3 and mGlu5 receptors: Potential targets for novel antidepressants

Neuropharmacology 66 (2013) 40e52

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Invited review

mGlu2/3 and mGlu5 receptors: Potential targets for novel antidepressants Shigeyuki Chaki a, *, Yukio Ago b, Agnieszka Palucha-Paniewiera c, Francesco Matrisciano d, e, Andrzej Pilc c, f a

Discovery Pharmacology, Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama, Saitama 331-9530, Japan Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1e6 Yamada-oka, Suita, Osaka 565-0871, Japan c Institute of Pharmacology, Polish Academy of Sciences, Sme˛ tna 12, 31-343 Krakow, Poland d The Psychiatric Institute, Department of Psychiatry, College of Medicine, The University of Illinois at Chicago, Chicago, IL 60612, USA e Department of Physiology and Pharmacology, University of Rome ‘Sapienza’, Piazzale Aldo Moro 5, 00185 Rome, Italy f Collegium Medicum, Jagiellonian University, Krakow, Poland b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 4 February 2012 Received in revised form 27 April 2012 Accepted 15 May 2012

Major depressive disorder is among the most prevalent forms of mental illness. All currently available antidepressant medications have stemmed from study of the mechanisms of serendipitously discovered drugs, and only 30e50% of patients exhibit remission and frequently at least 3e4 weeks are required for manifestation of significant therapeutic effects. To overcome these drawbacks, discovering novel neuronal mechanisms of pathophysiology of depression as well as more effective treatments are necessary. This review focuses on the metabotropic glutamate (mGlu) receptors and their potential for drug targets for the treatment of depression. In particular, accumulating evidence has indicated the potential importance and usefulness of agents acting on mGlu2/3 and mGlu5 receptors. Preclinical and clinical evidence of mGlu2/3 receptor ligands and mGlu5 receptor antagonists are described. Moreover, their potential in clinic will be discussed in the context of neuronal mechanisms of ketamine, an agent recently demonstrated a robust effect for patients with treatment-resistant depression. This article is part of a Special Issue entitled ‘Metabotropic Glutamate Receptors’. Ó 2012 Elsevier Ltd. All rights reserved.

Keywords: mGlu2/3 receptor mGlu5 receptor Depression Ketamine

1. Introduction The economic burden of mood disorders is immense, amounting to 100 billion USD in the US and 105 billion Euros in the EU (Greenberg et al., 2003; Andlin-Sobocki et al., 2005), making the mood disorders the most costly group out of all central nervous system (CNS) diseases. Depression represents also a social problem, with the lifetime prevalence rates of depression amounts to 16% in the USA (Kessler et al., 2003) and over 30 million people affected each year in the EU (Wittchen et al., 2011). With the advent of monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs) in the 1950s (Kuhn, 1958; Loomer et al., 1957), depression treatment was revolutionized, but remains virtually unchanged since then. Currently used drugs are barely adequate for depressive patients, particularly those diagnosed as treatmentresistant depression (TRD). The antidepressant drugs (ADs) are characterized by a slow onset of action (in double blind, placebo controlled trials, frequently at least 3e4 weeks of treatment are

* Corresponding author. Tel.: þ81 48 669 3089; fax: þ81 48 652 7254. E-mail address: [email protected] (S. Chaki). 0028-3908/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropharm.2012.05.022

required to see mood improvement), poor efficacy (about 30e50% of patients respond to the initial regimen), and approximately 30% of patients are resistant to a series of treatments (Fekadu et al., 2009; Rosenzweig-Lipson et al., 2007; Rush et al., 2006; Trivedi et al., 2006). A wide range of adverse effects of ADs create also problems for depressed patients. Importantly, meta- analyses suggest that antidepressants are only marginally efficacious compared to placebos, especially at moderate levels of initial depression (Kirsch et al., 2008; Pigott et al., 2010). Needless to say, more effective drugs are needed. Our knowledge of the pathophysiology of depression is far from being complete, in spite of the over 50 years of intensive research, which for years focused almost exclusively on monoamines (Lapin and Oxenkrug, 1969; Schildkraut, 1965), for review see: Maj et al. (1984). Therefore, there is a strong need to search beyond monoaminergic systems to understand better the pathophysiology of depression on one hand and to find better drugs on the other. While numerous attempts to identify new targets for antidepressants failed at the clinical level, the glutamatergic system emerges as a particularly important target to develop new antidepressants and to understand the mechanisms of their antidepressant effects (Hashimoto, 2011; Leheste et al., 2008; Sanacora et al., 2012; Skolnick et al., 2009).

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The antidepressant-like efficacy of ionotropic (NMDA) glutamate receptor antagonist was first demonstrated by Trullas and Skolnick (1990). Subsequently, functional changes in NMDA receptor complex following chronic antidepressant treatments were demonstrated (for review see (Skolnick et al., 2001, 2009)). After the demonstration that NMDA receptor antagonists had antidepressant-like actions in preclinical tests, an increasing number of clinical studies indicates that modulation of glutamatergic system might be a novel way to achieve rapid and sustained antidepressant effects in depression sufferers, including those diagnosed as TRD. The most promising data come from a series of studies on the antidepressant activity of an uncompetitive NMDA receptor antagonist, ketamine, which has a long history in analgesia and anesthesiology. The initial study by Berman et al. (2000) reported a significant efficiency of intravenously administered ketamine (0.5 mg/kg, 40 min) in a group of seven patients, who fulfilled DSM-IV criteria for major depression. The effect was strong [50% or greater decreases in Hamilton Depression Rating Scale (HDRS)]. A subsequent, randomized, placebo-controlled, double-blind crossover clinical study by Zarate et al. (2006) confirmed the robust and rapid antidepressant effects of ketamine (0.5 mg/kg) in the TRD patients. Considerable improvement was observed 2 h after ketamine infusion and continued to remain significant for 1 week. The antidepressant efficacy of ketamine was then reported in ECT-resistant major depressive disorder (MDD) (Ibrahim et al., 2011) and in treatment-resistant bipolar depression (Diazgranados et al., 2010). However, the number of very profound adverse effects precludes the routine use of ketamine (also a drug of abuse, known by such street names as “special K” which induces trance-like or hallucination states) to treat depression in the wider clinical practice. Preskorn et al. (2008) demonstrated promising clinical data on the antidepressant effect of NR2B subunit specific NMDA receptor antagonist CP-101,606 (traxoprodil) in patients with TRD. This placebo controlled, double-blind study clearly showed that patients receiving CP-101,606 had a grater decrease in both the Montgomery-Asberg Depression Rating Scale (MADRS) and HDRS scores than placebo control subjects. Furthermore, it was shown that 78% of CP-101,606- treated patients maintained the response status for one week and 32% for 30 days after the infusion. Interestingly, the mechanism involved in the inhibitory action of CP101,606 on the NMDA receptor differs from that of ketamine. CP101,606 makes the receptor more sensitive to inhibition by protons, acting as endogenous negative modulators of NMDA receptor (Mott et al., 1998). One must be aware that both in the ketamine and traxoprodil studies a functional unblinding may have occurred due to the rapid onset of psychotomimetic effects induced by both drugs. On the other hand, the studies on memantine, which is a low-affinity, uncompetitive, open-channel NMDA receptor blocker, showed equivocal results. Although in animal models of depression memantine was found to exhibit antidepressant-like activity (Moryl et al., 1993; Rogoz et al., 2002), the clinical study by Zarate et al. (2006) showed no antidepressant effect in the patients with MDD. More promising results came from the study by Muhonen et al. (2008) who showed antidepressant effects in the patients with MDD and co-morbid alcohol dependence, however, lack of placebo group in this study, is a critical limitation of the value of the results. Metabotropic glutamate (mGlu) receptors are a natural alternative to influence the glutamatergic system. These receptors are responsible for the modulation, but not for fast neuronal transmission (Nakanishi, 1992). The discovery of selective ligands of these receptors created new possibilities in the therapy of a variety of CNS diseases, including psychiatric disorders (Niswender and Conn, 2010; Wieronska and Pilc, 2009). At present, 8 subtypes of

