Targeting Metabotropic Glutamate Receptors for the Treatment of Depression and other Stress-Related Disorders

Abstract

The discovery of robust antidepressant effects of ketamine in refractory patients has led to increasing focus on agents targeting glutamatergic signaling as potential novel antidepressant strategy. Among the agents targeting the glutamatergic system, compounds acting at metabotropic glutamate (mGlu) receptors are among the most promising agents under studies for depressive disorders. Further, the receptor diversity, distinct distribution in the CNS, and ability to modulate the glutamatergic neurotransmission in the brain areas implicated in mood disorders make them an exciting target for stress-related disorders. In preclinical models, antidepressant and anxiolytic effects of mGlu₅ negative allosteric modulators (NAMs) have been reported. Interestingly, mGlu_2/3 receptor antagonists show fast and sustained antidepressant-like effects similar to that of ketamine in rodents. Excitingly, they can also induce antidepressant effects in the animal models of treatment-resistant depression and are devoid of the side-effects associated with ketamine. Unfortunately, clinical trials of both mGlu₅ and mGlu_2/3 receptor NAMs have been inconclusive, and additional trials using other compounds with suitable preclinical and clinical properties are needed. Although group III mGlu receptors have gained less attention, mGlu₇ receptor ligands have been shown to induce antidepressant-like effects in rodents. Collectively, compounds targeting mGlu receptors provide an alternative approach to fill the outstanding clinical need for safer and more efficacious antidepressants.

Introduction:

It has long been recognized that environmental stress plays a pivotal role in the pathogenesis of psychiatric disorders. Most of the early life stressful events have been suggested to exert a principal impact on brain development that may result in permanent functional changes contributing to lifelong risk for psychiatric disorders (anxiety, depression, and substance use disorders) (Heim and Binder, 2012). Indeed, during early periods of neuronal development, the brain areas involved in the regulation of mood and emotion undergo stress-dependent plasticity changes leading to an enhanced risk for developing major depressive disorders (MDD) and anxiety disorders (Hornung and Heim, 2014). Although stress is considered an important risk factor for several psychiatric disorders, it does not consistently lead to these mental disorders. Such divergence can be explained in part by gene-environment interactions, in which genetic vulnerability may influence the likelihood of having psychopathology after stress exposure (Silva et al., 2020). The difference in the nature and duration of stressors may also partially contribute to the variability in developing psychopathology (Fergusson et al., 2008; Hodgdon et al., 2018; Infurna et al., 2016). Further, the combined effect of multiple stressors may result in a severe pathological state leading to diminished quality of life. Based on this, various types of stressors (physical and psychosocial stressors) for a variable duration (acute or chronic) are used to induce different neurobiological and behavioral outcomes that serve as models for depression and anxiety in animals (Gururajan et al., 2019). Further, these animal models have helped to identify the pharmacological mechanisms and potential therapeutic effects of several drugs for treating stress-related disorders.

Among the stress-related disorders, major depressive disorder (MDD) and anxiety are significant health concerns worldwide. The prescribed medications include monoamine oxidase inhibitors, tricyclic antidepressants, serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors, serotonin receptor antagonists, norepinephrine reuptake inhibitors, norepinephrine-dopamine reuptake inhibitors, noradrenergic antagonist and neurosteroids. Owing to a relatively safe and tolerable side-effect profile, SSRIs have become the “first-line” antidepressants for MDD treatment (Koenig and Thase, 2009; Trivedi et al., 2006). However, SSRIs have several shortcomings and limitations. Not all patients respond to the monoamine-based antidepressants, and only one-third of patients achieve full remission of their depressive symptoms (Trivedi et al., 2006). Furthermore, there is a substantial delay in the therapeutic onset despite immediate effects on the central monoamines. Finally, available antidepressants fail to treat all symptoms effectively (Nutt et al., 2007), and their prolonged use often comes with side effects spanning a wide range of symptoms (Price et al., 2009). Thus, there remains a substantial unmet medical need for novel, efficacious, and rapid-acting therapeutics that alleviate all symptoms of MDD. Research has revealed strong comorbidity between depression and anxiety disorders (Cortese and Phan, 2005), and both disorders are characterized by disproportionate excitability within the brain areas regulating mood and emotions. L-glutamate is a primary excitatory neurotransmitter in the central nervous system (CNS) and regulates the neuronal activity, synaptic plasticity, and a variety of brain functions.

Mounting evidence points towards the dysregulation of the glutamatergic components of the limbic system as a hallmark feature of mood disorders (Duman et al., 2019). The evidence that glutamate is involved in the pathophysiology of stress-related disorders stemmed from the initial postmortem and imaging studies showing altered glutamate levels in the brain areas of depressed individuals (Sanacora et al., 2004; Yildiz-Yesiloglu and Ankerst, 2006). Changes in the glutamate levels have also been observed in cerebrospinal fluid (CSF) (Frye et al., 2007; Levine et al., 2000), plasma (Altamura et al., 1993; Kim et al., 1982), and serum (Mitani et al., 2006) of patients with mood disorders, and suicide victims (Holemans et al., 1993; Nowak et al., 1995). These findings are supported by clinical neuroimaging data reporting volumetric alterations in brain areas that predominantly express glutamatergic neurons or are innervated by glutamatergic projections (Colle et al., 2018; Dotson et al., 2009; Hamilton et al., 2008; MacQueen and Frodl, 2011; van Tol et al., 2010). Further, the dysregulation of genes involved in synaptic function/structure and glutamate receptor subunits have also been observed in the hippocampus of MDD patients and pre-clinical models of depression (Duric et al., 2013). Taken together, these studies provide evidence that disruption of synaptic and glutamatergic signaling pathways contribute to the pathophysiology of MDD and establish the glutamatergic system as an interesting target for designing novel therapeutics for MDD. Interestingly, a recent clinical study conducted on MDD patients who received subanesthetic dosages of ketamine showed increased volumes of several brain areas implicated in depression (Zhou et al., 2020). These encouraging results demonstrate the reversal of depression-related hippocampal atrophy and suggest this as one of the potential underlying mechanisms to the fast antidepressant action of ketamine. Ketamine is one of the most efficacious treatments for treatment-resistant depression, but not all patients respond to the ketamine (Kishimoto et al., 2016; Murrough et al., 2013) and it has serious adverse effects including psychotomimetic effects and abuse liability (Sos et al., 2013) that limit its clinical utility. However, the robust efficacy of ketamine, combined with the studies outlined above, has prompted a major interest in exploring the potential utility of other agents that regulate glutamatergic transmission in the CNS.

