Metabotropic glutamate receptors as novel targets for anxiety and stress disorders

Abstract

Anxiety and stress disorders are the most commonly occurring of all mental illnesses, and current treatments are less than satisfactory. So, the discovery of novel approaches to treat anxiety disorders remains an important area of neuroscience research. Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system, and G-protein-coupled metabotropic glutamate (mGlu) receptors function to regulate excitability via pre- and postsynaptic mechanisms. Various mGlu receptor subtypes, including group I (mGlu(1) and mGlu(5)), group II (mGlu(2) and mGlu(3)), and group III (mGlu(4), mGlu(7) and mGlu(8)) receptors, specifically modulate excitability within crucial brain structures involved in anxiety states. In addition, agonists for group II (mGlu(2/3)) receptors and antagonists for group I (in particular mGlu(5)) receptors have shown activity in animal and/or human conditions of fear, anxiety or stress. These studies indicate that metabotropic glutamate receptors are interesting new targets to treat anxiety disorders in humans.

Advances in the treatment of anxiety: Targeting glutamate

“…What follows is a rough sketch of the actions of several of these receptors; for a more comprehensive description, please see the recent review by Swanson et al 137 Briefly, eight receptors are divided into three groups (group I, mGluR1/5; group II, mGluR2/3; and group III, mGluR4/ 6/7/8). These G protein-coupled receptors serve to modulate and fine tune glutamatergic neurotransmission and may allow for specific and discrete pharmacological interventions in a number of different psychiatric and neurological diseases (e.g., depression, anxiety, addiction, epilepsy, cerebral ischemia, pain, and Parkinson's disease).…”

An Automated System for the Analysis of G Protein-Coupled Receptor Transmembrane Binding Pockets: Alignment, Receptor-Based Pharmacophores, and Their Application

“…They belong to class C GPCRs and differ from class A GPCRs by an exceptionally long extracellular amino-terminal domain (500-600 amino acids) that contains a "venus flytrap" module for agonist binding. 58 The recent discovery of allosteric modulators, which bind to the 7TM regions of the mGlu receptors, has raised interest in these GPCRs as attractive targets for the therapeutic treatment of psychiatric and neurological disorders. The negative allosteric modulator of mGlu5, 2-methyl-6-(phenyl)-pyridine (MPEP), has been shown to display anxiolytic and antidepressant activity in various rodent test models.…”

mGluR7 facilitates extinction of aversive memories and controls amygdala plasticity

“…In recent years, there has been a resurgence of interest in the role of glutamate in anxiety disorders. 2,3 The fast actions of glutamate on neurotransmitter release and cell excitability are mediated by ionotropic receptors, whereas metabotropic glutamate receptors (mGluRs) mediate its slower modulatory actions. 4 It is becoming clear that manipulation of the glutamatergic system by selective activation or blockade of mGluR subtypes can lead to altered anxiety and fear responses.…”

“…4 It is becoming clear that manipulation of the glutamatergic system by selective activation or blockade of mGluR subtypes can lead to altered anxiety and fear responses. 2 Further, in both rodents and humans, pharmacological modulation of glutamatergic neurotransmission enhances the extinction of learned fear, 5,6 suggesting it could be a useful adjunct to behavioural therapy for certain anxiety disorders. This possibility is of particular interest since classical anxiolytics impair the responsiveness to behavioural therapy.…”