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mGlu receptors have been identified, named from 1 to 8 (Pin et al., 1999; Pin and Duvoisin, 1995). mGlu receptors are currently divided into three different groups according to the DNA sequence homology, pharmacology profile and intracellular signal transduction pathways. Group I includes mGlu1 and mGlu5 subtypes, group II includes mGlu2 and mGlu3 receptors, and the group III includes mGlu4, mGlu6, mGlu7 and mGlu8 receptors (Conn and Pin, 1997; Pin and Duvoisin, 1995). A considerable number of papers have been published on mGlu receptors and depression/ antidepressant activity (Hashimoto, 2011; Krystal et al., 2010; Palucha and Pilc, 2007; Pilc et al., 2008; Swanson et al., 2005; Wieronska and Pilc, 2009). In this review, we focus on mGlu5 and mGlu2/3 receptors because most of the available data concern these receptor types. With regard to mGlu2/3 receptor, because paradoxical results that both mGlu2/3 receptor agonists and antagonists show antidepressant effects have been reported, we discussed potential of mGlu2/3 receptor agonists and antagonists separately in this review and addressed the reason of this discrepancy in Summary and conclusions. 2. mGlu2/3 receptor agonists/mGlu2 receptor potentiators 2.1. Preclinical evidence Recent evidence showed that both selective mGlu2/3 receptor agonists and antagonists exhibit antidepressant-like activity in animal screening procedures that provide promising paths for the discovery of new and improved medications (Palucha and Pilc, 2007; Pilc et al., 2008). Among most mGlu receptor ligands, mGlu2 and mGlu3 receptor agonists seem to be the drugs with the promising therapeutic potential and a good safety profile. mGlu2 and mGlu3 receptors have been shown to be altered in animal model of depression and in postmortem brain of depressed patients  ska et al., (Feyissa et al., 2010; Matrisciano et al., 2008a; Wieron 2008). The strongest preclinical evidence for the potential antidepressant effects of mGlu2/3 receptor agonists was the suppression of rapid eye movement (REM) sleep induced by ()-2-oxa-4aminobicyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY379268) (Feinberg et al., 2002), an effect similar to most ADs. More recently, it has been shown that systemic injection of low doses of the mGlu2/3 receptors agonist LY379268 shortens the temporal latency of classical ADs in reducing the expression of b1-adrenergic receptors in the hippocampus (a classical biochemical marker of antidepressant-induced neuroadaptation) and reducing the immobility time in the forced swim test (FST) in spontaneously depressed rats (Matrisciano et al., 2005, 2007). Measuring the down-regulation of b-adrenergic receptors in the hippocampus as an indicator of the neuroadaptation to antidepressant medication, the same research group found that both the mGlu2/3 receptor agonist, LY379268, and the preferential mGlu2/3 receptor antagonist, 2S-2-amino-2-(1S,2S-2-carboxycycloprop-1-yl)-3-(xanth-9yl)propanoic acid (LY341495), shortens the latency for the antidepressant action of imipramine in rats (Matrisciano et al., 2005). In particular, these researchers provided the evidence that chronic (but not acute) treatment with the TCA, imipramine, enhanced the expression of mGlu2/3 receptors in different brain regions without changing the expression of mGlu5 receptors (Matrisciano et al., 2002). Recently, a synergism between the antidepressant fluoxetine and LY379268 has been reported in cultured cerebellar neuroprogenitor cells, in which the two drugs amplified each other in enhancing cell proliferation and neuronal differentiation (Matrisciano et al., 2008b). mGlu2/3 receptors negatively modulate the hypothalamicepituitaryeadrenal axis (Scaccianoce et al., 2003), which is known to be up-regulated in MDD and other stress-related disorders (Mason and Pariante, 2006).

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In addition, (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6dicarboxylate monohydrate (LY354740) and biphenyl-indanone A (BINA), in a dose-dependent manner, suppressed REM sleep and prolonged its onset latency (Ahnaou et al., 2009), suggesting a synergistic effect on sleep pattern induced by modulation of mGlu2 receptor. Furthermore, LY354740 modestly enhanced the antidepressant-like activity of 5-hydroxytryptophan, although it did not have an antidepressant effect itself (Marek, 2002). Recently, it has been shown that a structurally novel, potent, and selective allosteric potentiator of human and rat mGlu2 receptors N-(4-((2(trifluoromethyl)-3-hydroxy-4-(isobutyryl)phenoxy)methyl) benzyl)-1-methyl-1H-imidazole-4-carboxamide (THIIC) produced robust activity in three assays that detect antidepressant-like activity, including the mouse FST, the rat differential reinforcement of low rate 72-s (DRL-72) assay, and the rat dominantsubmissive test. Importantly, the maximal response elicited by THIIC was similar to that observed with imipramine (Fell et al., 2011), suggesting an important role of mGlu2 receptor in the pathophysiology of depression. 2.2. Neuronal and molecular mechanisms mGlu2 and mGlu3 receptors are widely expressed in the CNS, particularly in regions of relevance for MDD, such as hippocampus, prefrontal cortex, amygdala, (Drevets, 2000). mGlu2/3 receptors are mainly localized presynaptically, where they modulate neurotransmitter release at a number of synapses (Anwyl, 1999; Cartmell and Schoepp, 2000) and have been presented as a suitable therapeutic target for AD development (Sanacora et al., 2008; Witkin et al., 2007). The pharmacology of mGlu2/3 receptors is complex, and includes orthosteric agonists (DCG-IV, 2R,4R-APDC, 1S,3R-ACPD, LY354740, LY379268), antagonists (LY341495, (1R,2R,3R,5R,6R)-2-Amino-3-(3,4-dichlorobenzyloxy)6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (MGS0039)), or allosteric modulators (BINA, N-(4-(2-Methoxyphenoxy)-phenyl-N(2,2,2-trifluoroethylsulfonyl)-pyrid-3-ylmethylamine (LY487379))) (reviewed by Nicoletti et al., 2011).

