Metabotropic glutamate receptor 5 in depression: Mechanisms and therapeutic potential

Glutamate serves as the primary excitatory neurotransmitter within the central nervous system (CNS), and disturbances in the glutamatergic system have been linked to a variety of CNS disorders, especially depression. In recent years, metabotropic glutamate receptor 5 (mGluR5) has attracted considerable attention for its crucial role in regulating glutamatergic transmission. In this review, we conducted a search of PubMed, Web of Science and Science Direct databases to explore the relationship between mGluR5 and depression, and summarized the antidepressant effects and mechanisms of action of various mGluR5 negative allosteric modulators (NAMs) based on the literatures in the past five years. A total of 112 articles meeting the screening criteria were included this review. We found that the pathological process of depression was accompanied by abnormally elevated levels of mGluR5 expression, and its hyperactivation might be involved in disease progression by impairing neuroplasticity. In addition, mGluR5 had the potential to interact with classical depressive targets. Accordingly, mGluR5 NAMs exerted antidepressant effects by directly or indirectly modulating synaptic plasticity, suppressing inflammatory responses, and regulating molecular pathways. Based on literature reports of mGluR5 NAMs, we conducted selective molecular docking simulations to validate their strong binding. Finally, we summarized the efficacy and safety data of mGluR5 modulators that had entered clinical trials. In conclusion, targeting the mGluR5 is a promising strategy to address the clinical need for more effective treatments for patients with depression, but the safety still needs attention.