Targeting mGlu receptors for optimization of antipsychotic activity and disease-modifying effect in schizophrenia

Ferdinando Nicoletti, Rosamaria Orlando, Luisa Di Menna, Milena Cannella, Serena Notartomaso, Giada Mascio, Luisa Iacovelli, Francesco Matrisciano, Francesco Fazio, Filippo Caraci, Agata Copani, Giuseppe Battaglia, Valeria Bruno

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number49
JournalFrontiers in Psychiatry
Volume10
Issue numberFEB
DOIs
Publication statusPublished - Jan 1 2019

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Metabotropic Glutamate Receptors
Antipsychotic Agents
Schizophrenia
Animal Models
Pharmaceutical Preparations
Corpus Striatum
Receptor, Serotonin, 5-HT2A
Dopamine Receptors
Interneurons
Cerebral Cortex
Psychotic Disorders
Anti-Inflammatory Agents
Ligands
Phenotype
Research

Keywords

  • Development of cortical interneurons
  • Metabotropic glutamate receptors
  • Positive allosteric modulator
  • Receptor cross-talk
  • Schizophrenia

ASJC Scopus subject areas

  • Psychiatry and Mental health

Cite this

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title = "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.",
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author = "Ferdinando Nicoletti and Rosamaria Orlando and Menna, {Luisa Di} and Milena Cannella and Serena Notartomaso and Giada Mascio and Luisa Iacovelli and Francesco Matrisciano and Francesco Fazio and Filippo Caraci and Agata Copani and Giuseppe Battaglia and Valeria Bruno",
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T1 - Targeting mGlu receptors for optimization of antipsychotic activity and disease-modifying effect in schizophrenia

AU - Nicoletti, Ferdinando

AU - Orlando, Rosamaria

AU - Menna, Luisa Di

AU - Cannella, Milena

AU - Notartomaso, Serena

AU - Mascio, Giada

AU - Iacovelli, Luisa

AU - Matrisciano, Francesco

AU - Fazio, Francesco

AU - Caraci, Filippo

AU - Copani, Agata

AU - Battaglia, Giuseppe

AU - Bruno, Valeria

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

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