mGlu2 receptors are uniquely localized in neurons and particularly in the preterminal region of axons, far from the active zone of neurotransmitter release (Tamaru et al., 2001), but can be activated by an excess of synaptic glutamate (Fig. 1(1)). The normalization of excessive glutamatergic neurotransmission through the activation of mGlu2 receptors may have therapeutic potential in a variety of psychiatric disorders, including anxiety/depression, as demonstrated by the selective allosteric potentiator of human and rat mGlu2 receptors THIIC (Fell et al., 2011; Johnson et al., 2005). Unlike orthosteric agonists, allosteric modulators do not activate the receptor directly but act at an allosteric site to selectively potentiate the response of mGlu2 receptors to glutamate (Fell et al., 2011). Using electrophysiological techniques, it has been shown that allosteric modulators have little or no effects on glutamate release under “normal conditions” but act to potentiate a negative feedback control under conditions of excessive glutamate release (Johnson et al., 2005). 2.3. Clinical applications The unique pharmacology of mGlu2 and mGlu3 receptors, their localization in key forebrain and limbic areas such as the prefrontal cortex, thalamus, striatum, hippocampus, and amygdala (Wright et al., 2001, 2013), and the promise of fine modulation of glutamatergic neurotransmission make these receptors intriguing targets for the development of improved medication for depressive disorder treatment. To date, only one structural class of selective agonists for mGlu2/3 receptors has been discovered and is undergoing translational research. In preclinical studies, mGlu2/3 receptor agonists LY379268, LY354740, and ()-(1R,4S,5S,6S)-4amino-2-sulfonylbicyclo[3.1.0.]hexane-4,6-dicarboxylic acid (LY404039) have behavioral and neurochemical effects in models predictive of antistress/anxiolytic and antipsychotic efficacy (Schoepp and Marek, 2002; Swanson et al., 2005). In addition, the ability shown by the allosteric modulators to recognize ‘pathological state’ or networks could result in therapeutic advantages in terms of safety and efficacy. Given the selectivity of mGlu2

Presynaptic mGlu2/3receptor mGlu2/3 receptor antagonists mGlu2 potentiators

Glutamate (1)

Glutamate

BDNF

(2) Trk Breceptor AMPA receptor mTOR

(3)

Synaptic proteins

Postsynaptic Fig. 1. Schematic representation of the mechanism of antidepressant-like action mediated by mGlu2/3 receptor antagonists or mGlu2 receptor potentiators.

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potentiators for mGlu2 over mGlu3 receptors, such potentiators are also interesting in order to differentiate the biological substrates driven by physiological or pathological conditions. In addition, it is noteworthy that mGlu2/3 receptor agonists produce antidepressant effects particularly when combined with classical antidepressants by shortening the clinical latency (Matrisciano et al., 2005, 2007; 2008a). This therapeutic lag seriously complicates the management of severely depressed patients, who are at high risk for suicide during the early phases of treatment. Paradoxically, suicide attempts may even increase during the first days of antidepressant medication because of the shorter latency of druginduced psychomotor activation. Fast-acting drugs or adjunctive drugs that shorten the clinical latency of classical antidepressants will provide a major breakthrough in the treatment of depression. The implications of these findings are that mGlu2/3 receptors represent attractive targets for the discovery of novel antidepressant medication with rapid onset activity. Taken together, these data raise the attractive possibility that mGlu2/3 receptor agonists may be used as adjunctive drugs to shorten the latency of antidepressant medication, provided that these drugs also exhibit a good profile of safety and tolerability as predicted from animal studies. 3. mGlu2/3 receptor antagonists 3.1. Preclinical evidence Antidepressant-like effects of the orthosteric mGlu2/3 receptor antagonists, MGS0039 and LY341495, were first found in the rat FST and mouse tail-suspension test (TST) using normal animals (Chaki et al., 2004). More recently, studies have attempted to evaluate the effects of these drugs in paradigms implicated in the etiology of human depression. MGS0039 exhibited antidepressant effects in the learned helplessness test where treatment with MGS0039 for 7 days significantly reduced the number of escape failures (Yoshimizu et al., 2006). Pa1ucha-Poniewiera et al. (2010) evaluate a potential antidepressant-like effect of MGS0039 in the olfactory bulbectomy (OB) model of depression in rats. A surgical lesion of the olfactory bulbs in animals induces significant behavioral, physiological, endocrine and immune changes, many of which were qualitatively similar to those observed in depressive patients (Kelly et al., 1997). Repeated administration of MGS0039 for 14 days attenuated the hyperactivity of olfactory bulbectomized rats in the open field test and attenuated the learning deficit in the passive avoidance test. Moreover, Kawasaki et al. (2011) have also examined the effect of MGS0039 on behaviors of social isolation-reared mice in the FST. Rearing rodents in isolation after weaning leads to changes in brain neurochemistry that produce perturbations in behavior (Fone and Porkess, 2008). Post-weaning chronic social isolation for more than 6 weeks increased immobility in the FST, suggesting that isolation rearing caused depression-like behavior. MGS0039 reversed the increased immobility of social isolationreared mice in the test. Recently, a selective mGlu2/3 receptor negative allosteric modulator (NAM) (4-[3-(2,6-Dimethylpyridin-4-yl)phenyl]-7methyl-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-one (RO4491533)) has been developed (Campo et al., 2011). RO4491533, like LY341495, exhibited dose-dependent reductions in the immobility time of mice in the FST at doses which antagonized an mGlu2/3 receptor agonist-induced hypolocomotion. In addition, both RO4491533 and LY341495 were active in the TST in a line of Helpless (H) mice, a putative genetic model of depression. Moreover, mGlu2 receptor knockout mice displayed antidepressant-like phenotype in the FST (Morishima et al., 2005), supporting the data obtained from experiments with the use of mGlu2/3 receptor antagonists. For reference, as described in 2.1, the

