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.
- Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics
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