Pharmacological Reports Copyright © 2013 2013, 65, 15061511 by Institute of Pharmacology ISSN 1734-1140 Polish Academy of Sciences
Review
Is the mGlu5 receptor a possible target for new antidepressant drugs?
Agnieszka Pa³ucha-Poniewiera1, Joanna M. Wieroñska1, Piotr Brañski1, Grzegorz Burnat1, Barbara Chruœcicka1, Andrzej Pilc1,2
1Institute of Pharmacology Polish Academy of Sciences, Department of Neurobiology, Smêtna 12, PL 31-343 Kraków, Poland
2Jagiellonian University, Collegium Medicum, Micha³owskiego 12, PL 31-126 Kraków, Poland
Correspondence: Agnieszka Pa³ucha-Poniewiera, e-mail: [email protected]
Abstract: The current treatment of depression, based on conventional antidepressant drugs that influence monoaminergic systems, is not satis- factory, and innovative antidepressant drugs are still needed. The next generation of treatments needs to be more effective, faster- acting 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 preclini- cal and clinical data show strong, rapid and sustained effects of the NMDA receptor antagonist ketamine in treatment-resistant de- pression. 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 involve- ment in the etiology and the therapy of depression has also been postulated. Here, we review data supporting the potential antidepres- sant 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 de- theory of depression. One of the new leading hy- rived neurotrophic factor, FST – forced swim test, iGlu recep- potheses of depression is the glutamatergic hypothe- tor – ionotropic glutamate receptor, mGlu receptor – meta- sis, which states that the main brain excitatory system botropic glutamate receptor, mTOR – mammalian target of ra- pamycin, NSF – novelty suppressed feeding test, OB – olfac- plays a role in the pathophysiology of depression and tory bulbectomy, PFC – prefrontal cortex, TRD – treatment re- suggests possible antidepressant activity of com- sistant depression, TST – tail suspension test pounds modulating glutamatergic neurotransmission via activation or inhibition of glutamatergic receptors [27, 31, 33]. Two distinct groups of glutamatergic re- ceptors have been described: ionotropic glutamate re- ceptors (iGlu receptors, including NMDA, AMPA and Introduction kainate receptors), which are coupled to ion channels, and metabotropic glutamate (mGlu) receptors, which It seems that a breakthrough in the therapy of depres- are a family of G-protein-coupled receptors [25] that sion will require going beyond a monoamine-based are classified into three groups according to their se-
1506 Pharmacological Reports, 2013, 65, 15061511 MGlu5 receptor as a target for new antidepressants Agnieszka Pa³ucha-Poniewiera et al.
quence homology, effector coupling and agonist se- plies a functional relationship. It has been demon- lectivity: group I (mGlu1 and mGlu5), group II strated that activation of the mGlu5 receptor (mGlu2 and mGlu3) and group III (mGlu4, mGlu6, potentiates NMDA receptor activity and that antago- mGlu7 and mGlu8) receptors [7]. nists of mGlu5 receptors decrease NMDA receptor Several studies have shown that functional antago- activation [2, 12]. Therefore, mGlu5 receptor antago- nists of NMDA receptors induce antidepressant-like nists may function as mild NMDA receptor negative effects in animal models of depression [33]. Some modulators (Fig. 1; for review, see [34]). clinical trials have also been undertaken. Although a low-affinity, uncompetitive, open-channel NMDA blocker, memantine, has not shown antidepressant ef- fects in humans [21, 40], studies on the uncompetitive Antagonists of mGlu5 receptors induce NMDA receptor-trapping blocker ketamine showed antidepressant-like effects in animal strong, rapid and sustained antidepressant effects in patients suffering from major treatment-resistant de- models of depression pression (TRD) [4, 39], electroconvulsive shock- resistant major depression [17] and bipolar TRD [11]. Behavioral studies have provided some promising re- However, ketamine has significant limitations, includ- sults showing potential antidepressant-like effects of ing undesirable side effects, abuse potential and a lim- mGlu5 receptor antagonists such as MPEP (2- ited route of administration. In all clinical studies methyl-6-(phenylethynyl)pyridine) [14] and MTEP investigating the antidepressant activity of the drug, (3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine) [8], ketamine was given intravenously by an anesthesiolo- which confirmed their possible application in the ther- gist and hospitalization for at least 24 h post-infusion apy of depression. Both compounds induced antide- was required [1]. Thus, ketamine cannot be consid- pressant-like effects in several models of depression, ered as a safe antidepressant drug (AD) for outpa- such as the forced swim test (FST) [3, 23], the tail tients. However, these studies have provided great hope that modulation of the glutamatergic system, in- cluding NMDA receptors, may lead to a new genera- tion of rapid and efficient ADs.