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apparently paradoxical observation that an mGlu2 receptor potentiator THIIC exhibits antidepressant-like effects in animal models of depression has been reported. 3.2. Neuronal and molecular mechanism 3.2.1. Mechanisms of action 3.2.1.1. AMPA receptor. mGlu2 receptors are largely present on the presynaptic membrane, where glutamatergic neurotransmission is modulated by regulating transmitter release and sensing glutamate spillover. Thus, mGlu2/3 receptor antagonists may increase the synaptic levels of glutamate which potentiates postsynaptic neural activities via AMPA receptors (Fig. 1(1,2)). The antidepressant effect of MGS0039 was blocked by pretreatment with 2,3-dihydroxy-6nitro-7-sulfamoylbenzo(f)-quinoxaline (NBQX), an AMPA receptor antagonist in the TST (Karasawa et al., 2005; Pa1ucha-Poniewiera et al., 2010), suggesting the involvement of AMPA receptor activation. In view of the fact that the antidepressant effects of ketamine are blocked by NBQX (Maeng et al., 2008; Koike et al., 2011a), the activation of the AMPA receptor may be a common pathway for the antidepressant effects of these compounds. Of note, AMPA receptor potentiators have been reported to exhibit antidepressant effects in animal models of depression (Alt et al., 2006). Moreover, although an AMPA receptor potentiator LY451395 did not improve cognition in patients with Alzheimer’s disease, subscale analysis of Neuropsychiatric Inventory score suggested that a number of depressivelike symptoms were improved (Chappell et al., 2007). 3.2.1.2. Monoaminergic system. Intravenous administration of MGS0039 or LY341495 significantly increased the firing rates of serotonergic (5-HTergic) dorsal raphe neurons of rats (Kawashima et al., 2005). Linked to this effect, MGS0039 increased extracellular serotonin (5-HT) levels in the medial prefrontal cortex. Moreover, the MGS0039-induced increase in prefrontal 5-HT release was attenuated by NBQX (Karasawa et al., 2005), indicating that AMPA receptor activation is responsible for the 5-HT efflux engendered by mGlu2/3 receptor blockade. These findings prompt us to speculate a possible involvement of the 5-HTergic system in the effects of mGlu2/3 receptor antagonists. However, Pa1ucha-Poniewiera et al. (2010) have reported that antidepressant-like action of mGlu2/3 receptor antagonists does not depend on activation of the 5-HTergic system. Pretreatment with p-chlorophenylalanine (PCPA), a 5-HT synthesis inhibitor, blocked the antidepressant activity of citalopram (a selective 5-HT reuptake inhibitor) but not MGS0039 in the TST. In addition, neither WAY100635, a 5-HT1A receptor antagonist, nor ritanserin, a 5HT2A/2C receptor antagonist, affected the antidepressant-like actions of MGS0039 and LY341495 in the TST. The dopaminergic system in the nucleus accumbens shell has been implicated in several physiological processes, such as motivation and reward, and in the etiology of depression (Shirayama and Chaki, 2006). Local injection of MGS0039 or LY341495 into the nucleus accumbens shell increased extracellular dopamine levels in this brain area, while local injection of the mGlu2/3 receptor agonist LY354740 caused a decrease in dopamine levels (Karasawa et al., 2006, 2010). Moreover, the increase in accumbal dopamine release by LY341495 was attenuated by NBQX, indicating that AMPA receptor activation is responsible for the dopamine efflux engendered by mGlu2/3 receptor blockade. Therefore, further studies are required to clarify whether AMPA receptormediated dopamine release is involved in the antidepressant-like action of mGlu2/3 receptor antagonists. 3.2.1.3. mTOR signaling. Recent studies have shown that ketamine activates mammalian target of rapamycin (mTOR) signaling

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through the stimulation of AMPA receptors, and implicating mTOR signaling in the antidepressant effects of ketamine (Li et al., 2010, 2011). The antidepressant effects of MGS0039 and LY341495 were observed both at 30 min and 24 h after the treatment in the TST, and this relatively sustained, but not acute, antidepressant effect of mGlu2/3 receptor antagonists was blocked by pretreatment with rapamycin, an mTOR antagonist (Koike et al., 2011b). The involvement of mTOR signaling in the antidepressant effects of mGlu2/3 receptor antagonists has recently been confirmed by the study in which rapamycin blocked the antidepressant effect of LY341495 in the FST (Dwyer et al., 2011). Moreover, in this report, they showed that LY341495 activates the mTOR pathway and synaptic protein synthesis. These findings suggest that blockade of the mGlu2/3 receptor activates mTOR signaling, presumably by potentiating the AMPA receptor (Fig. 1(3)). Since the activation of mTOR signaling in the prefrontal cortex enhances synaptic formation, the mTORmediated signaling pathways contribute, at least partly, to the antidepressant effects of mGlu2/3 receptor antagonists. 3.2.2. Change in mGlu2/3 receptor expression A recent postmortem study has shown that up-regulation of the expression of mGlu2/3 receptor protein was observed in the prefrontal cortex of patients with MDD, suggesting its etiological contribution via glutamatergic dysfunction (Feyissa et al., 2010). Consistent with the idea that depressive-like states upregulate mGlu2/3 receptors, rearing of mice in social isolation lead to an increase in the binding of the mGlu2/3 receptor antagonist [3H] LY341495 in the prefrontal cortex, cerebral cortical layers IeIII and hippocampus (Kawasaki et al., 2011). A saturation binding study of hippocampal membranes from isolation-reared mice revealed that the Bmax value increased significantly without any changes in the Kd, indicating an increase in mGlu2/3 receptor density. Since MGS0039 reversed the increased immobility of isolation-reared mice in the FST (Kawasaki et al., 2011), the increased mGlu2/3 receptor function may contribute to pathogenic mechanisms for depression-like behavior of isolation-reared mice. On the other hand, animal models of depression such as OB mice and Flinders Sensitive Line rats showed a decrease in mGlu2/3 receptor levels in  ska et al., the hippocampus (Matrisciano et al., 2008a; Wieron 2008). Chronic treatment with amitriptyline, a TCA, reversed the decrease in hippocampal mGlu2/3 receptor levels in olfactory bulbectomized mice, although amitriptyline caused a reduction in  ska et al., mGlu2/3 receptor expression in normal mice (Wieron 2008). Since amitriptyline attenuated the behavioral deficits in the OB model (Pa1ucha-Poniewiera et al., 2010), regulation of mGlu2/3 receptor expression or function in the hippocampus may be involved in the depression-like behavior of this model. 3.3. Clinical applications Currently, clinical studies are being conduced with RG1578 (RO4995819) (an mGlu2/3 receptor negative allosteric modulator) by Roche (see http://www.clinicaltrials.gov/ct2/show/ NCT01457677?term¼ro4995819&rank¼2), and with MGS0039 (also known as BCI-632) and its prodrug by BrainCells (see http:// www.braincellsinc.com/pipeline/bci-632). Both of these drugs appear to be targeted at depression. To date, no human proof-ofconcept data is available with mGlu2/3 receptor antagonists. However, clinical efficacy of mGlu2/3 receptor antagonists could be predicted by investigating similarities in the neural mechanisms between mGlu2/3 receptor antagonists and ketamine. Ketamine, an NMDA receptor antagonist, has been reported to exhibit rapid, prolonged and potent antidepressant effects in patients with TRD, and reduced suicidal ideation in some clinical studies (Murrough, 2012). Due to concerns including psychotomimetic effects, abuse

