Metabotropic glutamate receptor 3 as a potential therapeutic target for psychiatric and neurological disorders

Abstract

Glutamate is a major excitatory neurotransmitter in the central nervous system (CNS) and abnormalities in the glutamatergic system underlie various CNS disorders. As metabotropic glutamate receptor 3 (mGlu₃ receptor) regulates glutamatergic transmission in various brain areas, emerging literature suggests that targeting mGlu₃ receptors can be a novel approach to the treatment of psychiatric and neurological disorders. For example, mGlu₃ receptor negative allosteric modulators (NAMs) induce rapid antidepressant-like effects in both acute and chronic stress models. Activation of mGlu₃ receptors can enhance cognition in the rodents modeling schizophrenia-like pathophysiology. The mGlu₃ receptors expressed in the astrocytes induce neuroprotective effects. Although polymorphisms in GRM3 have been shown to be associated with addiction, there is not significant evidence about the efficacy of mGlu₃ receptor ligands in rodent models of addiction. Collectively, drugs targeting mGlu₃ receptors may provide an alternative approach to fill the unmet clinical need for safer and more efficacious therapeutics for CNS disorders.

Keywords: Antidepressants; Cognition; Depression; Glutamate; Neurodevelopmental disorders; Schizophrenia; Substance use disorders; mGlu3; mGlu5.