Is the mglu5 receptor a possible target for new antidepressant drugs?

Pharmacological Reports 2013, 65, 1506 1511 ISSN 1734-1140 Copyright 2013 by Institute of Pharmacology Polish Academy of Sciences Review Is the mglu5 receptor a possible target for new antidepressant drugs? Agnieszka Pa³ucha-Poniewiera 1, Joanna M. Wieroñska 1, Piotr Brañski 1, Grzegorz Burnat 1, Barbara Chruœcicka 1, Andrzej Pilc 1,2 1 Institute of Pharmacology Polish Academy of Sciences, Department of Neurobiology, Smêtna 12, PL 31-343 Kraków, Poland 2 Jagiellonian University, Collegium Medicum, Micha³owskiego 12, PL 31-126 Kraków, Poland Correspondence: Agnieszka Pa³ucha-Poniewiera, e-mail: nfpaluch@cyf-kr.edu.pl Abstract: The current treatment of depression, based on conventional antidepressant drugs that influence monoaminergic systems, is not satisfactory, and innovative antidepressant drugs are still needed. The next generation of treatments needs to be more effective, fasteracting and better tolerated than currently used antidepressants. A growing body of evidence indicates that compounds that modulate the glutamatergic system may be a group of novel and mechanistically distinct agents for the treatment of depression. Both preclinical and clinical data show strong, rapid and sustained effects of the NMDA receptor antagonist ketamine in treatment-resistant depression. However, ketamine cannot be considered as a novel antidepressant drug because of its side-effects and abuse potential. Because glutamatergic transmission is controlled not only by ionotropic but also by metabotropic glutamate receptors, their involvement in the etiology and the therapy of depression has also been postulated. Here, we review data supporting the potential antidepressant activity of mglu5 receptor antagonists as well as the involvement of mglu5 receptors in the pathophysiology of depression. Key words: antidepressant drugs, ketamine, mglu5 receptor, MTEP, MPEP, NMDA receptor Abbreviations: AD antidepressant drug, BDNF brain derived neurotrophic factor, FST forced swim test, iglu receptor ionotropic glutamate receptor, mglu receptor metabotropic glutamate receptor, mtor mammalian target of rapamycin, NSF novelty suppressed feeding test, OB olfactory bulbectomy, PFC prefrontal cortex, TRD treatment resistant depression, TST tail suspension test Introduction It seems that a breakthrough in the therapy of depression will require going beyond a monoamine-based theory of depression. One of the new leading hypotheses of depression is the glutamatergic hypothesis, which states that the main brain excitatory system plays a role in the pathophysiology of depression and suggests possible antidepressant activity of compounds modulating glutamatergic neurotransmission via activation or inhibition of glutamatergic receptors [27, 31, 33]. Two distinct groups of glutamatergic receptors have been described: ionotropic glutamate receptors (iglu receptors, including NMDA, AMPA and kainate receptors), which are coupled to ion channels, and metabotropic glutamate (mglu) receptors, which are a family of G-protein-coupled receptors [25] that are classified into three groups according to their se- 1506 Pharmacological Reports, 2013, 65, 1506 1511

MGlu5 receptor as a target for new antidepressants Agnieszka Pa³ucha-Poniewiera et al. quence homology, effector coupling and agonist selectivity: group I (mglu1 and mglu5), group II (mglu2 and mglu3) and group III (mglu4, mglu6, mglu7 and mglu8) receptors [7]. Several studies have shown that functional antagonists of NMDA receptors induce antidepressant-like effects in animal models of depression [33]. Some clinical trials have also been undertaken. Although a low-affinity, uncompetitive, open-channel NMDA blocker, memantine, has not shown antidepressant effects in humans [21, 40], studies on the uncompetitive NMDA receptor-trapping blocker ketamine showed strong, rapid and sustained antidepressant effects in patients suffering from major treatment-resistant depression (TRD) [4, 39], electroconvulsive shockresistant major depression [17] and bipolar TRD [11]. However, ketamine has significant limitations, including undesirable side effects, abuse potential and a limited route of administration. In all clinical studies investigating the antidepressant activity of the drug, ketamine was given intravenously by an anesthesiologist and hospitalization for at least 24 h post-infusion was required [1]. Thus, ketamine cannot be considered as a safe antidepressant drug (AD) for outpatients. However, these studies have provided great hope that modulation of the glutamatergic system, including NMDA receptors, may lead to a new generation of rapid and efficient ADs. Because the clinical value of ketamine and other NMDA receptor antagonists is limited, mglu ligands have been considered as possible ADs. These compounds are free of most adverse effects and possess a fast onset of action [27]. mglu5 receptors, which are functionally involved in the mild modulation of NMDA receptor activity, may become promising targets for new and safer ADs. mglu5 receptors predominantly have a postsynaptic localization around iglu receptors and are associated with the Homer family of proteins, which functionally link group I mglu receptors with Shank proteins. Shank proteins, on the other hand, function as a part of the NMDA receptor-associated PSD-95 complex [36, 38]. The spatial proximity of NMDA and mglu5 receptors implies a functional relationship. It has been demonstrated that activation of the mglu5 receptor potentiates NMDA receptor activity and that antagonists of mglu5 receptors decrease NMDA receptor activation [2, 12]. Therefore, mglu5 receptor antagonists may function as mild NMDA receptor negative modulators (Fig. 1; for review, see [34]). Antagonists of mglu5 receptors induce antidepressant-like effects in animal models of depression Behavioral studies have provided some promising results showing potential antidepressant-like effects of mglu5 receptor antagonists such as MPEP (2- methyl-6-(phenylethynyl)pyridine) [14] and MTEP (3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine) [8], which confirmed their possible application in the therapy of depression. Both compounds induced antidepressant-like effects in several models of depression, such as the forced swim test (FST) [3, 23], the tail mglu5 receptor ligands modulate NMDA receptor activity Fig. 1. Schematic representation of the mglu5 receptor and NMDA receptor synaptic localization. The spatial proximity of NMDA and mglu5 receptors implicates their functional relationship, i.e., mglu5 receptors are functionally involved in the mild modulation of the activity of NMDA receptors. Therefore, mglu5 receptor antagonists may function as mild NMDA receptor negative modulators and, to some extent, may imitate the action of NMDA receptor antagonists Pharmacological Reports, 2013, 65, 1506 1511 1507

