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 G_q/11, and all other subtypes are coupled to G_i/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-HT_2A 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.

Keywords: development of cortical interneurons; metabotropic glutamate receptors; positive allosteric modulator; receptor cross-talk; schizophrenia.

Figure 1

Hypothetical model highlighting the potential role of individual mGlu receptor subtypes in the pathophysiology and treatment of schizophrenia. Presynaptic mGlu2 receptors negatively modulate 5-HT_2A receptor signaling, and their activation restrains glutamate release at synapses between thalamo-cortical neurons and cortical pyramidal neurons (see chapter 6). mGlu5 receptors are found in both pyramidal neurons and interneurons (shown here) and functionally interact with NMDA receptors. mGlu5 receptor PAMs are under development for the treatment of schizophrenia (see chapter 4). Recent evidence indicates that mGlu3 receptor activation boost mGlu5 receptor signaling, and, therefore, selective mGlu3 receptor agonists or PAMs should be tested in preclinical models predictive of antipsychotic activity (chapter 3). The functional cross-talk between mGlu3 and mGlu5 receptors has been shown in pyramidal neurons (6). We speculate that the two receptors also interact in GABAergic interneurons, but this remains to be demonstrated. mGlu1 receptors and type-4 muscarinic cholinergic receptors (M4) interact in stimulating the production of endocannabinoids (ECBs) in striatal projection neurons. ECBs activate presynaptic CB1 receptors, thereby reducing dopamine (DA) release from meso-striatal terminals. Hence, mGlu1 receptor PAMs might be effective in improving positive symptoms in schizophrenia (chapter 5). Finally, mGlu4 receptor agonists/PAMs are effective in animal models that are predictive of antipsychotic activity. mGlu4 receptors might act to reduce glutamate release from excitatory nerve endings of pyramidal neurons and through other mechanisms. Not shown here: activation of mGlu3 and mGlu5 receptors may restrain neuroinflammation by driving microglia toward an antinflammatory phenotype, and activation of mGlu3 receptors stimulates the production of neurotrophic factors in astrocytes (see chapters 3 and 4).