potential and neurotoxicity, alternatives for ketamine which share the same neuronal circuits for antidepressant effects should be beneficial. Blockade of mGlu2/3 receptor and ketamine may converge to the same neuronal circuits, which include activation of AMPA receptor and mTOR signaling. Because both AMPA receptor stimulation and subsequent mTOR signaling activation are presumed to be involved in rapid action of ketamine for patients with TRD, mGlu2/3 receptor antagonists could exert the same effects in humans. This assumption is underpinned by animal studies. First, an mGlu2/3 receptor antagonist MGS0039 exhibited antidepressant effects in an animal model (the learned helplessness paradigm) which is refractory to currently prescribed antidepressants (Yoshimizu et al., 2006). Second, although evidence of rapid onset of action with mGlu2/3 receptor antagonists are absent, an AMPA receptor potentiator (as described above, AMPA receptor potentiation mediates antidepressant effects of mGlu2/3 receptor antagonists) has been reported to show faster effects (during the first week of treatment) compared to fluoxetine (after two weeks) in a dominant-submissive test (Knapp et al., 2002). Moreover, LY341495 exhibits a potent antidepressant effect in helpless mouse following acute administration, while fluoxetine exerts a full antidepressant effect following chronic (21 days) treatment (Campo et al., 2011; El Yacoubi et al., 2003). Therefore, blockade of mGlu2/3 receptor may show rapid and potent antidepressant effects in humans. In contrast, there still remain liabilities associated with mGlu2/3 receptor antagonists. First, psychotomimetic effects and abuse potential: NMDA receptor antagonists such as ketamine and CP101,606 have been observed to induce initial psychotomimetic effects at the dose which induces antidepressant effects in patients. Likewise, in rodents, LY341495, at rather high doses, has been reported to increase locomotor activity and to show habituation deficit to unfamiliar environment which is attenuated by antipsychotic drugs (Bespalov et al., 2007), and to increase dopamine release in the nucleus accumbens shell (Karasawa et al., 2010). Although it is highly unlikely that these are psychostimulants-like effects because the degree to increase locomotor activity and accumbal dopamine release is much weaker than that of psychostimulants, the potential for a psychotomimetic liability should be taken into account when mGlu2/3 receptor antagonists are administered to humans at higher doses. Moreover, it should be pointed out that role of initial psychotomimetic effects of ketamine and CP-101,606 in their antidepressant effects has not been fully addressed. However, as described above, activation of AMPA receptor and mTOR pathways can be shared by these NMDA receptor antagonists and mGlu2/3 receptor antagonists to exert antidepressant effects, and mGlu2/3 receptor antagonists exert antidepressant effects at doses which do not affect locomotor activity. Therefore, antidepressant effects of ketamine and CP101,606 may not be ascribed to psychotomimetic effects, although these assumptions must prove in clinical studies with compounds without psychotomimetic effects. Second, pro-convulsive effects: Given that mGlu7 receptor null mice exhibit an increased seizure susceptibility (Sansig et al., 2001), chronic blockade of presynaptic mGlu receptors including mGlu2/3 receptor could have the same liabilities. On-going clinical trials may give some ideas to answer these concerns, and the fact that one compound (RG1578) has been announced to move into phase II is encouraging to convince that mGlu2/3 receptor antagonists may not have the same liabilities as ketamine. Third, tachyphylaxis of the antidepressant effects: Agents with wake-promoting effects such as ketamine and mGlu2/3 receptor antagonists may have a risk to cause tachyphylaxis during repeated treatment. Daily treatment of MGS0039 for 5, 7 and 14 days did not diminish antidepressant effects in the TST, the learned helplessness

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test and the olfactory bulbectomy model, respectively (Chaki et al., 2004; Pa1ucha-Poniewiera et al., 2010; Yoshimizu et al., 2006). Moreover, repeated ketamine infusions have been reported to safely and successfully produce sustained remission in patients with TRD (Szymkowicz et al., 2011 in an abstract form). Therefore, antidepressant effects of these agents may not be reduced following repeated treatment. However, lack of tachyphylaxis issue of these agents has to be proven in larger and more prolonged studies in human. 4. mGlu5 receptor antagonists 4.1. Preclinical and clinical evidence The initial studies on potential antidepressant effects of mGlu5 receptor ligands demonstrated a marked antidepressant activity of the first nonselective mGlu5 receptor antagonist 2-methyl-6(phenylethynyl)pyridine (MPEP) in the TST (Tatarczynska et al., 2001). Further studies confirmed antidepressant-like activity of MPEP not only in the TST (Belozertseva et al., 2007) but also in the FST in mice (Li et al., 2006). MPEP was also tested in the OB model of depression. It has been found, that multiple, but not acute administration of MPEP reversed the OB-induced deficits in passive avoidance learning in a manner similar to the one observed following chronic (but not acute) treatment with a variety of typical or atypical antidepressants (Pilc et al., 2002; Wieronska et al., 2002). It should be noted, however, that MPEP application might lead to several off-target activities, including NMDA receptor blockade (O’Leary et al., 2000), inhibition of the norepinephrine transporter (Heidbreder et al., 2003) and positive allosteric modulation of mGlu4 receptor (Mathiesen et al., 2003). Since all these effects might, at least in part, account for antidepressant-like activity of MPEP, it was important to prove the involvement of mGlu5 receptor blockade in the mechanism of antidepressant action. A highly selective, uncompetitive mGlu5 receptor antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl]-pyridine (MTEP) (Cosford et al., 2003), turned out to be a good tool to confirm antidepressant-like activity in several behavioral models of depression. It was active in the TST (Belozertseva et al., 2007; Palucha et al., 2005) and in the FST, both in mice (Li et al., 2006) and rats (Belozertseva et al., 2007). Intra-lateral septal infusions of different doses of MTEP produced antidepressant effects in the DRL-72 paradigm (Molina-Hernandez et al., 2006). Moreover, the repeated administration of MTEP attenuated the OB-related hyperactivity of rats in the open field test, resembling the action of typical ADs in the OB model of depression (Palucha et al., 2005). Finally, the study by Li et al. (2006) showed an antidepressant-like behavioral phenotype (a significant decrease in the immobility) in mGlu5 receptor knockout mice in the FST, supporting the data obtained from the experiments with the use of mGlu5 receptor antagonists. Furthermore, imipramine decreased the immobility time in mGlu5 receptor knockout mice in the FST whereas MPEP was not effective in this test, confirming the specificity of its action (Li et al., 2006). Recently the data showing the activity of GRN-529, an mGlu5 receptor NAM in the FST and TST, as well as in the number of tests for anxiolytic or analgetic efficacy were published. The authors suggested that the broad spectrum of activity of GRN-529 may indicate its potential for efficacy in the TRD (Hughes et al., 2013). 4.2. Neuronal and molecular mechanisms 4.2.1. Mechanisms of action 4.2.1.1. NMDA receptor. Several possible neuronal and molecular mechanisms may explain antidepressant-like activity of mGlu5