mGlu5 receptor ligands modulate NMDA receptor activity
Because the clinical value of ketamine and other NMDA receptor antagonists is limited, mGlu ligands have been considered as possible ADs. These com- pounds 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 tar- gets for new and safer ADs. mGlu5 receptors pre- dominantly have a postsynaptic localization around iGlu receptors and are associated with the Homer family of proteins, which functionally link group I Fig. 1. Schematic representation of the mGlu5 receptor and NMDA receptor synaptic localization. The spatial proximity of NMDA and mGlu receptors with Shank proteins. Shank proteins, mGlu5 receptors implicates their functional relationship, i.e., mGlu5 on the other hand, function as a part of the NMDA receptors are functionally involved in the mild modulation of the activ- ity of NMDA receptors. Therefore, mGlu5 receptor antagonists may receptor-associated PSD-95 complex [36, 38]. The function as mild NMDA receptor negative modulators and, to some spatial proximity of NMDA and mGlu5 receptors im- extent, may imitate the action of NMDA receptor antagonists
Pharmacological Reports, 2013, 65, 15061511 1507 suspension test (TST) [3, 26, 35], the olfactory bul- rone concentration and that this effect was blocked bectomy (OB) model of depression [26, 30, 37] and with a 5-HT1A antagonist. Moreover, desensitization the novelty-suppressed feeding (NSF) test [18]. More of the HPA-axis to stimulation with a 5-HT1A agonist recently, Hughes et al. [16] confirmed and extended after repeated 5-day treatment with MPEP was re- these results, showing potential antidepressant-like ported [6]. Such effects of MPEP are typical of effects of the mGlu5 receptor negative allosteric monoamine-based ADs and suggest the involvement modulator GRN-529 using a battery of animal models of the serotonergic system in the action of MPEP. The of depression and the co-morbid symptoms overrepre- results of a recent behavioral study by Pa³ucha- sented in TRD, namely anxiety and pain. The authors Poniewiera et al. [28] showed that the mGlu5 receptor concluded that the broad-spectrum efficacy profile of antagonist MTEP, similar to fluoxetine used as a ref- GRN-529 indicated that this drug could represent an erence AD, did not induce antidepressant-like effects innovative therapeutic approach to the treatment of in mice pretreated with the tryptophan hydroxylase TRD [16]. inhibitor, PCPA (para-chlorophenylalanine). This re- Behavioral studies have also shown antidepressant- sult showed that the pharmacological depletion of se- like effects of a functional NMDA and mGlu5 recep- rotonin can completely block the antidepressant-like tor antagonist, acamprosate [15], which has been used activity of MTEP in the TST. Furthermore, the therapeutically in human alcoholics as an anti-craving 5HT2A/2C antagonist ritanserin, but not the 5-HT1A an- drug and is considered as a safe substance [5]. The re- tagonist WAY100635, 5HT1B antagonist SB224289 or sults of in vivo studies using the TST suggested that 5HT4 antagonist GR125487, reversed the antidepres- NMDA and mGlu5 receptors were crucial targets of sant- like effects of MTEP in the TST, indicating acamprosate in its antidepressant-like activity [29]. a role of 5HT2A/2C receptors in the antidepressant-like activity of the mGlu5 antagonist. Furthermore, a sub- effective dose of MTEP co-administered with a sub- effective dose of citalopram induced an antidepres- Neuronal and molecular mechanism sant-like effect in the TST in mice. Such an effect suggests the synergistic action of the SSRI and the of the antidepressant-like activity mGlu5 receptor antagonist, indicating that both com- of mGlu5 receptor antagonists pounds act at different targets to stimulate the same pathway. Several studies have been performed to investigate The mechanism of mGlu5 antagonist antidepres- the mechanism of the antidepressant-like