ReviewIs the mGlu5 receptor a possible target for new antidepressant drugs?
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.
References (40)
- et al.
Ketamine for depression: where do we go from here?
Biol Psychiatry
(2012) - et al.
Antidepressant-like effects of mGluR1 and mGluR5 antagonists in the rat forced swim and the mouse tail suspension tests
Eur Neuropsychopharmacol
(2007) - et al.
Antidepressant effects of ketamine in depressed patients
Biol Psychiatry
(2000) - et al.
Acamprosate for the treatment of alcohol dependence
Clin Ther
(2005) - et al.
Metabotropic glutamate receptor 5 antagonist-induced stimulation of hypothalamic-pituitary-adrenal axis activity: interaction with serotonergic systems
Neuropharmacology
(2003) - et al.
2-Methyl-6-(phenylethynyl)-pyridine (MPEP), a potent, selective and systemically active mGlu5 receptor antagonist
Neuropharmacology
(1999) - et al.
Rapid decrease in depressive symptoms with an N-methyl-D-aspartate antagonist in ECT-resistant major depression
Prog Neuropsychopharmacol Biol Psychiatry
(2011) - et al.
Acute and sustained effects of a metabotropic glutamate 5 receptor antagonist in the novelty-suppressed feeding test
Behav Brain Res
(2012) - et al.
Involvement of the mammalian target of rapamycin signaling in the antidepressant-like effect of group II metabotropic glutamate receptor antagonists
Neuropharmacology
(2011) - et al.
Brain-derived neurotrophic factor Val66Met allele impairs basal and ketamine-stimulated synaptogenesis in prefrontal cortex
Biol Psychiatry
(2012)
Potential antidepressant-like effect of MTEP, a potent and highly selective mGluR5 antagonist
Pharmacol Biochem Behav
Metabotropic glutamate receptor ligands as possible anxiolytic and antidepressant drugs
Pharmacol Ther
Involvement of mGlu5 and NMDA receptors in the antidepressant-like effect of acamprosate in the tail suspension test
Prog Neuropsychopharmacol Biol Psychiatry
Multiple MPEP administrations evoke anxiolytic-and antidepressant-like effects in rats
Neuropharmacology
NMDA but not AMPA glutamatergic receptors are involved in the antidepressant-like activity of MTEP during the forced swim test in mice
Pharmacol Rep
Antidepressants for the new millennium
Eur J Pharmacol
Coupling of mGluR/Homer and PSD-95 complexes by the Shank family of postsynaptic density proteins
Neuron
Homer regulates the association of group 1 metabotropic glutamate receptors with multivalent complexes of homer-related, synaptic proteins
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
Cited by (24)
Alterations of BDNF, mGluR5, Homer1a, p11 and excitatory/inhibitory balance in corticolimbic brain regions of suicide decedents
2023, Journal of Affective DisordersClinical investigations of compounds targeting metabotropic glutamate receptors
2022, Pharmacology Biochemistry and BehaviorTransplantation with mGluR5 deficiency bone marrow displays antidepressant-like effect in C57BL/6J mice
2019, Brain, Behavior, and ImmunityCitation Excerpt :It exerts its functions through binding to ion channel receptors (iGluRs) and metabotropic receptors (mGluRs) (Willard and Koochekpour, 2013). There is growing evidence to support that glutamate and its receptors play fundamental roles in pathophysiology of depression and modulation of antidepressant drugs (Belozertseva et al., 2007; Cryan et al., 2003; Palucha-Poniewiera et al., 2013). mGluRs are classified into three subgroups depends on their homology and functional signaling, including group I (mGluR1 and mGluR5), group II (mGluR2 and mGluR3), and group III (mGluR4, mGluR6, mGluR7, and mGluR8) (Julio-Pieper et al., 2011).
The search for rapid acting antidepressants: Research synthesis and perspectives
2019, Neurobiology of Depression: Road to Novel TherapeuticsmGlu2/3 receptor antagonists
2019, Advances in PharmacologyCitation Excerpt :In this chapter, I focus on the mGlu2 and mGlu3 receptors, and review mGlu2/3 receptor antagonists and their therapeutic potential, in particular, for the treatment of depression. In regard to the therapeutic potential of mGlu5 receptor antagonists for neuropsychiatric disorders, please refer to the cited review articles (Pałucha-Poniewiera et al., 2013; Stansley & Conn, 2018). mGlu2 and mGlu3 receptors are coupled to Gi/Go to negatively regulate adenylyl cyclase activity, and are also well positioned, both anatomically and physiologically, to regulate the activities of glutamate and other neurotransmitters within the CNS in brain regions associated with the control of mood and cognition.