RT Journal Article
SR Electronic
T1 Metabotropic Glutamate Receptors As Emerging Targets for the Treatment of Schizophrenia
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 275
OP 285
DO 10.1124/molpharm.121.000460
VO 101
IS 5
A1 Dogra, Shalini
A1 Conn, P. Jeffrey
YR 2022
UL http://molpharm.aspetjournals.org/content/101/5/275.abstract
AB 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.