activity of sant-like activity may also be related to the activity of mGlu5 antagonists. The results of behavioral studies the brain-derived neurotrophic factor (BDNF) and have suggested that the interaction between the mammalian target of rapamycin (mTOR)-dependent mGlu5 receptor and NMDA receptor plays an impor- signaling pathways, which have been proposed in the tant role in the antidepressant-like action of mGlu5 antidepressant effects of ketamine [22, 24]. Recent antagonists (Fig. 1). MTEP activity in the FST in mice studies by Duman’s group showed that the NMDA re- depended on NMDA receptor activity [32]. Similar ceptor antagonist ketamine induced rapid activation effects were observed when the antidepressant-like ef- of the mTOR signaling pathway, leading to neuroplas- fects of acamprosate were investigated using the TST tic processes involving increased levels of synaptic in mice [29]. The study by Cowen et al. [9], who signaling proteins and an increased number of func- showed that repeated administration of MTEP de- tional new spine synapses in the prefrontal cortices creased the expression of NMDA receptor NR1 (PFCs) of rats [22]. Seeing that activation of the subunit mRNA in the rat cerebral cortex, may also mTOR signaling pathway may be a key mechanism of suggest the importance of a functional relationship the rapid ketamine antidepressant effect, the possible between mGlu5 receptors and the NMDA receptor involvement of mTOR pathway activation in the anti- complex. depressant effects of mGlu receptor ligands should It has also been found that the antidepressant-like also be considered. It has been shown that the group II activity of mGlu5 antagonists depended on serotoner- mGlu receptor antagonists MGS0039 and LY341495 gic system activation. Bradbury et al. [6] showed that induce antidepressant-like effects using a mechanism a single dose of MTEP increased plasma corticoste- that involves increased mTOR pathway activity [13,
1508 Pharmacological Reports, 2013, 65, 15061511 MGlu5 receptor as a target for new antidepressants Agnieszka Pa³ucha-Poniewiera et al.
19]. In contrast, mTOR activation seems to not be in- Conclusions volved in the antidepressant-like activity of the mGlu5 receptor antagonist MPEP in the NSF test in mice [18]. However, a protein synthesis inhibitor ani- Glutamate receptors have become new important tar- somycin blocked the sustained effects of MPEP, sug- gets for medication development for the treatment of gesting the involvement of new protein synthesis. depression. Among mGlu receptors, the mGlu5 recep- Furthermore, the role of BDNF activity in the mecha- tor seems to be a good target for a novel AD. Numer- nism of MPEP antidepressant activity has been ex- ous preclinical data indicate that antagonists of plored. On the one hand, it has been shown that the mGlu5 receptors induce antidepressant-like effects. Trk (tyrosine kinase) inhibitor K252a did not block However, most of the compounds that exhibited bene- the sustained effect of MPEP in the NSF test in mice, ficial properties in the animal models of depression suggesting that BDNF–Trk B receptor signaling may have never been tested in humans. Currently, the not play a role in the activity of MPEP [18]. On the clinical trials of new mGlu5 antagonists are underway other hand, the study by Legutko et al. [20] showed that, in the next few years, should bring results that that MPEP, similar to the classic AD desipramine, in- determine the potential for clinical application of creased BDNF mRNA levels in the rat hippocampus mGlu5 antagonists. after chronic administration, suggesting that the blockade of mGlu5 receptors may induce expression of BDNF via the reduction of glutamatergic neuro- Acknowledgment: transmission that may finally result in the antidepres- This work was supported by the grant POIG.01.01.02-12-004/09 “Depression-Methods-Therapy”, task. 3.7. sant effect.
