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Neuropharmacology 60 (2011) 1017e1041

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Neuropharmacology

journal homepage: www.elsevier .com/locate/neuropharm

Metabotropic glutamate receptors: From the workbench to the bedside

F. Nicoletti a,b,*, J. Bockaert c, G.L. Collingridge d, P.J. Conn e, F. Ferraguti f,D.D. Schoepp g, J.T. Wroblewski h, J.P. Pin c

aDepartment of Physiology and Pharmacology, University of Rome, Sapienza, Piazzale Aldo Moro 5, 00185 Rome, Italyb I.N.M. Neuromed, Pozzilli, Italyc Institute of Functional Genomics, CNRS UMR 5203, INSERM U661, University of Montpellier 1 & 2, Montpellier, FrancedMRC Centre for Synaptic Plasticity, Department of Anatomy, University of Bristol, Bristol, UKeDepartment of Pharmacology, Vanderbilt Program in Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USAfDepartment of Pharmacology, Innsbruck Medical University, Innsbruck, AustriagNeuroscience, Merck and Company Inc., North Wales, NJ, USAhDepartment of Pharmacology, Georgetown University Medical Centre, Washington, DC, USA

a r t i c l e i n f o

Article history:Received 26 August 2010Received in revised form15 October 2010Accepted 21 October 2010

In memory of Prof. Erminio Costa.

Keywords:Metabotropic glutamate receptorsReceptor structuremGlu receptor ligandsClinical studies

* Corresponding author. Department of Physiology aof Rome, Sapienza, Piazzale Aldo Moro 5, 00185 Romefax: þ39 0865 927575.

E-mail address: ferdinandonicoletti@hotmail.com

0028-3908/$ e see front matter � 2010 Elsevier Ltd.doi:10.1016/j.neuropharm.2010.10.022

a b s t r a c t

Metabotropic glutamate (mGlu) receptors were discovered in the mid 1980s and originally described asglutamate receptors coupled to polyphosphoinositide hydrolysis. Almost 6500 articles have been pub-lished since then, and subtype-selective mGlu receptor ligands are now under clinical development forthe treatment of a variety of disorders such as Fragile-X syndrome, schizophrenia, Parkinson’s diseaseand L-DOPA-induced dyskinesias, generalized anxiety disorder, chronic pain, and gastroesophageal refluxdisorder. Prof. Erminio Costa was linked to the early times of the mGlu receptor history, when a fewresearch groups challenged the general belief that glutamate could only activate ionotropic receptors andall metabolic responses to glutamate were secondary to calcium entry. This review moves from thosenostalgic times to the most recent advances in the physiology and pharmacology of mGlu receptors, andhighlights the role of individual mGlu receptor subtypes in the pathophysiology of human disorders.

This article is part of a Special Issue entitled ‘Trends in Neuropharmacology: InMemory of Erminio Costa’.� 2010 Elsevier Ltd. All rights reserved.

1. Historical background

The evidence that quisqualate and glutamate stimulated inositolphosphate formation in cultured striatal neurons (Sladeczek et al.,1985) offered the first demonstration that excitatory amino acidscould activate receptors other than the classical ligand-gated ionchannels (named NMDA, “quisqualate” and kainate receptors atthat time). In themeantime, ibotenic acid, a heterocyclic amino acidnaturally occurring in the mushrooms Amanita muscaria andAmanita pantherina, was found to stimulate inositol phosphateformation in hippocampal slices (Nicoletti et al., 1986a,b). Gluta-mate was virtually inactive in adult brain slices, but was able tostimulate polyphosphoinositide (PI) hydrolysis to a great extent(as much as 20 fold in some experiments) in slices from 7- to 9-dayold rats (Nicoletti et al., 1986a). The latter findings were the productof the intuition, creativity, and long experience of Prof. Erminio

nd Pharmacology, University, Italy. Tel.: þ39 06 49912969;

(F. Nicoletti).

All rights reserved.