suspension test (TST) [3, 26, 35], the olfactory bulbectomy (OB) model of depression [26, 30, 37] and the novelty-suppressed feeding (NSF) test [18]. More recently, Hughes et al. [16] confirmed and extended these results, showing potential antidepressant-like effects of the mglu5 receptor negative allosteric modulator GRN-529 using a battery of animal models of depression and the co-morbid symptoms overrepresented in TRD, namely anxiety and pain. The authors concluded that the broad-spectrum efficacy profile of GRN-529 indicated that this drug could represent an innovative therapeutic approach to the treatment of TRD [16]. Behavioral studies have also shown antidepressantlike effects of a functional NMDA and mglu5 receptor antagonist, acamprosate [15], which has been used therapeutically in human alcoholics as an anti-craving drug and is considered as a safe substance [5]. The results of in vivo studies using the TST suggested that NMDA and mglu5 receptors were crucial targets of acamprosate in its antidepressant-like activity [29]. Neuronal and molecular mechanism of the antidepressant-like activity of mglu5 receptor antagonists Several studies have been performed to investigate the mechanism of the antidepressant-like activity of mglu5 antagonists. The results of behavioral studies have suggested that the interaction between the mglu5 receptor and NMDA receptor plays an important role in the antidepressant-like action of mglu5 antagonists (Fig. 1). MTEP activity in the FST in mice depended on NMDA receptor activity [32]. Similar effects were observed when the antidepressant-like effects of acamprosate were investigated using the TST in mice [29]. The study by Cowen et al. [9], who showed that repeated administration of MTEP decreased the expression of NMDA receptor NR1 subunit mrna in the rat cerebral cortex, may also suggest the importance of a functional relationship between mglu5 receptors and the NMDA receptor complex. It has also been found that the antidepressant-like activity of mglu5 antagonists depended on serotonergic system activation. Bradbury et al. [6] showed that a single dose of MTEP increased plasma corticosterone concentration and that this effect was blocked with a 5-HT 1A antagonist. Moreover, desensitization of the HPA-axis to stimulation with a 5-HT 1A agonist after repeated 5-day treatment with MPEP was reported [6]. Such effects of MPEP are typical of monoamine-based ADs and suggest the involvement of the serotonergic system in the action of MPEP. The results of a recent behavioral study by Pa³ucha- Poniewiera et al. [28] showed that the mglu5 receptor antagonist MTEP, similar to fluoxetine used as a reference AD, did not induce antidepressant-like effects in mice pretreated with the tryptophan hydroxylase inhibitor, PCPA (para-chlorophenylalanine). This result showed that the pharmacological depletion of serotonin can completely block the antidepressant-like activity of MTEP in the TST. Furthermore, the 5HT 2A/2C antagonist ritanserin, but not the 5-HT 1A antagonist WAY100635, 5HT 1B antagonist SB224289 or 5HT 4 antagonist GR125487, reversed the antidepressant- like effects of MTEP in the TST, indicating a role of 5HT 2A/2C receptors in the antidepressant-like activity of the mglu5 antagonist. Furthermore, a subeffective dose of MTEP co-administered with a subeffective dose of citalopram induced an antidepressant-like effect in the TST in mice. Such an effect suggests the synergistic action of the SSRI and the mglu5 receptor antagonist, indicating that both compounds act at different targets to stimulate the same pathway. The mechanism of mglu5 antagonist antidepressant-like activity may also be related to the activity of the brain-derived neurotrophic factor (BDNF) and mammalian target of rapamycin (mtor)-dependent signaling pathways, which have been proposed in the antidepressant effects of ketamine [22, 24]. Recent studies by Duman s group showed that the NMDA receptor antagonist ketamine induced rapid activation of the mtor signaling pathway, leading to neuroplastic processes involving increased levels of synaptic signaling proteins and an increased number of functional new spine synapses in the prefrontal cortices (PFCs) of rats [22]. Seeing that activation of the mtor signaling pathway may be a key mechanism of the rapid ketamine antidepressant effect, the possible involvement of mtor pathway activation in the antidepressant effects of mglu receptor ligands should also be considered. It has been shown that the group II mglu receptor antagonists MGS0039 and LY341495 induce antidepressant-like effects using a mechanism that involves increased mtor pathway activity [13, 1508 Pharmacological Reports, 2013, 65, 1506 1511