References:
Possible clinical applications of mGlu5 1. Aan Het Rot M, Zarate CA Jr, Charney DS, Mathew SJ: receptor antagonists in the therapy Ketamine for depression: where do we go from here? of depression Biol Psychiatry, 2012, 72, 537–547. 2. Awad H, Hubert GW, Smith Y, Levey AI, Conn PJ: Acti- vation of metabotropic glutamate receptor 5 has direct excitatory effects and potentiates NMDA receptor cur- An important role for mGlu5 receptors in depression rents in neurons of the subthalamic nucleus. J Neurosci, has been suggested by studies in humans. Post- 2000, 20, 7871–7879. 3. mortem analyses of prefrontal cortices from major de- Belozertseva IV, Kos T, Popik P, Danysz W, Bespalov AY: Antidepressant-like effects of mGluR1 and mGluR5 pression disorder (MDD) subjects showed lower lev- antagonists in the rat forced swim and the mouse tail sus- els of mGlu5 protein expression in the prefrontal cor- pension tests. Eur Neuropsychopharmacol, 2007, 17, tex relative to controls [10]. Furthermore, positron 172–179. emission tomography (PET) studies in humans 4. Berman RM, Cappiello A, Anand A, Oren DA, Heninger showed lower levels of mGlu5 binding in several GR, Charney DS, Krystal JA: Antidepressant effects of ketamine in depressed patients. Biol Psychiatry, 2000, brain regions of unmedicated patients with MDD 47, 351–354. compared to healthy control subjects [10]. 5. Boothby LA, Doering PL: Acamprosate for the treatment Preclinical studies investigating the potential anti- of alcohol dependence. Clin Ther, 2005, 27, 695–714. depressant effects of mGlu5 receptor antagonists led 6. Bradbury MJ, Giracello DR, Chapman DF, Holtz G, Schaffhauser H, Rao SP, Varney MA, Anderson JJ: to the introduction of two different mGlu5 receptor Metabotropic glutamate receptor 5 antagonist-induced antagonists, namely RG7090 (RO4917523, Roche) stimulation of hypothalamic-pituitary-adrenal axis activ- and AZD2066 (Astra-Zeneca), into Phase II trials in ity: interaction with serotonergic systems. Neuropharma- patients with TRD or MDD. Currently, a Phase II cology, 2003, 44, 562–572. 7. study with RG7090 is underway as adjunctive therapy Conn PJ, Pin JP: Pharmacology and functions of meta- botropic glutamate receptors. Ann Rev Pharmacol Toxi- in patients with MDD (see http://www.clinicaltri- col, 1997, 37, 205–237. als.gov/ct2/show/NCT01437657?term=RO4917523& 8. Cosford ND, Tehrani L, Roppe J, Schweiger E, Smith rank=6). ND, Anderson J, Bristow L et al.: 3-[(2-Methyl-1,3-
Pharmacological Reports, 2013, 65, 15061511 1509 thiazol-4-yl)ethynyl]-pyridine: a potent and highly selec- 20. Legutko B, Szewczyk B, Pomierny-Chamio³o L, Nowak tive metabotropic glutamate subtype 5 receptor antago- G, Pilc A: Effect of MPEP treatment on brain-derived nist with anxiolytic activity. J Med Chem, 2003, 46, neurotrophic factor gene expression. Pharmacol Rep, 204–206. 2006, 58, 427–430. 9. Cowen MS, Djouma E, Lawrence AJ: The metabotropic 21. Lenze EJ, Skidmore ER, Begley AE, Newcomer JW, glutamate 5 receptor antagonist 3-[(2-methyl-1,3- Butters MA, Whyte EM: Memantine for late-life depres- thiazol-4-yl)ethynyl]-pyridine reduces ethanol self- sion and apathy after a disabling medical event: a 12- administration in multiple strains of alcohol-preferring week, double-blind placebo-controlled pilot study. Int rats and regulates olfactory glutamatergic systems. J Geriatr Psychiatry, 2012, 27, 974–980. J Pharmacol Exp Ther, 2005, 315, 590–600. 22. Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, 10. Deschwanden A, Karolewicz B, Feyissa AM, Treyer V, Li XY et al.: mTOR-dependent synapse formation under- Ametamey SM, Johayem A, Burger C et al.: Reduced lies the rapid antidepressant effects of NMDA antago- metabotropic glutamate receptor 5 density in major de- nists. Science, 2010, 329, 959–964. pression determined by [11C]ABP688 PET and postmor- 23. Li X, Need AB, Baez M, Witkin JM: Metabotropic glu- tem study. Am J Psychiatry, 2011, 168, 727–734. tamate 5 receptor antagonism is associated with 11. Diazgranados N, Ibrahim L, Brutsche NE, Newberg A, antidepressant-like effects in mice. J Pharmacol Exp Kronstein P, Khalife S, Kammerer WA et al.: A random- Ther, 2006, 319, 254–259. ized add-on trial of an N-methyl-D-aspartate antagonist 24. Liu RJ, Lee FS, Li XY, Bambico F, Duman RS, in treatment-resistant bipolar depression. Arch Gen Psy- Aghajanian GK: Brain-derived neurotrophic factor chiatry, 2010, 67, 793–802. Val66Met allele impairs basal and ketamine-stimulated 12. Doherty AJ, Palmer MJ, Bortolotto ZA, Hargreaves A, synaptogenesis in prefrontal cortex. Biol Psychiatry, Kingston AE, Ornstein PL, Schoepp DD et al.: A novel, 2012, 71, 996–1005. competitive mGlu5 receptor antagonist (LY344545) 25. Nakanishi S: Molecular diversity of glutamate receptors blocks DHPG-induced potentiation of NMDA responses and implications for brain function. Science, 1992, 258, but not the induction of LTP in rat hippocampal slices. 597–603. Br J Pharmacol, 2000, 131, 239–244. 26. Pa³ucha A, Brañski P, Szewczyk B, Wieroñska JM, 13. Dwyer JM, Lepack AE, Duman RS: mTOR activation is K³ak K, Pilc A: Potential antidepressant-like effect of required for the antidepressant effects of mGluR2/3 MTEP, a potent and highly selective mGluR5 antagonist. blockade. Int J Neuropsychopharmacol, 2012, 15, Pharmacol Biochem Behav, 2005, 81, 901–906. 429–434. 27. Pa³ucha A, Pilc A: Metabotropic glutamate receptor 14. Gasparini F, Lingenhöhl K, Stoehr N, Flor PJ, Heinrich ligands as possible anxiolytic and antidepressant drugs. M, Vranesic I, Biollaz M et al.: 2-Methyl-6-(phenylethy- Pharmacol Ther, 2007, 115, 116–147. nyl)-pyridine (MPEP), a potent, selective and systemi- 28. Pa³ucha-Poniewiera A, Brañski P, Wieroñska JM, cally active mGlu5 receptor antagonist. Neuropharma- Stachowicz K, S³awiñska A, Pilc A: The antidepressant- cology, 1999, 38, 1493–1503. like action of mGlu5 receptor antagonist, MTEP, in 15. Harris BR, Prendergast MA, Gibson DA, Rogers DT, the tail suspension test in mice is serotonin dependent. Blanchard JA, Holley RC, Fu MC: Acamprosate inhibits Psychopharmacology, 2013, doi: 10.1007/s00213-013- the binding and neurotoxic effects of trans-ACPD, sug- 3206-6. gesting a novel site of action at metabotropic glutamate 29. Pa³ucha-Poniewiera A, Pilc A: Involvement of mGlu5 receptors. Alcohol Clin Exp Res, 2002, 26, 1779–1793. and NMDA receptors in the antidepressant-like effect of 16. Hughes ZA, Neal SJ, Smith DL, Sukoff Rizzo SJ, Puli- acamprosate in the tail suspension test. Prog Neuropsy- cicchio CM, Lotarski S, Lu S.: Negative allosteric modu- chopharmacol Biol Psychiatry, 2012, 39, 102–106. lation of metabolic glutamate receptor 5 results in broad 30. Pilc