Group II Metabotropic Glutamate Receptors as Targets for Novel Antipsychotic Drugs

Abstract

Schizophrenia is a chronic psychiatric disorder which substantially impairs patients’ quality of life. Despite the extensive research in this field, the pathophysiology and etiology of schizophrenia remain unknown. Different neurotransmitter systems and functional networks have been found to be affected in the brain of patients with schizophrenia. In this context, postmortem brain studies as well as genetic assays have suggested alterations in Group II metabotropic glutamate receptors (mGluRs) in schizophrenia. Despite many years of drug research, several needs in the treatment of schizophrenia have not been addressed sufficiently. In fact, only 5–10% of patients with schizophrenia successfully achieve a full recovery after treatment. In recent years mGluRs have turned up as novel targets for the design of new antipsychotic medications for schizophrenia. Concretely, Group II mGluRs are of particular interest due to their regulatory role in neurotransmission modulating glutamatergic activity in brain synapses. Preclinical studies have demonstrated that orthosteric Group II mGluR agonists exhibit antipsychotic-like properties in animal models of schizophrenia. However, when these compounds have been tested in human clinical studies with schizophrenic patients results have been inconclusive. Nevertheless, it has been recently suggested that this apparent lack of efficacy in schizophrenic patients may be related to previous exposure to atypical antipsychotics. Moreover, the role of the functional heterocomplex formed by 5-HT2A and mGlu2 receptors in the clinical response to Group II mGluR agonists is currently under study.

Allosteric Modulation of GPCRs: New Insights and Potential Utility for Treatment of Schizophrenia and Other CNS Disorders

“…Orthosteric agonists that activate both mGlu 2 and mGlu 3 have robust antipsychotic-like effects in preclinical models (Muguruza et al, 2016; Niswender and Conn, 2010). Unfortunately, while group II mGlu receptor agonists showed significant improvements in both positive and negative symptoms in an initial phase II trial (Patil et al, 2007), subsequent larger clinical studies failed to demonstrate significant efficacy of these agents compared to placebo (Kinon et al, 2011).…”

Uncovering complex disease subtypes by integrating clinical data and imputed transcriptome from genome-wide association studies: Applications in psychiatry and cardiovascular medicine

“…For the second cluster, some of the involved pathways included arachidonic acid metabolism 49,50 , glutathione conjugation 51,52 , glutathione-mediated detoxification 53 and others. As for the third cluster, some significant pathways included DNA damage reversal 54,55 , Vitamin D3 (cholecalciferol) metabolism 56 , metabotropic glutamate/pheromone receptors 57,58 . Some enriched pathways were shared among different clusters while some were not.…”

Group II Metabotropic Glutamate Receptors: Role in Pain Mechanisms and Pain Modulation

“…Group II consists of mGluR2 and mGluR3, which are G i/o coupled and promote the inhibition of adenylyl cyclase ( Tanabe et al, 1992 ) and voltage-dependent calcium channels, as well as the activation of voltage-dependent potassium channels ( Niswender and Conn, 2010 ; Nicoletti et al, 2011 ; Muguruza et al, 2016 ).…”

“…They contribute to and modulate synaptic transmission and neuroplasticity, acting at the preterminal region away from the active zone of the synapse as autoreceptors on glutamatergic neurons or heteroreceptors on GABAergic neurons mediating a negative feedback signal ( Nicoletti et al, 2011 ). As perisynaptic receptors, they are located on the pre-synaptic membrane distant from the synaptic cleft, where they can be activated by substantial synaptic glutamate release or astrocytic glutamate ( Muguruza et al, 2016 ; Maksymetz et al, 2017 ). However, some evidence suggests that mGluR2 and mGluR3 are also expressed post-synaptically.…”

“…However, some evidence suggests that mGluR2 and mGluR3 are also expressed post-synaptically. Whereas mGluR2 seems to be present exclusively on neurons, mGluR3 is also found on glia cells ( Muguruza et al, 2016 ). It is becoming clear now that group II mGluRs interact closely with other mGluRs, which has important functional implications.…”