Glutamate acts as a neurotransmitter through two principal classes of receptors: ionotropic glutamate receptors (iGlu receptors) and metabotropic glutamate receptors (mGlu receptors) (Nakanishi, 1992). Based on the glutamate analogs activating them more selectively than glutamate, iGlu receptors are further divided into three subtypes: the α-amino-3-hydroxy-5-methyl-isoxazole-4-proprionic acid (AMPA) receptor, and the N-methyl-d-aspartate (NMDA) receptor, and kainate receptors. These ion channels are tetrameric complexes of receptor subunits that mediate fast cation flux and synaptic transmission across the postsynaptic neuronal membrane. The mGlu receptors are members of class C G-protein coupled receptors (GPCRS) and based on the sequence homology, G-protein coupling, ligand selectivity, and function, they are sub-classified into three groups: group I (mGlu₁ and mGlu₅), group II (mGlu₂ and mGlu₃), and group III (mGlu₄, mGlu₆, mGlu₇ and mGlu₈) receptors (Niswender and Conn, 2010). The mGlu receptors are heptahelical membrane-bound proteins with a large extracellular N-terminal domain named as Venus flytrap domain (VFD) containing a glutamate-binding site. Glutamate binding to the VFD induces conformational changes which are propagated from VFD to the heptahelical domain-C-terminal tail, and intracellular signaling partners, to regulate multiple cellular processes (Niswender and Conn, 2010).

Considering the significance of glutamate in the brain, pharmacological interventions for the stress disorders should target excesses in glutamate transmission. Because of their ability to modulate glutamatergic neurotransmission, and the functional diversity and distinct distribution, targeting mGlu receptors may lead to the development of novel strategies for the treatment of psychiatric disorders. The available compounds acting at mGlu receptors are often allosteric modulators, which “fine-tune” receptor activity and are believed to have fewer side effects than those associated with orthosteric ligand binding. Further, a plethora of preclinical literature suggests the utility of ligands targeting specific mGlu receptor subtypes for the management of mood disorders such as depression and anxiety.

Targeting group I (mGlu₁ and mGlu₅) mGlu receptors for stress-related disorders:

The group I mGlu (mGlu₁ and mGlu₅) receptors are coupled to Gαq heterotrimeric G-proteins, and ligand binding to these receptors activates phospholipase C beta which hydrolyzes phosphatidylinositol bisphosphate (PIP₂) to generate second messengers diacylglycerol (DAG) and inositol triphosphate (IP₃). These second messengers propagate and amplify Gq-mediated signal with intracellular calcium mobilization and protein kinase C activation to evoke tissue- or cell-specific responses. Group I mGlu receptors are primarily enriched at postsynaptic sites and are known to homodimerize via interactions at VFD of each monomer (Niswender and Conn, 2010). Although mGlu₁ and mGlu₅ receptors share structural and functional homology, there is evidence that they share distinct monomeric and dimeric neurodevelopmental expression patterns in native systems and following challenge with NMDA receptor antagonists (Lum et al., 2016). Since group I mGlu receptors are targeted for the treatment of several psychiatric and neurodevelopmental disorders (Maksymetz et al., 2017), the receptor dimerization profile may affect ligand pharmacology at specific ages and is worth investigating. Further, a functional interdependence has been observed between mGlu₁ and mGlu₅ receptors in a heterologous system, which appears to be independent of canonical heterodimerization and might have a physiological relevance in a native system co-expressing these receptors (Sevastyanova and Kammermeier, 2014).

In stress-related disorders research, mGlu₅ receptor has gained more attention than mGlu₁ receptor (Table 1). This is in part due to findings that mGlu₅- and NMDA receptors are functionally linked by a variety of intracellular mechanisms, which allow mGlu₅ receptor to modulate NMDA receptor function (Marino and Conn, 2002; Niswender and Conn, 2010). Preclinical studies using the mGlu₅ receptor negative allosteric modulator (NAM), MPEP has demonstrated marked antidepressant-like effects in the tail suspension test (TST) (Belozertseva et al., 2007; Tatarczynska et al., 2001) and forced swim test (FST) (Li et al., 2006). Further, multiple administrations of MPEP have been shown to reverse the passive avoidance deficits in the olfactory bulbectomized (OB) model of depression (Pilc et al., 2002; Wieronska et al., 2002), indicating that inhibitors of mGlu₅ receptors may induce antidepressant-like effects in rodents.

Table 1.

Summary of the preclinical effects of Group I mGlu receptor ligands

Compound	Effects in the experimental model	References
mGlu 1 receptor antagonists
AIDA	Anxiolytic-like effects in the conflict drinking test and EPM	Klodzinska et al., 2004; Lima et al., 2008
JNJ16259685	Anxiolytic-like activity in the lick suspension test	Lavreysen et al., 2004b
	Reduced immobility time in the TST	Belozertseva et al., 2007
LY456236	Anxiolytic-like effects in Vogel conflict and lick suppression test	Tatarczynska et al., 2001; Varty et al., 2005
mGlu5 receptor NAMs
GRN-529	Decreased immobility time in FST and TST, attenuated stress-induced hyperthermia and increased punished crossings in the four-plate test	Hughes et al., 2013
MTEP	Reduced immobility in the TST and FST	Belozertseva et al., 2007; Palucha et al., 2005
	Reduced the OB-related hyperactivity in the open field test	Palucha et al., 2005
mGlu5 receptor inverse agonists
CTEP	Rescue chronic social defeat stress-induced reduction of locomotion in the open field and social interaction test	Wagner et al., 2015
DSR-98776	Reduced immobility time in FST in rats and mice	Kato et al., 2015
Partial mGlu 5 receptor NAMs
M-5MPEP	Reduced immobility time in FST (in rats) and TST (in mice), prevented stress-induced hyperthermia, reduced the number of marbles buried	Gould et al., 2016
Br-5MPEPy	Reduced immobility time in FST in rats, reduced the stress-induced hyperthermia, decreased the number of marbles buried	Gould et al., 2016
VU0477573	Dose-dependently inhibited marble burying in CD-1 mice	Nickols et al., 2016

Selective mGlu₅ receptor NAMs for the treatment of mood disorders

In addition to MPEP, which is known to have several off-target activities (Heidbreder et al., 2003; O’Leary et al., 2000), another highly selective mGlu₅ receptor NAM, MTEP showed antidepressant-like activity in the TST and in the FST (Belozertseva et al., 2007; Palucha et al., 2005). Besides these effects, the repeated administration of MTEP, similar to chronic treatment with typical antidepressants, reduced the OB-related hyperactivity in the open field test (Palucha et al., 2005), supporting mGlu₅ receptor as a potential therapeutic target for depression. Similarly, mice with genetic deletion of Grm5 (the gene encoding the mGlu₅ receptor) also display antidepressant-like effects in FST (Li et al., 2006). Another mGlu₅ receptor NAM, GRN-529 has also been shown to exert antidepressant-like (decreased immobility time in FST and TST), anxiolytic-like (attenuated stress-induced hyperthermia and increased punished crossings in the four-plate test), and analgesic activity (reversal of hyperalgesia due to sciatic nerve ligation or inflammation) in mice (Hughes et al., 2013). Since GRN-529 showed efficacy in models of anxiety and pain, which are often co-morbid in treatment resistant depression (TRD), negative allosteric modulation of the mGlu₅ receptor could represent a novel therapeutic approach for treating TRD. Another mGlu₅ receptor NAM, DSR-98776, induces rapid antidepressant-like actions in Wistar rats (Kato et al., 2015), raising the possibility that mGlu₅ receptor NAMs could share the ability of ketamine to provide fast-acting antidepressant activity. Interestingly chronic administration of mGlu₅ receptor inverse agonist, CTEP was able to rescue chronic social defeat stress-induced reduction of locomotion in the open field and social interaction test (Wagner et al., 2015). Since alterations in the brain circuitry regulating social behavior are often associated with depressive disorders, these findings indicate the therapeutic potential of mGlu₅ receptor NAMs for treating anhedonic symptoms, which are generally associated with poor disease prognosis and suboptimal response to antidepressant treatment (Buckner et al., 2008).