A, K³odziñska A, Brañski P, Nowak G, Pa³ucha A, spectrum activity relevant to treatment resistant depres- Szewczyk B, Tatarczyñska E: Multiple MPEP admini- sion. Neuropharmacology, 2012, 66, 202–214. strations evoke anxiolytic- and antidepressant-like ef- 17. Ibrahim L, Diazgranados N, Luckenbaugh DA, fects in rats. Neuropharmacology, 2002, 43, 181–187. Machado-Vieira R, Baumann J, Mallinger AG, Zarate 31. Pilc A, Wieroñska JM, Skolnick P: Glutamate-based an- CA Jr: Rapid decrease in depressive symptoms with an tidepressants: Preclinical Psychopharmacology. Biol N-methyl-D-aspartate antagonist in ECT-resistant major Psychiatry, 2013, 73, 1125–113. depression. Prog Neuropsychopharmacol Biol Psychia- 32. Pomierny-Chamio³o L, Poleszak E, Pilc A, Nowak G: try, 2011, 35, 1155–1159. NMDA but not AMPA glutamatergic receptors are in- 18. Iijima M, Fukumoto K, Chaki S: Acute and sustained ef- volved in the antidepressant-like activity of MTEP dur- fects of a metabotropic glutamate 5 receptor antagonist ing the forced swim test in mice. Pharmacol Rep, 2010, in the novelty-suppressed feeding test. Behav Brain Res, 62, 1186–1190. 2012, 235, 287–292. 33. Skolnick P: Antidepressants for the new millennium. Eur 19. Koike H, Iijima M, Chaki S: Involvement of the mam- J Pharmacol, 1999, 375, 31-40. malian target of rapamycin signaling in the 34. Szewczyk B, Pa³ucha-Poniewiera A, Poleszak E, Pilc A, antidepressant-like effect of group II metabotropic gluta- Nowak G: Investigational NMDA receptor modulators mate receptor antagonists. Neuropharmacology, 2011, for depression. Expert Opin Investig Drugs, 2012, 21, 61, 1419–1423. 91–102.
1510 Pharmacological Reports, 2013, 65, 15061511 MGlu5 receptor as a target for new antidepressants Agnieszka Pa³ucha-Poniewiera et al.
35. Tatarczyñska E, K³odziñska A, Chojnacka-Wójcik E, of group 1 metabotropic glutamate receptors with multi- Pa³ucha A, Gasparini F, Kuhn R, Pilc A: Potential anxio- valent complexes of homer-related, synaptic proteins. lytic- and antidepressant-like effects of MPEP, a potent, Neuron, 1998, 21, 707–716. selective and systemically active mGlu5 receptor antago- 39. Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli nist. Br J Pharmacol, 2001, 132, 1423–1430. R, Luckenbaugh DA, Charney DS, Manji HK: A ran- 36. Tu JC, Xiao B, Naisbitt S, Yuan JP, Petralia RS, Brake- domized trial of an N-methyl-D-aspartate antagonist in man P, Doan A et al.: Coupling of mGluR/Homer and treatment-resistant major depression. Arch Gen Psychia- PSD-95 complexes by the Shank family of postsynaptic try, 2006, 63, 856–864. density proteins. Neuron, 1999, 23, 583–592. 40. Zarate CA Jr, Singh JB, Quiroz JA, De Jesus G, 37. Wieroñska JM, Szewczyk B, Brañski P, Pa³ucha A, Pilc Denicoff KK, Luckenbaugh DA, Manji HK, Charney A: Antidepressant-like effect of MPEP, a potent, selec- DS: A double-blind, placebo-controlled study of meman- tive and systemically active mGlu5 receptor antagonist tine in the treatment of major depression. Am J Psychia- in the olfactory bulbectomized rats. Amino Acids, 2002, try, 2006, 163, 153–155. 23, 213–216. 38. Xiao B, Tu JC, Petralia RS, Yuan JP, Doan A, Breder Received: July 18, 2013; in the revised form: September 20, 2013; CD, Ruggiero A et al.: Homer regulates the association accepted: September 23, 2013.
Pharmacological Reports, 2013, 65, 15061511 1511