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.