Partial mGlu₅ receptor negative allosteric modulators (NAMs) have the potential to induce antidepressant- and anxiolytic- like effects with fewer adverse effects

Prototypical mGlu₅ receptor NAMs can induce adverse effects in humans and psychotomimetic-like effects in animals, indicating a narrow therapeutic window. However, recent studies have been successful in developing partial mGlu₅ receptor NAMs that only partially block mGlu₅ receptor signaling at concentrations that fully occupy the receptor (Nickols et al., 2016; Rodriguez et al., 2005). Interestingly, while the prototypical mGlu₅ receptor NAM MTEP potentiates PCP-induced hyperlocomotion in rodents (Gould et al., 2016), a partial mGlu₅ receptor NAM induces antidepressant- and anxiolytic-like effects without inducing sedation and exacerbating the PCP-induced hyperlocomotion (Gould et al., 2016; Nickols et al., 2016). Since partial mGlu₅ receptor NAMs are sufficient to produce effects similar to full mGlu₅ receptor NAMs and exhibit fewer side effects, they have the potential to provide safer therapeutic agents than full NAMs.

The mGlu₅ receptor modulators showed mixed effects in clinical studies

The antidepressant- and anxiolytic-like effects of mGlu₅ receptor NAMs are supported by positron emission tomography (PET) imaging data showing increased mGlu₅ receptor density in the amygdala, anterior cingulate cortex (ACC), and medial orbitofrontal cortex of Obsessive-compulsive disorder (OCD) patients (Akkus et al., 2014). Since OCD patients with obsessions have high a prevalence of anxiety symptoms (Hasler et al., 2005), the obsessions that involve stress or anxiety might be associated with increased glutamatergic neurotransmission and blockers of mGlu₅ receptor might be able to correct them. In contrast, lower levels of mGlu₅ receptor binding have been observed patients suffering from MDD (Deschwanden et al., 2011), which is in agreement with the lower mGlu₅ receptor protein expression observed in the postmortem brain tissues from depressed patients. Therefore, it is possible that drugs targeting mGlu₅ receptors may be particularly useful in depressed patients with comorbid anxiety disorders. Based upon this, mGlu₅ receptor NAMs were tested in clinical trials for their efficacy to treat depressive symptoms. A six-week Phase IIa clinical trial of mGlu₅ receptor NAM, AZD2066 involving 131 patients with MDD failed to show any efficacy over the placebo control (ClinicalTrials.gov Identifier: NCT01145755). In addition, Basimglurant (RG7090, RO4917523), a potent mGlu₅ receptor-selective NAM with excellent drug-like properties, and antidepressant- as well as anxiolytic-like effects in rodents (Lindemann et al., 2015), was also tested in the clinical trials. Treatment with adjunctive basimglurant for six weeks did not show a significant difference relative to placebo in the major outcomes of depression in Phase IIb clinical trials (Quiroz et al., 2016). However, higher doses did induce significant improvements in secondary outcomes, particularly patient-related measures (Quiroz et al., 2016). These encouraging findings combined with a favorable tolerability profile warrant need for further investigating basimglurant and other mGlu₅ receptor NAMs in depressive disorders and highlight the importance of dose selection before evaluating any medications in the clinical trials.

Potential anxiolytic effects of mGlu₁ receptor antagonists

In addition to mGlu₅ receptor, mGlu₁ receptor is also expressed in the brain areas implicated in anxiety and depression behavior- the prefrontal cortex (PFC), amygdala, hypothalamus, hippocampus, nucleus accumbens (NAc), and periaqueductal gray (Lavreysen et al., 2004a; Shigemoto et al., 1992). Further, mGlu₁ receptor agonists are known to depress GABAergic transmission (Gereau and Conn, 1995; Ohno-Shosaku et al., 2002) in multiple brain areas, while antagonists can increase GABAergic signaling (Battaglia et al., 2001) and can induce anxiolytic effects similar to GABA modulators such as Benzodiazepines (Griffin et al., 2013). Based on this, mGlu₁ receptor antagonists were tested in a battery of behavioral assays correlating anxiety phenotype in rodents (Table 1). For example, the anxiolytic-like activity of mGlu₁ receptor antagonist, JNJ16259685 (Lavreysen et al., 2004b) was observed in the lick suppression test, but not in elevated zero maze (EZM) test (Steckler et al., 2005). Similarly, LY456236 induced anxiolytic-like effects in Vogel conflict and lick suppression test (Tatarczynska et al., 2001; Varty et al., 2005). Further, systemic as well as central administration of mGlu₁ receptor antagonist, AIDA induced anxiolytic-like effects in the conflict drinking test and the elevated plus maze (EPM) test in rats (Klodzinska et al., 2004; Lima et al., 2008). In addition to the anxiolytic-like effects, JNJ-16567083 reduced immobility time in the TST (Belozertseva et al., 2007) indicating the antidepressant potential of mGlu₁ receptor antagonists. Consistent with this, increased expression of mGlu₁ receptor has been observed in the OB model of depression, which was reversed by chronic treatment with antidepressant amitriptyline (Wieronska et al., 2008). Also, chronic treatment with imipramine decreases the responsiveness of rat CA1 neurons to mGlu₁ activation (Pilc et al., 1998; Zahorodna and Bijak, 1999). Collectively, these studies suggest that a reduction in mGlu₁ receptor expression and function may lead to antidepressant-like activity, and an mGlu₁ receptor antagonist may induce antidepressant-like effects. Mechanistic studies have indicated that mGlu₁ receptor is essential for the expression of long-term depression (LTD) at PFC-NAc synapses (Turner et al., 2018). Notably, activation of PFC inputs to the NAc inhibits the effect of chronic social defeat stress on social avoidance behavior (Covington et al., 2010; Vialou et al., 2014), and mGlu₁ receptor NAM may act by inhibiting long term depression on PFC-NAc inputs leading to the antidepressant-like effects. However, further studies are needed to test the efficacy of mGlu₁ receptor ligands in the context of stress physiology, emotion, and reward, and to more fully evaluate the mechanistic underpinnings of actions of these compounds.

