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Review ArticleMinireview

Metabotropic Glutamate Receptors As Emerging Targets for the Treatment of Schizophrenia

Shalini Dogra and P. Jeffrey Conn
Molecular Pharmacology May 2022, 101 (5) 275-285; DOI: https://doi.org/10.1124/molpharm.121.000460
Shalini Dogra
Department of Pharmacology and Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee
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P. Jeffrey Conn
Department of Pharmacology and Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee
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Abstract

Accumulating evidence of glutamatergic abnormalities in the brains of schizophrenia patients has led to efforts to target various components of glutamatergic signaling as potential new approaches for schizophrenia. Exciting research suggests that metabotropic glutamate (mGlu) receptors could provide a fundamentally new approach for better symptomatic relief in patients with schizophrenia. In preclinical studies, the mGlu5 receptor positive allosteric modulators (PAMs) show efficacy in animal models relevant for all symptom domains in schizophrenia. Interestingly, biased pure mGlu5 receptor PAMs that do not potentiate coupling of mGlu5 receptors to N-methyl-D-aspartate (NMDA) receptors lack neurotoxic effects associated with mGlu5 PAMs that enhance coupling to NMDA receptors or have allosteric agonist activity. This provides a better therapeutic profile for treating schizophrenia-like symptoms. Additionally, the mGlu1 receptor PAMs modulate dopamine release in the striatum, which may contribute to their antipsychotic-like effects. Besides group I mGlu (mGlu1 and mGlu5) receptors, agonists of mGlu2/3 receptors also induce robust antipsychotic-like and procognitive effects in rodents and may be effective in treating symptoms of schizophrenia in a selective group of patients. Additionally, mGlu2/4 receptor heterodimers modulate glutamatergic neurotransmission in the prefrontal cortex at selective synapses activated in schizophrenia and therefore hold potential as novel antipsychotics. Excitingly, the mGlu3 receptor activation can enhance cognition in rodents, suggesting that mGlu3 receptor agonist/PAM could provide a novel approach for the treatment of cognitive deficits in schizophrenia. Collectively, the development of mGlu receptor-specific ligands may provide an alternative approach to meet the clinical need for safer and more efficacious therapeutics for schizophrenia.

SIGNIFICANCE STATEMENT The currently available antipsychotic medications do not show significant efficacy for treating negative symptoms and cognitive deficits in schizophrenia. Emerging preclinical and clinical literature suggests that pharmacological targeting of metabotropic glutamate receptors could potentially provide an alternative approach for designing safer and more efficacious therapeutics for treating schizophrenia.

Footnotes

    • Received November 16, 2021.
    • Accepted February 22, 2022.
  • This work was supported by National Institutes of Health National Institute of Mental Health [Grant R01-MH062646] (to P.J.C.) and National Institute of Neurological Disorders and Stroke [Grant R37-NS031373] (to P.J.C.).

  • P.J.C. receives research support from Acadia Pharmaceuticals and Boehringer Ingelheim. P.J.C. is an inventor on multiple patents for allosteric modulators of metabotropic glutamate receptors. S.D. has no competing interests to declare.

  • https://doi.org/10.1124/molpharm.121.000460.

  • Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 101 (5)
Molecular Pharmacology
Vol. 101, Issue 5
1 May 2022
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Review ArticleMinireview

mGlu Receptors: Novel Therapeutic Targets for Schizophrenia

Shalini Dogra and P. Jeffrey Conn
Molecular Pharmacology May 1, 2022, 101 (5) 275-285; DOI: https://doi.org/10.1124/molpharm.121.000460

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Review ArticleMinireview

mGlu Receptors: Novel Therapeutic Targets for Schizophrenia

Shalini Dogra and P. Jeffrey Conn
Molecular Pharmacology May 1, 2022, 101 (5) 275-285; DOI: https://doi.org/10.1124/molpharm.121.000460
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  • Article
    • Abstract
    • Introduction
    • Genomic Variants in GRM5 and mGlu5 Receptor Hypofunction Are Associated with Schizophrenia
    • mGlu5 Potentiators Reduce Behavioral Disruptions That Are Relevant for Schizophrenia in Rodent Models
    • Biased mGlu5 Receptor PAMs That Do Not Potentiate Coupling of mGlu5 Receptors to NMDA Receptors or Exert Allosteric Agonist Activity Do Not Induce Observable Adverse Effects
    • mGlu1 Receptor PAMs May Have Potential Antipsychotic Effects
    • The mGlu1 Receptor Ligands Display Antipsychotic-Like Effects in Rodents
    • Group II (mGlu2/3) Receptor Agonists Show Efficacy for Treating Behavioral Correlates of Schizophrenia
    • Clinical Trials Using mGlu2/3 Receptor Agonists Yielded Inconclusive Results
    • mGlu2 Receptor PAMs May Have Potential Antipsychotic Activity
    • Genetic Variants in GRM3 Are Associated with Schizophrenia
    • mGlu3 Receptor Is a Promising Target for Enhancing Cognition in Schizophrenia
    • mGlu4 Receptor Ligands Have the Potential To Treat Positive Symptoms of Schizophrenia
    • Potential Utility of mGlu2-mGlu4 Receptor Heterodimers As Novel Antipsychotics
    • Deletion or Blockade of mGlu7 Receptor Impairs Cognition
    • mGlu7 Receptor NAMs Can Rescue Schizophrenia-Like Symptoms in Rodents
    • Deletion of GRM8 Does Not Induce Consistent Endophenotypes of Schizophrenia
    • Concluding Remarks
    • Authorship Contributions
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    • Abbreviations
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