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receptor antagonists. Firstly, it might be related to the functional relationship of mGlu5 receptors with NMDA receptor complex. It has been found that postsynaptic mGlu5 receptors localized around ionotropic Glu (iGlu) receptors, and are linked to the Homer family of proteins which are functionally associated with Shank proteins, as part of the NMDA receptor e associated PSD-95 complex (Brakeman et al., 1997; Tu et al., 1999). All members of the cluster (i.e.: mGlu, Homer, Shank and NMDA) work in a strong functional relationship. Activation of the mGlu5 receptor has been reported to potentiate NMDA receptor activity, and on the other hand, antagonists of mGlu5 receptors have been shown to reduce NMDA receptor activity in a number of brain areas (Attucci et al., 2001; Awad et al., 2000; Doherty et al., 2000; Pisani et al., 2001). It has been also shown that repeated administration of MTEP decreased the expression of the mRNA encoding the NR1 subunit of NMDA receptor in the rat cerebral cortex (Cowen et al., 2005). Since clinical data have demonstrated a marked antidepressant efficacy of ketamine, an NMDA antagonist (see above), the inhibition of mGlu5 receptors which leads to a decrease in NMDA receptor-mediated neurotransmission may contribute to the antidepressant activity of mGlu5 receptor antagonists without causing profound adverse effects of NMDA antagonists. 4.2.1.2. BDNF. The mechanism of antidepressant-like activity of mGlu5 antagonists may be also related to the action on BDNF, which has been proposed to be responsible for the therapeutic efficiency of antidepressants (Vaidya and Duman, 2001). The mGlu5 antagonist, MPEP, similarly to the classical antidepressant desipramine, has been shown to increase BDNF mRNA level in the rat hippocampus after chronic administration (Legutko et al., 2006), suggesting that the blockade of mGlu5 receptors may induce expression of BDNF via the reduction of glutamatergic neurotransmission (for discussion see: Pilc et al., 2008). 4.2.1.3. Glutamate level. Several lines of evidence indicate that in depression there is a hyperfunction of glutamatergic neurotransmission (Sanacora et al., 2008) and that chronic treatment with ADs reduces glutamate release in the rat brain (Bonanno et al., 2005; Golembiowska and Dziubina, 2000). Three potential mechanisms which might be correlated with the influence of mGlu5 antagonists on the reduction of glutamate level in the brain are described below. 1) The mGlu5/NMDA receptor complexes were shown to be localized predominantly postsynaptically (Lujan et al., 1996) and in the hippocampus and prefrontal cortex, brain regions known to be involved in depression, those receptors are extensively expressed on GABAergic interneurons (van Hooft et al., 2000; Zhou and Hablitz, 1997). As shown in Fig. 2, the inhibition of mGlu5 receptors placed and the GABAergic neuron (Fig. 2(1)) may lead to the disinhibition of intermediate interneurons, which in turn inhibits the glutamatergic target neuronal element, decreasing the glutamatergic transmission. 2) It has been found that mGlu5 receptors are localized not only postsynaptically, but also play a role as presynaptic autoreceptors, which regulate the release of glutamate in the rat forebrain, and that mGlu5 antagonists decrease glutamate release via inhibition of these autoreceptors (Thomas et al., 2000). Therefore, if antidepressant effect is related to the reduction in glutamate release, mGlu5 antagonists might contribute to the antidepressant efficacy (Fig. 2(2)). 3) The involvement of 5-HTergic system in the antidepressantlike action of mGlu5 receptor antagonists was also suggested. Acute treatment with MPEP has been shown to increase plasma corticosterone concentrations, and this effect was blocked with

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Fig. 2. Schematic representation of the mechanism of antidepressant-like action mediated by mGlu5 receptor antagonist. The number of symbols indicates the amount of the neurotransmitter released: three symbols e transmission decreased, six symbols e transmission normal, twelve symbols e transmission enhanced.

a 5-HT1A antagonist (Bradbury et al., 2003). Furthermore, desensitization of the HPA axis to stimulation with a 5-HT1A agonist was reported after repeated 5-day treatment with MPEP (Bradbury et al., 2003). These neuroendocrine effects of MPEP are typical of conventional monoamine-based ADs, and suggest the involvement of the 5-HTergic system in the action of MPEP. Behavioral study by Belozertseva et al. (2007) have shown that MTEP induced a dose-dependent reduction in the immobility time and an increase in the swimming behavior, whereas it induced no changes in the climbing behavior of rats in the FST. This profile of action also suggests that the mechanism of the antidepressant-like activity of MTEP was related to the modulation of the 5-HTergic system (Detke et al., 1995). A recent behavioral study by Palucha-Poniewiera et al. (2011) demonstrated that antidepressant effects of MTEP in the TST was blocked in mice after pharmacological depletion of 5-HT with PCPA, indicating that regular level of 5-HT is necessary to induce antidepressant effects in this test. Furthermore, it was demonstrated that a 5HT2A/2C receptor antagonist, ritanserin, but not a 5HT1A receptor antagonist, WAY100635, blocked behavioral activity of MTEP in the TST, suggesting that 5HT2A/ 2C receptors play a role in the antidepressant-like activity of mGlu5 receptor antagonists. However, one must be aware that the evidence is based on one model of depression such as the TST. Since 5-HT2 receptors, which exert excitatory effects (Brandão et al., 1991), are positioned on GABAergic neurons (Griffiths and Lovick, 2002) and the stimulation of 5-HT2 receptors releases GABA in the prefrontal cortex (Abisaab et al., 1999), it can contribute to antidepressant efficacy of mGlu5 antagonists, via an increased inhibition of glutamatergic target neuron (see Fig. 2). Since the 5-HTergic system is closely related to the efficacy of many clinically used ADs, the interaction between mGlu5 receptors and 5HT2 receptor system may contribute to the antidepressant activity of mGlu5 receptor antagonists. Additionally, both MPEP and the closely related mGlu5 receptor NAM MTEP were shown to increase 5-HT release in the hippocampus and frontal cortex (Smolders et al., 2008; Stachowicz et al., 2007). The 5HT2A/2C antagonist ritanserin has been shown to block the anxiolytic-like effects of MTEP in the Vogel conflict-drinking test (Stachowicz et al., 2007), and M100907, an antagonist of 5-HT2A receptors blocked the MPEP-induced increase in locomotor activity in mice (Halberstadt et al., 2011). The data indicate the existence of significant interactions between 5-HT2 and mGlu5 receptors on several levels contributing not only antidepressant but also to anxiolytic efficacy of mGlu5 receptor antagonists and influencing the locomotion.

4.2.2. Change in mGlu5 receptor expression The involvement of group I mGlu receptors in depression and in the mechanism of action of conventional ADs has been postulated in the early 1990s. Initial biochemical studies by Pilc and coworkers showed that repeated electroconvulsive shock (ECS) treatment or TCAs decreased cAMP accumulation in rat cortical slices, induced by a group I mGlu receptor agonist, ibotenic acid (Pilc, 1991; Pilc and Legutko, 1995). Further electrophysiological studies using rat hippocampal slices clearly showed that the increase in the amplitude of the population spike evoked by a nonselective group I mGlu receptors agonist (1S,3R)-ACPD, as well as by a selective group I mGlu receptors agonist (R,S)-3,5-DHPG, was markedly attenuated by both repeated imipramine or ECS treatment, thus confirming decreased responsiveness of neurons to group I mGlu agonists after repeated AD administration (Palucha et al., 1997; Pilc et al., 1998). Subsequent studies focused on the influence of repeated AD treatment on the expression of group I mGlu receptors. It was found that chronic imipramine, as well as ECS treatment led to the increase in the expression of mGlu1a receptor and mGlu5a receptor immunoreactivity in the rat hippocampus. The expression of mGluR5a increased significantly after chronic imipramine in the CA1, and after chronic ECS in the CA3 region (Smialowska et al., 2002). A significant rise in expression mGlu5 receptor in the hippocampus was demonstrated recently by Morley-Fletcher et al. (2011) after chronic agomelatine administration. Agomelatine is an effective novel AD with a mixed melatonin receptor agonist and 5HT2C receptor antagonist (de Bodinat et al., 2010). In the light of electrophysiological and biochemical studies suggesting a subsensitivity of group I mGlu receptors resulting from antidepressants treatment, the increase in the protein level of group I mGlu receptors might be considered a compensatory mechanism resulting from that subsensitivity. The results of studies using animal models of depression such as the effect of chronic mild stress (CMS), exogenous corticosterone (CORT) administration or prenatal restraint stress model (PRS) revealed a significant reduction in mGluR5 receptor protein expression in the CA3 region of the hippocampus and in the whole hippocampus (Iyo et al., 2010; Morley-Fletcher et al., 2011; Wieronska et al., 2001). The effect of PRS on mGlu5 receptor level was reversed by chronic agomelatine treatment (Morley-Fletcher et al., 2011). The data presented above demonstrate that changes in expression of mGlu5 receptors in depression models and induced by antidepressant treatment go in opposite directions. The recent study by Deschwanden et al. (2011) on human subjects diagnosed as MDD strongly supports the hypothesis on the involvement of mGlu5 receptors in depression. Firstly, positron emission tomography (PET) study on unmedicated patients with