Targeting group II mGlu (mGlu₂ and mGlu₃) receptors for stress-related disorders

Among the agents targeting the glutamatergic system, group II mGlu (mGlu₂ and mGlu₃) receptors have emerged as potential targets for developing novel antidepressants (Table 2). These receptors are primarily located at presynaptic sites, while mGlu₃ receptors are also present at postsynaptic locations and on glia (Jin et al., 2018). These receptors couple with Gi/o family of G-proteins. Activation of these receptors inhibits adenylyl cyclase activity leading to decrease in the production of cyclic-AMP (cAMP) and activity of cAMP-dependent protein kinase. It is now clear that group II mGlu receptors are capable of signaling through other non-canonical pathways that lead to the potentiation of Gq signaling. For example, co-activation of mGlu₃ receptors in the brain tissues potentiates stimulation of phosphoinositide hydrolysis caused by the activation of mGlu₅ receptor (Di Menna et al., 2018; Schoepp et al., 1996). Furthermore, activation of mGlu₃ receptor in the cortical pyramidal neurons enhances mGlu₅ receptor-mediated somatic Ca²⁺ mobilization (Di Menna et al., 2018). Besides these effects, coincident activation of mGlu₃ receptors with β-adrenergic receptors (βAR) in the hippocampal astrocytes induces an increase in cyclic-AMP (cAMP) accumulation and release of adenosine, which in turn acts to counteract the effects of βAR on synaptic plasticity at SC-CA1 synapse (Walker et al., 2017). This could present a protective feedback mechanism to prevent excitotoxicity injury during instances of intense stress.

Table 2.

Summary of the preclinical effects of Group II mGlu receptor ligands

Compound	Effects in the experimental model	References
mGlu 2/3 receptor agonists
LY354740	Reduced expression of fear-potentiated startle in rats	Schoepp et al., 2003; Tizzano et al., 2002
	Increased open-arm time in the EPM	Linden et al., 2004; Linden et al., 2005; Schoepp et al., 2003
LY279268	Administration with chlorimipramine reduced the increased immobility time in Flinders-sensitive line rats	Matrisciano et al., 2007
mGlu 2/3 receptor antagonists
MGS0039	Reduced immobility in the FST and TST	Chaki et al., 2004
	Suppressed marble-burying in mice	Shimazaki et al., 2004
	Attenuated freezing behavior in a conditioned fear stress model and reduced escape failures in the learned helplessness paradigm in rats	Yoshimizu et al., 2006
	Reduced stress-induced hyperthermia	Iijima et al., 2007
	Anxiolytic-like effects in Vogel conflict drinking test	Stachowicz et al., 2011
	Improved the reduced sucrose preference in the susceptible mice after social defeat stress and attenuated stress-induced increased immobility time in FST and TST	Dong et al., 2017
LY341495	Reduced immobility in the FST / TST)	Chaki et al., 2004; Fukumoto et al., 2016
	Reduced stress-induced hyperthermia	Iijima et al., 2007
	Reversal of chronic unpredictable stress-induced reduced sucrose preference in rats	Dwyer et al., 2013
	Shortened latency to feed in novelty suppressed feeding test	Fukumoto et al., 2014
	Induces antidepressant effects in the CD-1 mice	Witkin et al., 2016
	Administration with sub-effective dosage of ketamine reduced immobility in FST	Podkowa et al., 2016; Palucha-Poniewiera et al., 2019
	Promoted stress resilience	Highland et al., 2019
LY3020371	Reduced immobility in FST	Witkin et al., 2017a
mGlu 2/3 receptor NAM
Ro4491533	Reduced immobility time in FST and TST	Campo et al., 2011
mGlu 2 receptor PAM
THIIC	Increased the number of water reinforcements received, decreased immobility in FST, responses emitted in the DRL 72-s assay, the difference in dominance level in the dominant-submissive test in rats, and suppressed marble burying, stress-Induced Hyperthermia and stress-induced increase in cerebellar cGMP	Fell et al., 2011
mGlu 2 receptor NAM
VU6001966	Increase latency to immobility and decreased total immobile time in the FST; Reversed anhedonia induced by chronic corticosterone (CORT) treatment or exposure to chronic variable stress (CVS)	Joffe et al., 2020
mGlu 3 receptor NAMs
VU650786	Inhibited marble burying in mice	Engers et al., 2015
	Decreased immobility in the FST in rats	Engers et al., 2015
	Prevented motivational deficits induced by acute stress	Joffe et al., 2019
	Increased latency to immobility and decreased total immobile time in the FST and TST; Reversed anhedonia induced by chronic CORT treatment or exposure to CVS	Joffe et al., 2020
VU6010572	Reduced immobility time in the TST in CD-1 mice	Engers et al., 2017

Their localization in the brain areas implicated in the regulation of depression and anxiety behavior such as the PFC, striatum, NAc, thalamus, hippocampus, and amygdala (Wright et al., 2001), and ability to modulate glutamatergic signaling make them intriguing targets for developing improved pharmacotherapies for depressive disorders. Altered expression of this class of receptors has been observed in preclinical and clinical studies. Increased mGlu_2/3 receptor expression in the PFC and hippocampus has been observed in the mice reared under isolated conditions (Kawasaki et al., 2011), and increased levels of mGlu_2/3 receptor have been observed in the postmortem PFC of MDD patients (Feyissa et al., 2010), indicating that elevated function of mGlu_2/3 receptors may play a role in the etiology of depression.

Potential antidepressant effects of mGlu_2/3 receptor antagonists:

Emerging literature suggests beneficial effects of the antagonists of group II mGlu receptors in preclinical models of depression. Interestingly, mGlu_2/3 receptor antagonists and NAMs have been reported to display fast and prolonged antidepressant-like response in both acute and chronic models of depression (Campo et al., 2011; Chaki et al., 2004; Dwyer et al., 2013; Fukumoto et al., 2016; Joffe et al., 2020; Koike et al., 2013; Podkowa et al., 2015). In chronic stress models, while conventional antidepressants show therapeutic delay and take several weeks to manifest the antidepressant response, mGlu_2/3 receptor antagonists, MGS0039 and LY341495 exert antidepressant-like effects as early as one day after administration (Dong et al., 2017; Dwyer et al., 2013). Notably, the effects of a single injection of mGlu_2/3 receptor antagonists last for at least a week demonstrating sustained antidepressant effects of mGlu_2/3 receptor antagonists (Dong et al., 2017; Dwyer et al., 2013). These sustained antidepressant effects cannot be attributed to the pharmacokinetic profile, because both MGS0039 and LY341495 are cleared from the body within one day after a single administration. These results point out that persistent change in synaptic plasticity may be involved in the rapid and prolonged antidepressant properties of group II antagonists.

