Is the mGlu5 receptor a possible target for new antidepressant drugs?

doi:10.1016/S1734-1140(13)71511-1

Pharmacological Reports

Volume 65, Issue 6, November–December 2013, Pages 1506-1511

https://doi.org/10.1016/S1734-1140(13)71511-1 Get rights and content

Abstract

The current treatment of depression, based on conventional antidepressant drugs that influence monoaminergic systems, is not satisfactory, and innovative antidepressant drugs are still needed. The next generation of treatments needs to be more effective, fasteracting and better tolerated than currently used antidepressants. Agrowing body of evidence indicates that compounds that modulate the glutamatergic system may be a group of novel and mechanistically distinct agents for the treatment of depression. Both preclinical and clinical data show strong, rapid and sustained effects of the NMDA receptor antagonist ketamine in treatment-resistant depression. However, ketamine cannot be considered as a novel antidepressant drug because of its side-effects and abuse potential. Because glutamatergic transmission is controlled not only by ionotropic but also by metabotropic glutamate receptors, their involvement in the etiology and the therapy of depression has also been postulated. Here, we review data supporting the potential antidepressant activity of mGlu5 receptor antagonists as well as the involvement of mGlu5 receptors in the pathophysiology of depression.

Introduction

It seems that a breakthrough in the therapy of depression will require going beyond a monoamine-based theory of depression. One of the new leading hypotheses of depression is the glutamatergic hypothesis, which states that the main brain excitatory system plays a role in the pathophysiology of depression and suggests possible antidepressant activity of compounds modulating glutamatergic neurotransmission via activation or inhibition of glutamatergic receptors [27, 31, 33]. Two distinct groups of glutamatergic receptors have been described: ionotropic glutamate receptors (iGlu receptors, including NMDA, AMPAand kainate receptors), which are coupled to ion channels, and metabotropic glutamate (mGlu) receptors, which are a family of G-protein-coupled receptors [25] that are classified into three groups according to their sequence homology, effector coupling and agonist selectivity: group I (mGlu1 and mGlu5), group II (mGlu2 and mGlu3) and group III (mGlu4, mGlu6, mGlu7 and mGlu8) receptors [7].

Several studies have shown that functional antagonists of NMDA receptors induce antidepressant-like effects in animal models of depression [33]. Some clinical trials have also been undertaken. Although a low-affinity, uncompetitive, open-channel NMDA blocker, memantine, has not shown antidepressant effects in humans [21, 40], studies on the uncompetitive NMDA receptor-trapping blocker ketamine showed strong, rapid and sustained antidepressant effects in patients suffering from major treatment-resistant depression (TRD) [4, 39], electroconvulsive shockresistant major depression [17] and bipolar TRD [11]. However, ketamine has significant limitations, including undesirable side effects, abuse potential and a limited route of administration. In all clinical studies investigating the antidepressant activity of the drug, ketamine was given intravenously by an anesthesiologist and hospitalization for at least 24 h post-infusion was required [1]. Thus, ketamine cannot be considered as a safe antidepressant drug (AD) for outpatients. However, these studies have provided great hope that modulation of the glutamatergic system, including NMDA receptors, may lead to a new generation of rapid and efficient ADs.

Section snippets

mGlu5 receptor ligands modulate NMDA receptor activity

Because the clinical value of ketamine and other NMDA receptor antagonists is limited, mGlu ligands have been considered as possible ADs. These compounds are free of most adverse effects and possess a fast onset of action [27]. mGlu5 receptors, which are functionally involved in the mild modulation of NMDA receptor activity, may become promising targets for new and safer ADs. mGlu5 receptors predominantly have a postsynaptic localization around iGlu receptors and are associated with the Homer

Antagonists of mGlu5 receptors induce antidepressant-like effects in animal models of depression

Behavioral studies have provided some promising results showing potential antidepressant-like effects of mGlu5 receptor antagonists such as MPEP (2-methyl-6-(phenylethynyl)pyridine) [14] and MTEP (3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine) [8], which confirmed their possible application in the therapy of depression. Both compounds induced antidepressant-like effects in several models of depression, such as the forced swim test (FST) [3, 23], the tail suspension test (TST) [3, 26, 35], the

Neuronal and molecular mechanism of the antidepressant-like activity of mGlu5 receptor antagonists

Several studies have been performed to investigate the mechanism of the antidepressant-like activity of mGlu5 antagonists. The results of behavioral studies have suggested that the interaction between the mGlu5 receptor and NMDA receptor plays an important role in the antidepressant-like action of mGlu5 antagonists (Fig. 1). MTEP activity in the FST in mice depended on NMDA receptor activity [32]. Similar effects were observed when the antidepressant-like effects of acamprosate were

Possible clinical applications of mGlu5 receptor antagonists in the therapy of depression

An important role for mGlu5 receptors in depression has been suggested by studies in humans. Postmortem analyses of prefrontal cortices from major depression disorder (MDD) subjects showed lower levels of mGlu5 protein expression in the prefrontal cortex relative to controls [10]. Furthermore, positron emission tomography (PET) studies in humans showed lower levels of mGlu5 binding in several brain regions of unmedicated patients with MDD compared to healthy control subjects [10].

Preclinical

Conclusions

Glutamate receptors have become new important targets for medication development for the treatment of depression. Among mGlu receptors, the mGlu5 receptor seems to be a good target for a novel AD. Numerous preclinical data indicate that antagonists of mGlu5 receptors induce antidepressant-like effects. However, most of the compounds that exhibited beneficial properties in the animal models of depression have never been tested in humans. Currently, the clinical trials of new mGlu5 antagonists

Acknowledgment

This work was supported by the grant POIG.01.01.02-12-004/09 “Depression-Methods-Therapy”, task. 3.7.

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ReviewIs the mGlu5 receptor a possible target for new antidepressant drugs?

Abstract

Introduction

Section snippets

mGlu5 receptor ligands modulate NMDA receptor activity

Antagonists of mGlu5 receptors induce antidepressant-like effects in animal models of depression

Neuronal and molecular mechanism of the antidepressant-like activity of mGlu5 receptor antagonists

Possible clinical applications of mGlu5 receptor antagonists in the therapy of depression

Conclusions

Acknowledgment

Biol Psychiatry

Eur Neuropsychopharmacol

Biol Psychiatry

Clin Ther

Neuropharmacology

Neuropharmacology

Prog Neuropsychopharmacol Biol Psychiatry

Behav Brain Res

Neuropharmacology

Biol Psychiatry

Pharmacol Biochem Behav

Pharmacol Ther

Prog Neuropsychopharmacol Biol Psychiatry

Neuropharmacology

Pharmacol Rep

Eur J Pharmacol

Neuron

Neuron

Activation of metabotropic glutamate receptor 5 has direct excitatory effects and potentiates NMDA receptor currents in neurons of the subthalamic nucleus

J Neurosci

Pharmacology and functions of metabotropic glutamate receptors

Ann Rev Pharmacol Toxicol

Review
Is the mGlu5 receptor a possible target for new antidepressant drugs?