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MDD showed lower levels of mGlu5 binding in several brain regions including frontal, temporal, and parietal cortices, hippocampus, insula and thalamus, compared to psychiatrically healthy subjects. Furthermore, it has been found that the severity of depression was negatively correlated with mGlu5 receptor binding in the hippocampus (Deschwanden et al., 2011). At the same time, a postmortem study on brain samples of depressed patients revealed lower levels of mGlu5 receptor (but not mGlu1 receptor) protein expression in the prefrontal cortex, compared to healthy control subjects (Deschwanden et al., 2011). Therefore, both in the clinic and in preclinical models of depression, mGlu5 receptor expression tend to be lower. Antidepressant treatment increases mGlu5 receptor expression level in animals, which can lead to a functional hyposensitivity of receptors. Decreased function of mGlu5 receptors, which are excitatory in nature should decrease the function of glutamatergic system, which seems to be enhanced in depression (see below). These data strongly support the hypothesis that mGlu5 receptor may be a target for the novel antidepressant therapy. 4.3. Clinical applications The delayed onset of action of antidepressants, efficacy problem and a large population of TRD patients (see introduction) lies in striking contrast with the rapid and robust action of ketamine (see above). However, the range of adverse effects precludes the clinical use of ketamine in general psychiatric practice, and the blockade of mGlu5 receptors, which modulate the function of NMDA receptors might be a resolution to that problem. Fenobam, discovered in 1978 as a nonbenzodiazepine anxiolytic (Itil et al., 1978), was in 2005 described as an mGlu5 receptor antagonist (Porter et al., 2005). The antidepressant effects of fenobam were also reported by Lapierre and Oyewumi (1982), who described an improvement in the Hopkins Symptom Checklist depression score in patients treated with the drug. Depersonalization and derealization were observed with fenobam during testing in patients with anxiety disorders (Porter et al., 2005). However, fenobam binds in the primates to the sites which are not recognized by some of the mGlu5 receptor NAMs (Raboisson et al., 2011), moreover, no significant adverse effects of fenobam in fragile X syndrome were reported (Berry-Kravis et al., 2009; Jacquemont et al., 2011). Also, in the contrast to NMDA receptor antagonists, the mGlu5 receptor NAMs lack cortical neurotoxocity associated with the psychotomimetic-side effects (Gass, 2011). However, the potential of psychomimetic activity of mGlu5 receptor NAMs has to be investigated in depth in the future studies. Two clinical studies of mGlu5 receptor antagonists have been conducted with RG7090 (RO4917523, Roche) or AZD2066 (AstraZeneca) in the Phase II in patients with TRD or MDD, both of which have been terminated. Currently, a Phase II study with RG7090 is underway as adjunctive therapy in patients with MDD (see http:// www.clinicaltrials.gov/ct2/show/NCT01437657? term¼ro4917523&rank¼5). Given that both AstraZeneca and Roche have measured receptor occupancy for their compounds, it is likely that one or both of these trials are truly testing the clinical hypothesis that blockade of mGlu5 receptors will result in antidepressant effects. The mGlu5 receptor antagonists are currently tested in the number of clinical trials including the treatment of fragile X syndrome, L-DOPA induced dyskinesias, esophageal reflux disease, diabetic neuropathy or migraine (Zerbib et al., 2011; see also http:// clinicaltrials.gov.), opening additional possibilities to evaluate the antidepressant potential of those agents. One must be aware that mGlu5 receptors play an important role in memory and learning as demonstrated by Lu et al. (1997), who

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reported that mice lacking mGlu5 receptor show impaired learning in the Morris water maze and reduced CA1 long-term potentiation. It has been shown that mGlu5 receptor mediates the interaction between late-LTP and learning (Bikbaev et al., 2008). The number of data show that the systemic administration of MPEP or MTEP impaired fear conditioning (Gravius et al., 2005; Schulz et al., 2001; for recent review see Gravius et al., 2010). The impairment of learning after fenobam administration has also been reported (Jacob et al., 2009). As a number of novel, potent long acting mGlu5 receptor inhibitors are developed (for recent review see: Emmitte, 2011), the questions should be answered in the future. However, acamprosate, which has been proposed to be an mGlu5 and NMDA receptor functional antagonist (Harris et al., 2002) and has been used in human alcoholics as an anti-craving drug for more than twenty years, is considered as safe and well-tolerated drug, with no considerable impairments of learning and memory (Boothby and Doering, 2005). 5. Summary and conclusions Glutamatergic abnormalities have been suggested in pathophysiology of depression, based on changes in glutamate levels in blood and brain, and glutamate transmission in the brain regions of depressive patients by magnetic resonance spectroscopy (Sanacora et al., 2012). This hypothesis has recently been underpinned by the clinical evidence that agents acting on glutamatergic transmission such as ketamine, CP-101,606 and riluzole are effective for patients with MDD. In particular, robust and rapid antidepressant effects of ketamine for patients with TRD are striking, and research on neuronal mechanisms underlying antidepressant effects of ketamine paved a new way to finding alternative glutamate-based approaches which maintain efficacy but reduce unwanted side effects of ketamine. mGlu receptors are promising candidates as an alternative, because they have a modulatory role of glutamatergic transmission, distinct from iGlu receptors including NMDA receptor which are involved in fast neuronal transmission. Thus, modulation of mGlu receptors may be devoid of unwanted side effects observed in iGlu receptor based drugs. As described in the text, accumulating evidence has indicated the potential importance and usefulness of agents acting on mGlu2/ 3 and mGlu5 receptors. Both mGlu2/3 receptor ligands and mGlu5 receptor antagonists have been demonstrated antidepressant effects in several animal models of depression, and their neural mechanisms are being elucidated. Importantly, they (particularly, mGlu2/3 receptor antagonists and mGlu5 receptor antagonists) share some mechanisms with ketamine, CP-101,606 and riluzole. Thus, mGlu5 receptor antagonists antagonize NMDA receptor activity and produce an increase in BDNF production, while mGlu2/ 3 receptor antagonists stimulate AMPA receptor and increase mTOR signaling pathway to exert antidepressant effects. Because increase in BDNF and mTOR signaling has been postulated to be important features for antidepressant effects of NMDA receptor antagonists such as ketamine and CP-101,606 in terms of rapid effects for TRD, and activation of AMPA receptor signaling may also be involved in antidepressant effects of riluzole, it is expected that both mGlu2/3 receptor antagonists and mGlu5 receptor antagonists could have similar efficacy to drugs which have been proven to be effective for TRD in the clinical settings. Based on the evidence described above, possible interactions between mGlu receptors and iGlu receptors are proposed (Fig. 3). Ketamine blocks NMDA receptor and activates AMPA receptor (partly by increased glutamate release through blockade of NMDA receptor), subsequently increasing BDNF production (or secretion) which results in increase in synaptic activity. mGlu5 receptor blockade functionally reduces NMDA receptor activity and increases BDNF production. Moreover, blockade of mGlu5 receptor may enhance

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ketamine

mGlu5 receptor antagonist NMDA receptor blockade

mGlu2/3 receptor antagonist

AMPA receptor stimulation

5-HTergic 5-HT2A/2C

BDNF

(?)