Further, conventional antidepressants like imipramine do not show efficacy at effective doses in both learned helplessness (LH) models (Yoshimizu et al., 2006) and corticosterone-treated models (Ago et al., 2013; Iijima et al., 2010). At the same time, a single injection of ketamine has been shown to induce strong antidepressant-like effects in these models (Koike et al., 2011, 2013). Therefore, the LH paradigm can be considered as a rodent model that is resistant to conventional antidepressants. Excitingly, mGlu_2/3 receptor antagonists are effective in the LH model and lack any dose-related side effects suggesting mGlu_2/3 receptor antagonists as safer antidepressants. Studies in rodents using mGlu_2/3 receptor antagonist, LY341495 indicate that blockade of mGlu_2/3 receptors during stress promotes stress resilience (Highland et al., 2019), and induces antidepressant effects in the CD-1 mice (Witkin et al., 2016), which are relatively resistant to SSRIs. This encouraging preclinical evidence reveals that mGlu_2/3 receptor antagonists may be effective for treatment-resistant depression in which currently prescribed antidepressants are not efficacious. Excitingly, an orthosteric mGlu_2/3 receptor antagonist, LY3020371 induces antidepressant effect comparable to ketamine in FST (Witkin et al., 2017a) but did not produce ketamine-like adverse effects, such as motor and cognitive deficits, abuse liability, and toxicity (Witkin et al., 2017b). These studies indicate that mGlu_2/3 receptor antagonists possess the qualities of fast-acting antidepressants and the desired safety profile required for further studies in patients. Similarly, mGlu_2/3 receptor NAM, Ro4491533 also induces antidepressant-like effects in acute tests like FST and TST (Campo et al., 2011).

The mGlu_2/3 receptor ligands may induce anxiolytic effects

Multiple lines of evidence suggest that mGlu_2/3 receptors play a role in anxiety. Anxiolytic effects of mGlu_2/3 receptor agonists and mGlu₂ receptor PAMs are known in rodent models of anxiety (Fell et al., 2011; Linden et al., 2004; Linden et al., 2005; Schoepp et al., 2003; Tizzano et al., 2002). In healthy humans, anxiolytic effects of mGlu_2/3 receptor agonist LY354740 were observed in the fear-potentiated startle paradigm (Grillon et al., 2003). In this test, administration of LY354740 was able to reduce the increase in startle magnitude during shock anticipation and state of anxiety and negative affect during the fear-potentiated startle (Grillon et al., 2003). Further, LY544344, a potent and selective mGlu_2/3 receptor agonist and a prodrug of LY354740, has shown efficacy for the treatment of patients with a generalized anxiety disorder in an 8-week clinical trial (Dunayevich et al., 2008). LY544344 was well tolerated and lacked treatment-associated side-effects. However, based on the findings of convulsions reported in preclinical studies, the trial was discontinued early (Dunayevich et al., 2008). The findings of this clinical study support the potential utility of mGlu_2/3 receptor agonists for the treatment of anxiety disorders and further substantiate the need to evaluate the preclinical and clinical safety and tolerability. Similar to these studies, several groups have indicated the anxiolytic-like effects of mGlu_2/3 receptor antagonists in preclinical models of anxiety. For example, mGlu_2/3 receptor antagonist, MGS0039 showed anxiolytic-like effects in Vogel conflict test, fear conditioning, stress-induced hyperthermia, and marble-burying test (Iijima et al., 2007; Shimazaki et al., 2004; Stachowicz et al., 2011; Yoshimizu et al., 2006). Also, another mGlu_2/3 receptor antagonist, LY341495 showed efficacy in the novelty suppressed feeding test, marble-burying test and stress-induced hyperthermia (Fukumoto et al., 2014; Iijima et al., 2007; Shimazaki et al., 2004). Interestingly, both MGS0039 and LY341495 failed to show any efficacy in the EPM test of anxiety, which is sensitive to benzodiazepine class of anxiolytics, indicating a different anxiolytic profile of group II antagonists. Further mechanistic studies revealed that mGlu_2/3 receptor antagonists may induce anxiolytic-like effects via several other mechanisms, such as serotonin-1A (5-HT_1A) receptor stimulation (Fukumoto et al., 2014; Stachowicz et al., 2011), AMPA receptor stimulation (Iijima et al., 2007), or modulating GABAergic transmission (Stachowicz et al., 2011). Collectively, these studies indicate that both mGlu_2/3 receptor agonists and antagonists may have potential roles in the treatment of different types of anxiety disorders and may provide an additional benefit as anxiety symptoms are often observed in depressed individuals.

Potential utility of mGlu_2/3 receptor ligands as adjunctive drugs for the treatment of depressive disorders

Increased expression of mGlu_2/3 receptors in the hippocampus and NAc has been observed after chronic treatment with tricyclic antidepressant imipramine (Matrisciano et al., 2007), which was reasoned to be responsible for neuroadaptation (downregulation of β-adrenergic receptors) following chronic antidepressant treatment. Interestingly, co-treatment of imipramine with a low dosage of either mGlu_2/3 receptor agonist, LY379268, or antagonist, LY341495 reduced that latency time of the β-adrenergic receptors downregulation. Further, administration of LY279268 with antidepressant chlorimipramine for three days decreased increased immobility time in Flinders-sensitive line rats (Matrisciano et al., 2007), which show spontaneous depressive behavior (Overstreet, 1993). These studies raise the possibility that a low dosage of mGlu_2/3 receptor ligands could be used as adjunctive drugs to decrease the latency of monoamine antidepressant drugs. Moreover, a combination of sub-effective dosage of mGlu_2/3 receptor antagonist, LY341495 and ketamine has been shown to induce antidepressant effects via activation of the AMPA, mTOR and BDNF/TrkB pathway and lacked ketamine-induced motor deficits and hyperactivity (Palucha-Poniewiera et al., 2019; Podkowa et al., 2016). This indicates that a combination therapy comprising mGlu_2/3 receptor antagonist and ketamine may be able to reduce the effective dosage of ketamine and thereby the ketamine-associated side-effects in patients.

Based on the extensive preclinical literature, a selective mGlu_2/3 receptor NAM, decoglurant was launched into the clinical trials as an adjunctive treatment to SSRIs and/or serotonin-norepinephrine reuptake inhibitors (SNRIs) in patients with partially refractory MDD. In a phase II trial consisting of 6-week drug treatment, decoglurant was well tolerated overall. However, no significant difference was observed between any active drug treatment and placebo on both primary outcomes (reducing Montgomery-Asberg Depression Rating Scale score) and secondary outcomes (improvement in performance in cognitive tests) of depression (Umbricht et al., 2020). Further, an unusually high placebo response was observed and the patients selected lacked clinically relevant cognitive impairments, which collectively may have suppressed the ability to detect antidepressant and precognitive effects of the decoglurant, respectively. Therefore, careful selection of MDD patients depending upon the duration of previous drug exposure, and presence of additional symptoms like anxiety behavior and cognitive impairments, may help to address these issues in future clinical trials with mGlu_2/3 receptor NAMs. Further, there is evidence that activation of the mGlu₂ receptor may produce neurotoxic effects, while activation of mGlu₃ receptors is neuroprotective and may induce pro-cognitive effects (Caraci et al., 2011; Corti et al., 2007; Dogra et al., 2021). So, it is plausible that mGlu₂ receptor activation could have masked the pro-cognitive effects of decoglurant. Therefore, testing receptor subtype-selective compounds in a battery of tests for depression and cognition will provide unprecedented opportunities to completely understand specific signaling pathways and potentially design safer and efficacious drugs.