MGlu5 receptor as a target for new antidepressants Agnieszka Pa³ucha-Poniewiera et al. 19]. In contrast, mtor activation seems to not be involved in the antidepressant-like activity of the mglu5 receptor antagonist MPEP in the NSF test in mice [18]. However, a protein synthesis inhibitor anisomycin blocked the sustained effects of MPEP, suggesting the involvement of new protein synthesis. Furthermore, the role of BDNF activity in the mechanism of MPEP antidepressant activity has been explored. On the one hand, it has been shown that the Trk (tyrosine kinase) inhibitor K252a did not block the sustained effect of MPEP in the NSF test in mice, suggesting that BDNF Trk B receptor signaling may not play a role in the activity of MPEP [18]. On the other hand, the study by Legutko et al. [20] showed that MPEP, similar to the classic AD desipramine, increased BDNF mrna levels in the rat hippocampus after chronic administration, suggesting that the blockade of mglu5 receptors may induce expression of BDNF via the reduction of glutamatergic neurotransmission that may finally result in the antidepressant effect. Conclusions Glutamate receptors have become new important targets for medication development for the treatment of depression. Among mglu receptors, the mglu5 receptor seems to be a good target for a novel AD. Numerous preclinical data indicate that antagonists of mglu5 receptors induce antidepressant-like effects. However, most of the compounds that exhibited beneficial properties in the animal models of depression have never been tested in humans. Currently, the clinical trials of new mglu5 antagonists are underway that, in the next few years, should bring results that determine the potential for clinical application of mglu5 antagonists. Acknowledgment: This work was supported by the grant POIG.01.01.02-12-004/09 Depression-Methods-Therapy, task. 3.7. References: Possible clinical applications of mglu5 receptor antagonists in the therapy of depression An important role for mglu5 receptors in depression has been suggested by studies in humans. Postmortem analyses of prefrontal cortices from major depression disorder (MDD) subjects showed lower levels of mglu5 protein expression in the prefrontal cortex relative to controls [10]. Furthermore, positron emission tomography (PET) studies in humans showed lower levels of mglu5 binding in several brain regions of unmedicated patients with MDD compared to healthy control subjects [10]. Preclinical studies investigating the potential antidepressant effects of mglu5 receptor antagonists led to the introduction of two different mglu5 receptor antagonists, namely RG7090 (RO4917523, Roche) and AZD2066 (Astra-Zeneca), into Phase II trials in patients with TRD or MDD. Currently, a Phase II study with RG7090 is underway as adjunctive therapy in patients with MDD (see http://www.clinicaltrials.gov/ct2/show/nct01437657?term=ro4917523& rank=6). 1. Aan Het Rot M, Zarate CA Jr, Charney DS, Mathew SJ: Ketamine for depression: where do we go from here? Biol Psychiatry, 2012, 72, 537 547. 2. Awad H, Hubert GW, Smith Y, Levey AI, Conn PJ: Activation of metabotropic glutamate receptor 5 has direct excitatory effects and potentiates NMDA receptor currents in neurons of the subthalamic nucleus. J Neurosci, 2000, 20, 7871 7879. 3. Belozertseva IV, Kos T, Popik P, Danysz W, Bespalov AY: Antidepressant-like effects of mglur1 and mglur5 antagonists in the rat forced swim and the mouse tail suspension tests. Eur Neuropsychopharmacol, 2007, 17, 172 179. 4. Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JA: Antidepressant effects of ketamine in depressed patients. Biol Psychiatry, 2000, 47, 351 354. 5. Boothby LA, Doering PL: Acamprosate for the treatment of alcohol dependence. Clin Ther, 2005, 27, 695 714. 6. Bradbury MJ, Giracello DR, Chapman DF, Holtz G, Schaffhauser H, Rao SP, Varney MA, Anderson JJ: Metabotropic glutamate receptor 5 antagonist-induced stimulation of hypothalamic-pituitary-adrenal axis activity: interaction with serotonergic systems. Neuropharmacology, 2003, 44, 562 572. 7. Conn PJ, Pin JP: Pharmacology and functions of metabotropic glutamate receptors. Ann Rev Pharmacol Toxicol, 1997, 37, 205 237. 8. Cosford ND, Tehrani L, Roppe J, Schweiger E, Smith ND, Anderson J, Bristow L et al.: 3-[(2-Methyl-1,3- Pharmacological Reports, 2013, 65, 1506 1511 1509

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