GABA release Glutamate release

5-HTergic Dopaminergic

BDNF mTOR Spine density Synaptic activity

Normalization of glumatatergic dysfunction Fig. 3. Neurocircuitry models of mGlu2/3 receptor antagonists and mGlu5 receptor antagonists and their similarity to those of ketamine. Ketamine blocks NMDA receptor and activates AMPA receptor to normalize glutamatergic abnormalities observed in depression. mGlu2/3 receptor antagonists and mGlu5 receptor antagonists share some of those neuronal mechanisms, and in different ways may eventually normalize glutamatergic abnormalities at the synaptic transmission level as well as the synaptic connectivity level.

5-HTergic transmission, which stimulates postsynaptic 5HT2A/2C receptors and subsequently stimulates GABA release. Thus, this mechanism also eventually ameliorates glutamate dysfunction by inhibiting glutamate overload. In contrast, mGlu2/3 receptor blockade enhances AMPA receptor transmission, presumably through increased glutamate release by blockade of perisynaptic autoreceptors. Stimulation of AMPA receptor may increase mTOR signaling through an increase in BDNF signaling, which results in increase in spine density and synaptic formation. Moreover, mGlu2/3 receptor blockade, through AMPA receptor stimulation, increases in dopaminergic transmission in the nucleus accumbens shell and 5HTergic transmission in the medial prefrontal cortex, both of which may contribute to antidepressant effects. With regard to roles of mGlu receptors in depression, there are some issues to be resolved. (1) Role of mGlu2/3 receptors: Because both mGlu2/3 receptor antagonists and agonists (or potentiators) exhibit antidepressant effects, a plausible explanation of this apparent paradox is needed. One has to remember that glutamatergic abnormalities may differ, depending on brain regions and states of depression. Thus, both increase and decrease in synaptic glutamate release may occur during a course of depression. Indeed, decrease in glutamate in some brain regions has been reported whereas glutamate overload has also been observed in other regions. Based on these findings, mGlu2/3 receptor antagonists and agonists could be effective in different types of depression. It should be noted that an mGlu2/3 receptor agonist does not exhibit an antidepressant effect whereas an mGlu2 receptor potentiator does. Therefore, efficacy of stimulation of mGlu2 receptor may depend on extrasynaptic glutamate concentration, which also indicates that role of mGlu2 receptor depends on states of glutamate dysfucntion. Moreover, it should be noted that mGlu2/3 receptor antagonists and mGlu2/3 receptor agonists, assuming that both could have antidepressant potential, could be used for different types of patients. Because an mGlu2/3 receptor antagonist has been reported to have wake-promoting effect (Feinberg et al., 2005), they may be useful in patients with increased sleep, while mGlu2/3 receptor agonists which increase sleep (Feinberg et al., 2005) may be beneficial in patients with disturbed sleep patterns.

(2) Stimulation or inhibition of glutamate transmission: both mGlu5 receptor antagonists and mGlu2/3 receptor agonists/ potentiators may inhibit glutamate transmission whereas mGlu2/3 receptor antagonists increase it. It should be taken into account that ketamine has both effects on glutamate transmission, depending on brain regions and cell types, and ketamine enhances glutamatergic signaling in the prefrontal cortex, potentially through inhibition of GABA interneurons and subsequent disinhibition of cortical pyramidal neurons. Thus, it is conceivable that functional blockade of NMDA receptor by mGlu5 receptor antagonists exerts not only inhibitory effects but also excitatory effects on glutamate transmission (later may be true in case both ketamine and mGlu5 receptor antagonists blocks NMDA receptor on GABA interneurons which regulate pyramidal neurons in the prefrontal cortex). Again, as mentioned above, glutamatergic abnormalities observed in depression may not be explained by simply “hyperglutamatergic” or “hypoglutamatergic”, and overall normalization of glutamatergic should be important. For example, the dorsolateral and dorsomedial regions of prefrontal cortex has been reported to be underactive during a MDD episode whereas ventral cortical structures are hyperactivated, and ketamine has been reported to ameliorate these abnormalities as demonstrated by magnetic resonance imaging (Deakin et al., 2008). Interestingly, direct stimulation of the medial prefrontal cortex using optogenetic techniques displays a rapid antidepressant effect in a social defeat stress paradigm in mice (Covington et al., 2010), suggesting that activation of glutamatergic transmission may in some brain regions exert an antidepressant action. Additional studies are required to fully resolve the roles of mGlu receptors in depression in a context of selective brain regions and course of depressive states. (3) Involvement of psychotomimetic effects in antidepressant effects: As descrived in earlier sections, it has not been solved whether initial psychotomimetic effects of ketamine and CP101,606 is necessary to exert robust antidepressant effects, thus, whether antidepressant effects of both mGlu2/3 receptor antagonists/NAMs and mGlu5 receptor NAMs are not related to psychotomimetic effects. Nonetheless, accumulating evidence clearly indicates that mGlu receptor ligands, particularly those acting on mGlu2/3 and mGlu5

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receptors may be beneficial for the treatment of depression, and share some of neuronal circuits which mediate the striking antidepressant effects of ketamine. Therefore, targeting mGlu2/3 and mGlu5 receptors should be effective alternatives for ketamine, although efficacy and safety in humans remain to be confirmed in clinical trials. Moreover the on-going works with both mGlu2/3 receptor antagonists/NAMs and mGlu5 receptor NAMs provide exciting clinical tests for a range of hypotheses that can be suggested for the provocative observations of rapid antidepressant effects of ketamine and CP-101,606. References Abisaab, W.M., Bubser, M., Roth, R.H., Deutch, A.Y., 1999. 5-HT2 receptor regulation of extracellular GABA levels in the prefrontal cortex. Neuropsychopharmacology 20, 92e96. Ahnaou, A., Dautzenberg, F.M., Geys, H., Imogai, H., Gibelin, A., Moechars, D., Steckler, T., Drinkenburg, W.H., 2009. Modulation of group II metabotropic glutamate receptor (mGlu2) elicits common changes in rat and mice sleepwake architecture. Eur. J. Pharmacol. 603, 62e72. Alt, A., Nisenbaum, E.S., Bleakman, D., Witkin, J.M., 2006. A role for AMPA receptors in mood disorders. Biochem. Pharmacol. 71, 1273e1288. Andlin-Sobocki, P., Jonsson, B., Wittchen, H.U., Olesen, J., 2005. Cost of disorders of the brain in Europe. Eur. J. Neurol. 1 (12 Suppl.), 1e27. Anwyl, R., 1999. Metabotropic glutamate receptors: electrophysiological properties and role in plasticity. Brain Res. Brain Res. Rev. 29, 83e120. Attucci, S., Carla, V., Mannaioni, G., Moroni, F., 2001. Activation of type 5 metabotropic glutamate receptors enhances NMDA responses in mice cortical wedges. Br. J. Pharmacol 132, 799e806. Awad, H., Hubert, G.W., Smith, Y., Levey, A.I., Conn, P.J., 2000. 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