Genetic deletion of mGlu₂ receptor has antidepressant-like effects

Initial studies with mGlu_2/3 receptors antagonist, LY341495 using whole body receptor-selective knock out (KO) mice revealed that LY341495 lost its antidepressant-like effects in mice lacking mGlu₂ receptor (Gleason et al., 2013). The antidepressant-like effects of LY341495 were retained in mice lacking mGlu₃ receptor (Gleason et al., 2013) suggesting that the mGlu₂ receptor, not the mGlu₃ receptor, plays role in the antidepressant-like properties of mGlu_2/3 receptor antagonists. Moreover, knockout mice lacking the mGlu₂ receptor exhibited reduced immobility in FST, showed resilience to developing anhedonia induced by chronic social defeat stress, and increased escape failure induced by inescapable shock or corticosterone treatment (Highland et al., 2019; Morishima et al., 2005). All these studies indicate that Grm2 (gene encoding the mGlu₂ receptor) KO mice are resilient to the induction of depressive-like behavior and that mGlu₂ receptor signaling is important for the antidepressant-like actions of mGlu_2/3 receptor antagonists. On the contrary, studies using Grm3 (gene encoding the mGlu₃ receptor) KOs have shown mixed findings to passive coping behaviors (Highland et al., 2019; Morishima et al., 2005). Although these studies have provided important insight into the regulation of depressive behaviors, the results observed in the receptor-specific global KOs may be biased by the compensatory upregulation of the other receptor subtype (Lyon et al., 2008), which may compensate for or modify the effects of gene deletion. Further, these global KOs have upregulated NR2A expression and downregulated levels of glutamate transporter expression that specify modified NMDA receptor signaling and response to altered synaptic glutamate levels in these mice (Lyon et al., 2008). These concerns raise the need for receptor-selective compounds to tease apart the role of individual receptor subtypes in mediating antidepressant-like response.

Selective mGlu₂ and mGlu₃ receptor NAMs may be efficacious as rapid antidepressants

With the advent of systemically active NAMs of mGlu₂ and mGlu₃ receptors that lack activity at the other mGlu receptor subtypes (Engers et al., 2017; Engers et al., 2015; Felts et al., 2015), several exciting discoveries advance our understanding of how mGlu₂ and mGlu₃ receptors regulate transmission in different brain areas and associated behaviors (Joffe et al., 2019; Joffe et al., 2020; Walker et al., 2015). For example, antidepressant-like and anxiolytic-like effects of a selective mGlu₃ receptor NAM have been observed in the FST and marble-burying test, respectively (Engers et al., 2015). Excitingly, selective mGlu₃ receptor NAM exerts antidepressant effects comparable to ketamine in acute depression models like TST, while a selective mGlu₂ receptor NAM fails to show a significant effect in the same test (Engers et al., 2017). Recently, both mGlu₂ and mGlu₃ receptor NAMs have been shown to reverse passive coping behavior in the FST (Joffe et al., 2020). Further, a single treatment with either mGlu₂ receptor or mGlu₃ receptor NAM reverses anhedonia induced by chronic corticosterone treatment or exposure to chronic variable stress suggesting rapid antidepressant-like actions of both mGlu₂ and mGlu₃ receptor NAMs in chronic stress models. Notably, the authors revealed that systemic treatment with an mGlu₂ or mGlu₃ receptor NAM activates unique PFC pyramidal cell ensembles, enhances thalamocortical transmission, and inhibits long-term depression by distinct mechanisms (Joffe et al., 2020). This exciting study revealed that both mGlu₂ and mGlu₃ receptors may be responsible for rapid antidepressant effects of mGlu_2/3 receptor NAMs, although the extent of the contributions of each receptor in mediating the effects remains to be elucidated. Further, mGlu₃ receptor NAM is efficacious in preventing motivational deficits and changes in the amygdalo-cortical plasticity induced by acute stress (Joffe et al., 2019) which further strengthens the utility of mGlu₃ receptor NAM for treating stress-related psychiatric disorders where motivational deficits are often observed. Taken together, these findings indicate that developing selective tools to modulate mGlu₂ and mGlu₃ receptors will provide novel approaches to address depressive symptomology in stress-related psychiatric disorders and is critical to know their precise mechanism of action to mitigate off-target effects.

Targeting group III (mGlu₄, mGlu₆, mGlu₇ and mGlu₈) mGlu receptors for stress-related disorders

Group III mGlu receptors (mGlu₄, mGlu₆, mGlu₇ and mGlu₈) function as presynaptic auto-receptors. Similar to group II mGlu receptors, these receptors couple with Gi/o family of G-proteins and their activation leads to the inhibition of adenylyl cyclase activity and decrease in cAMP production. The role of group III mGlu receptors in depression and the antidepressant potential of agents acting on group III mGlu receptors have received lesser attention than other mGlu receptors, likely because of the limited access to receptor-selective and brain penetrant ligands. Nevertheless, these mGlu receptors have been shown to play roles in regulating glutamatergic and GABAergic transmission in CNS (Acuna-Goycolea et al., 2004; Gosnell et al., 2011; Summa et al., 2013) and are considered as potential therapeutic targets for treating depression and anxiety disorders (Table 3). Central administration of Group III mGlu receptor agonist, ACPT-I at higher dosage decreased the immobility time in FST but did not affect locomotor activity (Palucha et al., 2004). Further, local and/or systemic administration of ACPT-I, PHCCC and AMN082 has been shown to induce anxiolytic-like effects (Palucha et al., 2004; Stachowicz et al., 2006, 2007; Stachowicz et al., 2009; Tatarczynska et al., 2001) suggesting anti-anxiety effects of group III agonists. Co-administration of a non-effective dosage of ACPT-1 with mGlu₄ receptor selective PAM, PHCCC has been shown to induce antidepressant-like effects (Klak et al., 2007), which indicated mGlu₄ receptor as a target in the future treatment of the stress-related disorder. Follow up study have demonstrated that microinfusion of mGlu₄ receptor PAM, PHCCC into the basolateral amygdala induces anxiolytic-like effects in the conflict-drinking test (Stachowicz et al., 2004) and have suggested mGlu₄ receptor PAMs as an alternative therapeutics for treating anxiety-related disorders.

Table 3.

