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 mGlu_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, mGlu_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 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.