Targeting mGlu Receptors for Optimization of Antipsychotic Activity and Disease-Modifying Effect in Schizophrenia

Abstract

Metabotropic glutamate (mGlu) receptors are considered as candidate drug targets for the treatment of schizophrenia. These receptors form a family of eight subtypes (mGlu1 to −8), of which mGlu1 and −5 are coupled to Gq/11, and all other subtypes are coupled to Gi/o. Here, we discuss the possibility that selective ligands of individual mGlu receptor subtypes may be effective in controlling the core symptoms of schizophrenia, and, in some cases, may impact mechanisms underlying the progression of the disorder. Recent evidence indicates that activation of mGlu1 receptors inhibits dopamine release in the meso-striatal system. Hence, selective positive allosteric modulators (PAMs) of mGlu1 receptors hold promise for the treatment of positive symptoms of schizophrenia. mGlu5 receptors are widely expressed in the CNS and regulate the activity of cells that are involved in the pathophysiology of schizophrenia, such as cortical GABAergic interneurons and microglial cells. mGlu5 receptor PAMs are under development for the treatment of schizophrenia and cater the potential to act as disease modifiers by restraining neuroinflammation. mGlu2 receptors have attracted considerable interest because they negatively modulate 5-HT2A serotonin receptor signaling in the cerebral cortex. Both mGlu2 receptor PAMs and orthosteric mGlu2/3 receptor agonists display antipsychotic-like activity in animal models, and the latter drugs are inactive in mice lacking mGlu2 receptors. So far, mGlu3 receptors have been left apart as drug targets for schizophrenia. However, activation of mGlu3 receptors boosts mGlu5 receptor signaling, supports neuronal survival, and drives microglial cells toward an antiinflammatory phenotype. This strongly encourages research of mGlu3 receptors in schizophrenia. Finally, preclical studies suggest that mGlu4 receptors might be targeted by novel antipsychotic drugs, whereas studies of mGlu7 and mGlu8 receptors in animal models of psychosis are still at their infancy.

Cognitive control network connectivity differentially disrupted in treatment resistant schizophrenia

“…1H-MRS does not measure NMDARs specifically but total glutamate within a voxel. This includes mGluRs, which are also implicated in the psychopathology of schizophrenia ( Nicoletti et al, 2019 ). Given the heterogeneity in clinical profiles, even within treatment-resistant and treatment-responsive subtypes, the specific nature of glutamatergic dysfunction that might underlie treatment-resistance is yet to be established.…”

Proof of mechanism and target engagement of glutamatergic drugs for the treatment of schizophrenia: RCTs of pomaglumetad and TS-134 on ketamine-induced psychotic symptoms and pharmacoBOLD in healthy volunteers

“…While further clinical and preclinical work is required to confirm a curvilinear dose-response curve for mGluR2/3 agonists, support comes from both the literature and consulting with Dr. Darryl Schoepp (who developed a series of mGluR compounds, including POMA, as VP for Neuroscience Research at Lilly 1987–2007). As previously reviewed [ 38 ], mGluR3 activation may be neuroprotective via astrocyte induced neurotrophic factors, including transforming-growth factor- β1 or glial cell-derived neurotrophic factor [ 39 – 41 ]. Receptor desensitization, particularly for mGluR3s, could occur at higher occupancy levels [ 42 ].…”

Dopamine Receptor Subtypes, Physiology and Pharmacology: New Ligands and Concepts in Schizophrenia

“…D1 receptors strongly enhance action potential firing in this subset of cortico-cortical neurons and VIP+ interneurons and the modulation via D1 receptors can influence both excitatory and disinhibitory microcircuits in the PFCx ( Anastasiades et al., 2019 ). This PV+ interneuron circuits are a the main point of interaction between mGlu5/NMDA and D1 (D2-like) receptors, both involved in the control of the glutamatergic input from pyramidal cells ( Nicoletti et al., 2019 ). D1 is important for the correct migration of the dopaminergic terminals which increase throughout adolescence across species.…”