Summary of the preclinical effects of Group III mGlu receptor ligands

Compound	Effects in the experimental Model	References
Group III mGlu receptor agonist
ACPT-I	Increased the number of shocks accepted during the experimental session in the conflict drinking test; decreased the immobility time in FST	Palucha et al., 2004; Tatarczynska et al., 2001
	Anxiolytic effects in stress-induced hyperthermia (SIH), EPM in mice and in the Vogel test in rats	Stachowicz et al., 2009
mGlu 4 receptor PAM
PHCCC	Induced anxiolytic-like effects in Vogel conflict drinking test	Stachowicz et al., 2004, 2006, 2007
mGlu 4 receptor agonist
LSP4–2022	Increased immobility in TST and FST (pro-depressive like effects)	Podkowa et al., 2015
mGlu 7 receptor NAMs
ADX71743	Reducing the number of buried marbles and increased open arm exploration in C57Bl6/J mice	Kalinichev et al., 2013
MMPIP	Increased open-arm choices, reduced immobility time in the TST, and decreased the number of marbles buried and digging events in the marble-burying test in neuropathic pain model	Palazzo et al., 2015
	Decreased social interaction and no effect on SIH or TST in mice	Hikichi et al., 2010
XAP044	Reduced immobility time in the TST, and decreased the number of marbles buried and digging events in the marble-burying test in neuropathic pain model	Palazzo et al., 2015
mGlu 7 receptor allosteric agonist
AMN082	Decreased immobility time of WT animals in the FST	Palucha et al., 2007; Palucha-Poniewiera and Pilc, 2013
	Anxiolytic-like effects in SIH and four-plate tests in Swiss mice	Stachowicz et al., 2008
mGlu 8 receptor agonists
(S)-3,4-DCPG	Increased the time spent in open arms in elevated zero maze in WT mice	Duvoisin et al., 2010;
RS-PPG	Decreased immobility time in the FST	Palucha et al., 2004
mGlu 8 receptor-selective PAM
AZ12216052	Increased the time spent in open arms in elevated zero maze in WT mice	Duvoisin et al., 2010;

Blockade of mGlu₄ receptor signaling may induce antidepressant effects

In contrast to the above-mentioned studies, mGlu₄ receptor agonist, LSP4-2022 has been shown to induce pro-depressive like effects in the tests of behavior despair (FST and TST), and these effects were absent in Grm4 (gene encoding the mGlu₄ receptor) KO mice (Podkowa et al., 2015), suggesting pro-depressive-like effects of mGlu₄ receptor stimulation. These studies are fortified by clinical observations of increased levels of GRM4 expression in the prefrontal cortex of depressed subjects (Lopez et al., 2014). Interestingly, mechanistic studies using human neural progenitor cells (NPCs) have observed a reduction in the expression GRM4 at both mRNA and the protein level following chronic treatment with either imipramine or citalopram (Lopez et al., 2014), which indicate that targeting mGlu₄ receptor could be therapeutically beneficial for treating depressive disorders. Consistent with these clinical studies, the levels of Grm4 were upregulated in the PFC of rats exposed to chronic unpredictable mild stress (CUMS) and were normalized 24 hours after ketamine treatment (Wan et al., 2018). Further, ketamine treatment increased the expression of miR-29b-3p microRNA (miRNA), which is known to act on Grm4. Excitingly, viral-mediated overexpression of miR-29b-3p led to significant recovery of depressive symptoms and lower Grm4 expression in CUS exposed rats (Wan et al., 2018). Similarly, a recent study reported increased levels of Grm4 in the brain stem of rodents exposed chronically to stressors (Dygalo et al., 2020). Collectively these studies indicate the possibility that an increase in mGlu₄ receptor may be related to depressive behavior and blockade of mGlu₄ receptor may induce antidepressant effects.

Potential antidepressant and anxiolytic effects of mGlu₇ receptor ligands

Besides ligands of the mGlu₄ receptor, molecules targeting mGlu₇ receptor have gained attention as potential antidepressants. Preclinical studies using Grm7 (the gene encoding the mGlu₇ receptor) specific KOs demonstrated antidepressant and anxiolytic effects of Grm7 deletion. For example, mice with global deletion of Grm7 displayed significantly less immobility as compared to their littermate controls in FST and TST (Cryan et al., 2003). Further, these mice showed anxiolytic-like activity in the light-dark box test, EPM, the staircase test, and the stress-induced hyperthermia test (Cryan et al., 2003) and marble burying task (Callaerts-Vegh et al., 2006) suggesting the anti-anxiety potential of global Grm7 deletion. Moreover, Grm7 KO mice have elevated levels of brain-derived neurotrophic factor that may partially account for the antidepressant-like phenotype observed in these animals (Mitsukawa et al., 2006). These KO studies are supported by findings by Peterlik et al (Peterlik et al., 2017) that Grm7 deficiency relieved chronic psychosocial stress-induced anxiety-prone phenotype and other physiological and immunological consequences. These KO studies provide a key piece of evidence for the involvement of the mGlu₇ receptor in the regulation of response to chronic stress exposure. The stress-protective phenotype of Grm7 deletion suggests that pharmacological blockade of the mGlu₇ receptor may be a relevant option for the treatment of chronic stress-related dysfunctions. In line with this, systemically active mGlu₇ receptor NAM, ADX71743 has been shown to induce robust anxiolytic-like effects in the marble-burying test and EPM test in C57Bl6/J mice (Kalinichev et al., 2013). Similarly, another mGlu₇ receptor NAM, MMPIP increased open-arm choices, reduced immobility time in the TST, and the number of marbles buried and of digging events in the marble-burying test in neuropathic pain model (Palazzo et al., 2015). XAP044, a mGlu₇ receptor NAM that binds within the Venus flytrap domain (VFTD) close to the glutamate binding site, was also efficacious in reducing affective impairments associated with the neuropathic pain conditions (Palazzo et al., 2015). Further, XAP044 reduced freezing during the acquisition of fear conditioning response, stress-induced hyperthermia, immobility time in TST, and anxiety-related behavior in EPM which is consistent with the spectrum of phenotypes observed in Grm7 KO mice (Peterlik et al., 2017), and Grm7 siRNA knockdown studies (O’Connor et al., 2013).

In addition to the antidepressant- and anxiolytic-like effects of mGlu₇ receptor NAMs and the effects observed in Grm7 KO mice, the mGlu₇ receptor allosteric agonist, AMN082 has also been shown to induce similar behavioral responses in rodents (Palucha et al., 2007; Stachowicz et al., 2008). Further, the antidepressant-like effects of AMN082 were blocked by a selective mGlu₇ receptor antagonist, MMPIP (Palucha-Poniewiera and Pilc, 2013) and were absent in Grm7 KO mice (Palucha et al., 2007), which suggest that the antidepressant-like effects of AMN082 are mediated by mGlu₇ receptor. To note, the tested dose of MMPIP (10mg/kg) did not induce an antidepressant-like effect in the FST in rats (Palucha-Poniewiera and Pilc, 2013) or TST in mice (Hikichi et al., 2010). Collectively, these studies suggest the role of mGlu₇ receptor in a range of behaviors in rodent models that are relevant for affective disorders but raise a question if the stimulation or blockade of mGlu₇ receptors is responsible for the antidepressant-like efficacy. Therefore, better pharmacological tools are needed to advance our understanding of mGlu₇ receptor function in CNS.

