Potential Psychiatric Applications of Metabotropic Glutamate Receptor Agonists and Antagonists

Abstract

Drugs acting at metabotropic glutamate receptors (mGluRs) are among the most promising agents under development for the treatment of psychiatric disorders. The research in this area is at a relatively early stage, as there are no drugs acting at mGluRs that have been approved for the treatment of any psychiatric disorder. However, in the areas of schizophrenia, anxiety disorders and mood disorders, research conducted in animal models appears to translate well into efficacy in human laboratory-based models of psychopathology and in preliminary clinical trials. Further, the genes coding for mGluRs are implicated in the risk for a growing number of psychiatric disorders. This review highlights the best studied mGluR strategies for psychiatry, based on human molecular genetics, studies in animal models and preliminary clinical trials. It describes the potential value of mGluR2 and mGluR5 agonists and positive allosteric modulators for the treatment of schizophrenia. It also reviews evidence that group II mGluR agonists and positive allosteric modulators as well as group I mGluR antagonists might also treat anxiety disorders and some forms of depression, while mGluR2 and group I mGluR antagonists (particularly mGluR5 antagonists) might have antidepressant properties. This review also links growing insights into the role of glutamate in the pathophysiology of these disorders to hypothesized mGluR-related treatment mechanisms.

Homer1/mGluR5 Activity Moderates Vulnerability to Chronic Social Stress

“…Given the increasing body of evidence showing that NMDA receptor targeting agents produce rapid-acting antidepressant effects (Krystal et al, 2013;Kavalali and Monteggia, 2012), a Homer1a-mediated overactivation of this signaling pathway may profoundly affect antidepressant treatment efficacy. The development of new drugs that target this system, mainly via mGluR5, is therefore of great value and importance Krystal et al, 2010).…”

“…Modulation of glutamate receptor function has therefore been proposed as a promising target for antidepressant, anxiolytic, and antipsychotic drug development . Positive and negative modulators of mGluR subtype 5 (mGluR5), in particular, have been suggested as novel agents for the treatment of depression (Palucha et al, 2005;Krystal et al, 2010;Pilc et al, 2008), but the exact molecular mechanisms that mediate their potential therapeutic effects are yet to be fully understood.…”

Acute Shift in Glutamate Concentrations Following Experimentally Induced Panic with Cholecystokinin Tetrapeptide—A 3T-MRS Study in Healthy Subjects

“…Moreover, the NMDA receptor agonist D-cycloserine has been shown to enhance effects of cognitive behavioral therapy in anxiety disorders in a couple of clinical studies based on its capacity to influence memory consolidation (Otto et al, 2010;Ressler et al, 2004). With regard to mGlu receptors, anxiolytic properties have been proposed for an allosteric modulator of the mGluR2/3 receptor subtype (Krystal et al, 2010). Moreover, patients with generalized anxiety disorder reported a significant decrease in anxiety sensitivity and worry after treatment with riluzole, which decreases glutamate release (Mathew et al, 2005;Pittenger et al, 2008).…”

Fine-tuning mGluRs

“…Previous human genetic studies implicated mGluR mutations in various neuropsychiatric illnesses including schizophrenia, depression and anxiety. 3 At least 10 companies are developing mGluR modulators for neuropsychiatric and neurodegenerative indications.…”