Metabotropic Glutamate Receptors As Emerging Targets for the Treatment of Schizophrenia

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 mGlu(5) receptor positive allosteric modulators (PAMs) show efficacy in animal models relevant for all symptom domains in schizophrenia. Interestingly, biased pure mGlu(5) receptor PAMs that do not potentiate coupling of mGlu(5) receptors to N-methyl-D-aspartate (NMDA) receptors lack neurotoxic effects associated with mGlu(5) 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 mGlu(1) receptor PAMs modulate dopamine release in the striatum, which may contribute to their antipsychotic-like effects. Besides group I mGlu (mGlu(1) and mGlu(5)) receptors, agonists of nnGlu(2/3) 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, nnGlu(2/4) receptor heterodimers modulate glutamatergic neurotransmission in the prefrontal cortex at selective synapses activated in schizophrenia and therefore hold potential as novel antipsychotics. Excitingly, the mGlu(3) receptor activation can enhance cognition in rodents, suggesting that mGlu(3) 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.

Automated summary

Research suggests that targeting metabotropic glutamate receptors could provide a new approach for treating schizophrenia, with mGlu receptor PAMs showing efficacy in animal models and development of ligands for specific mGlu receptors aiming to meet the need for safer and more effective treatments.