Potential utility of enhancing mGlu₈ receptor signaling for anxiolytic effects:

Characterization of Grm8 (gene encoding the mGlu₈ receptor) KO animals has provided some evidence of a role for the mGlu₈ receptor in anxiety-related pathways. Linden et al. (2002) showed that Grm8-deficient mice displayed increased anxiety-related behavior in the EPM test performed in low illumination conditions. Further, these mice showed increased open arm avoidance without any effect on the total number of arm entries (Linden et al., 2002). Notably, the behavioral differences between the Grm8 KOs and the control mice were abolished following stressful conditions like testing under fluorescent light or after exposure to restraint stress. Furthermore, the effects of these stressors on Grm8 deficient animals were not additive in measurements of anxiety-like response in the EPM leading to similar values in stress-exposed WT controls and Grm8 KOs (Linden et al., 2002), indicating that mGlu₈ receptor may regulate response to a stressful environment. Similar increased anxiety-like behavior was also observed in the open field test (Duvoisin et al., 2005). This is in contrast to the phenotypes observed in Grm7 KO mice, which show anxiolytic-like effects in various tests of anxiety (Cryan et al., 2003). Since both mGlu₇ and mGlu₈ receptors are presynaptic receptors, the opposite results of receptor deletion on anxiety-like behaviors point to a fundamental difference in their location and physiological functions. In addition, Grm8 KO mice displayed contextual fear deficits, while showed normal freezing response during presentations of the CS suggesting no deficits in learning or expression of fear response in these mice (Fendt et al., 2010). These KO studies are supplemented by the pharmacological studies showing anxiolytic-like effects of mGlu₈ receptor-selective agonist, (S)-3, 4-DCPG and the mGlu₈ receptor-selective PAM, AZ12216052 in the open field test and EPM test (Duvoisin et al., 2010). In another study, central administration of mGlu₈ receptor-preferring agonist, RS-PPG has been shown to induce dose-dependent antidepressant-like effects in the FST (Palucha et al., 2004). Taken together, the above-mentioned literature indicates the utility of targeting mGlu₈ receptor signaling for treating anxiety disorders involving exaggerated contextual fear and psychiatric conditions with comorbid anxiety. Taken together, remarkable progress has been made in our understanding of group III mGlu receptors’ physiology and roles in stress and anxiety-related behavior, which highlights the therapeutic potential of ligands targeting group III mGlu receptors for treating stress-related disorders.

Concluding Remarks:

Encouraging evidence from both preclinical and clinical research suggested an association of the abnormalities in glutamatergic neurotransmission with stress-related disorders. This hypothesis has been corroborated by the clinical observations that agents (ketamine, CP-101606, and riluzole) acting on the glutamatergic system show efficacy for treating patients with MDD. Significantly, ketamine is highly efficacious for TRD but induces undesirable side-effects. The mGlu receptors are promising alternative candidates because they exert a modulatory role on excitatory transmission and their regulation may be free of side effects observed with iGlu receptor-based drugs. This hypothesis led investigators to test the mGlu receptors as potential antidepressants and anxiolytics, which can induce their beneficial effects via directly modulating glutamatergic signaling and/or indirectly modulating NMDA receptors. In line with this, clinical trials with a mGlu₅ receptor-selective NAM, basimglurant at higher dosage showed significant improvements in secondary outcomes of depression (Quiroz et al., 2016). Further, a biased mGlu₅ receptor NAM may be useful as a safer antidepressant without any psychotomimetic effects (Gould et al., 2016). Therefore, this class of compounds needs to be tested in a variety of preclinical studies to know the safety and efficacy profiles before testing them in the clinical setup.

An emerging literature has indicated the therapeutic potential of mGlu_2/3 receptor antagonists as effective treatment agents for depressive disorders. Exciting recent studies have revealed that mGlu_2/3 receptor antagonists/NAMs were efficacious in treatment resistance depression-like conditions and induced fast and sustained antidepressant effects similar to ketamine. To note, these ligands lack any adverse effects generally observed with ketamine, indicating that they may act as novel therapeutics to meet the clinical need in depressive disorders. Since anxiety is often comorbid with depression and affects disease severity, the anxiolytic effects of mGlu_2/3 receptor agonists/antagonists are considered as an additional benefit for the treatment of depression. However, one of mGlu_2/3 receptor NAM, decoglurant, failed to show efficacy in patients with partial treatment resistance depression (Umbricht et al., 2020). This does not rule out the potential of mGlu_2/3 receptor inhibitors as antidepressants and indicates the need for further human proof-of-concept studies with appropriate study design to clarify the potential of mGlu_2/3 receptor antagonists for clinical use in patients with MDD. Recently, selective mGlu₂ and mGlu₃ receptor NAMs has been shown to induce rapid antidepressant-like effects in chronic stress models of depression (Joffe et al., 2020). These receptor-selective NAMs may help to avoid the undesirable effects induced by the other receptor subtype and help to design safer and efficacious therapeutics for depressive disorders.

Besides mGlu₅ and mGlu_2/3 receptors, the mGlu₇ receptor is also a promising target for treating chronic psychosocial stress disorders. Several preclinical studies have shown robust anxiolytic- and antidepressant-like effects of mGlu₇ receptor NAMs. This emerging evidence suggests the need to further investigate the potential effects of mGlu₇ receptor modulation in the context of chronic stress. For other group III mGlu receptors, it will be important to clarify whether receptor stimulation or inhibition is required for antidepressant-like effects and whether they can induce robust antidepressant effects similar to that of ketamine. Collectively, extensive research and discovery of receptor-selective compounds have uncovered new mechanisms of action of mGlu receptors, which may allow for the development of novel therapeutic strategies for mood disorders. These tools hold a great promise to provide unparalleled insights into the underlying mechanism of psychiatric disorders.

Highlights:

1. Ketamine shows efficacy for treating patients with treatment-resistant depression, but adverse effects associated with ketamine administration limit its clinical utility.

2. Partial mGlu₅ receptor negative allosteric modulators (NAMs) induce antidepressant-like effects without inducing psychotomimetic-like effects in rodents.

3. NAMs of mGlu₂ and mGlu₃ receptors induce robust and rapid antidepressant-like effects in preclinical models of depression.

4. The mGlu₁ NAMs, mGlu_2/3 receptor ligands, and group III antagonists all have potential anxiolytic effects in rodents.

5. Further preclinical studies are needed to establish the safety and efficacy of mGlu receptor modulation in depression.