article
- Brexpiprazole Reduces 5-HT7 Receptor Function on Astroglial Transmission Systems.International journal of molecular sciences · 2022Article
- Can rodent models elucidate the pathomechanisms of genetic epilepsy?British journal of pharmacology · 2022Review
- Determining What Changed Japanese Suicide Mortality in 2020 Using Governmental Database.Journal of clinical medicine · 2021Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Pharmacological mechanisms of gold-standard antipsychotics against treatment-refractory schizophrenia, such as clozapine (CLZ), remain unclear. We aimed to explore the mechanisms of CLZ by investigating the effects of MK801 and CLZ on tripartite synaptic transmission in the thalamocortical glutamatergic pathway using multi-probe microdialysis and primary cultured astrocytes. l-glutamate release in the medial prefrontal cortex (mPFC) was unaffected by local MK801 administration into mPFC but was enhanced in the mediodorsal thalamic nucleus (MDTN) and reticular thalamic nucleus (RTN) via GABAergic disinhibition in the RTN-MDTN pathway. The local administration of therapeutically relevant concentrations of CLZ into mPFC and MDTN increased and did not affect mPFC l-glutamate release. The local administration of the therapeutically relevant concentration of CLZ into mPFC reduced MK801-induced mPFC l-glutamate release via presynaptic group III metabotropic glutamate receptor (III-mGluR) activation. However, toxic concentrations of CLZ activated l-glutamate release associated with hemichannels. This study demonstrated that RTN is a candidate generator region in which impaired N-methyl-d-aspartate (NMDA)/glutamate receptors likely produce thalamocortical hyperglutamatergic transmission. Additionally, we identified several mechanisms of CLZ relating to its superiority in treatment-resistant schizophrenia and its severe adverse effects: (1) the prevention of thalamocortical hyperglutamatergic transmission via activation of mPFC presynaptic III-mGluR and (2) activation of astroglial l-glutamate release associated with hemichannels. These actions may contribute to the unique clinical profile of CLZ.
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Registered trials
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.