Costa, who, at that time, was the Director of the Laboratory ofPreclinical Pharmacology of NIMH, St. Elizabeth’s Hospital, Wash-ington, DC. Independent work by Carl Cotman and his associatesdemonstrated that L-2-amino-4-phosphonobutanoate (L-AP4) andL-serine-O-phosphate (L-SOP), which at that time were consideredas excitatory amino acid receptor antagonists, reduced excitatorysynaptic transmission at mossy fibre/CA3 pyramidal cell synapsesof the guinea pig hippocampus (Cotman et al., 1986), thus providingthe first indirect evidence for the existence or presynaptic group-IIImGlu autoreceptors (see below). In 1987, Prof. Sugyiama and hiscolleagues introduced the terminology of “metabotropic glutamatereceptors” to indicate quisqualate-sensitive receptors expressed inXenopus oocytes injected with rat brain mRNA (Sugiyama et al.,1987). The cloning of the first metabotropic glutamate subtypes(named mGluR1 or mGlu1 receptor) in the lab of Prof. Nakanishi(Masu et al., 1991) was the milestone for any further growth of thefield. The eight mGlu receptor subtypes identified so far are dividedinto three groups, with group I including mGlu1 and mGlu5, groupII including mGlu2 and mGlu3, and group III including mGlu4,mGlu6, mGlu7, and mGlu8. mGlu1 and mGlu5 receptors arecoupled to Gq/G11, whereas all other subtypes are coupled to Gi/Go

Fig. 1. Modular structure of mGlu receptors. a) Ribbon view of the open (left) andclosed (right) mGlu1 receptor Venus Fly Trap (VFT) bound with glutamate (back).Images were prepared using the coordinates of the glutamate-bound mGlu1 receptorVFT dimer (pdb 1EWK), in which one VFT is closed while the other is open. b) Sideview of the mGlu1 receptor dimer bearing the VFT in its empty “resting” state (left)(pdb 1EWT), or agonist occupied “active” orientation (right) (pdb 1EWK). The frontVFT is in light grey, while the one in the back is black. c) General organization of anmGlu receptor deduced from the structure of the dimeric mGlu3 extracellular domain(VFT þ CRD) (pdb 1E4U) associated with two rhodopsin-like 7-TM domains.

F. Nicoletti et al. / Neuropharmacology 60 (2011) 1017e10411018

in heterologous expression systems (see below). The pharmacologyof mGlu receptors has expanded dramatically in the last few years,and subtype-selective ligands are now under clinical development.As described above, quisqualate and ibotenic acid were the firstreported molecules active at mGlu receptors coupled to PI hydro-lysis. These molecules, however, are not selective and show activityat ionotropic glutamate receptors. The first breakthrough in thepharmacology of mGlu receptors was the discovery that trans-1-amino-cyclopentanedicarboxylic acid (trans-ACPD) could acti-vate PI hydrolysis in brain slices with no effect at ionotropicglutamate receptors (Schoepp et al., 1991). One of the isomers oftrans-ACPD, 1S,3R-ACPD, activates both group-I and group-II mGlureceptors (reviewed by Schoepp et al., 1999), and is still widely usedas a non-selective mGlu receptor agonist. L-AP4, L-SOP and L-2-amino-3-phosphonopropionic acid (L-AP3) were described asantagonists of mGlu receptors coupled to PI hydrolysis in brainslices (Nicoletti et al., 1986a,b,c; Schoepp and Johnson, 1989). L-AP3is now obsolete, whereas L-AP4 and L-SOP are considered asprototypical agonists of group-III mGlu receptors. Jeff Watkins andhis associates introduced a series of phenylglycine derivatives aspharmacological tools for investigating the role of mGlu receptorsin the CNS (Birse et al., 1993). One of these derivatives, R,S-a-methyl-4-carboxyphenylglycine (MCPG), has been widely usedas a non-subtype-selective mGlu receptor antagonist (Eaton et al.,1993). The modern pharmacology of mGlu receptors coincideswith the advent of orthosteric ligands bearing a cyclopropyl moietyin their structure. (2S,3S,4S)-2-(Carboxycyclopropyl)glycine(L-CCG-I) and (2S,10R,20R,30R)-2-(2,3-dicarboxycyclopropyl)glycine(DCG-IV), synthesized in the lab of Prof. Shinozaki (Shinozaki andIshida, 1993), have been used for many years, and are still used,as potent mGlu2/3 receptor agonists. More recent compoundssynthesized by Jim Monn at Eli Lilly, e.g. (1S,2S,5R,6S)-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740) and(1R,4R,5S,6R)-4-amino-2-oxabicyclo[3.1.0]hexane-4,6-dicarboxylicacid (LY379268), show nanomolar potency as mGlu2/3 receptoragonists and are systemically active (reviewed by Schoepp et al.,1999). Other drugs, including positive and negative allostericmodulators (PAMs and NAMs) of individual mGlu receptorsubtypes, are described in the appropriate sections below. Bydefinition, these drugs bind tomGlu receptor sites distinct from theprimary glutamate recognition site. No endogenous ligands(“endocoids”) of thesemodulatory sites have been identified, as yet.Their existence is unlikely because the 7-transmembrane (7TM)region, which contains the binding sites of most PAMs and NAMs, isnot highly conserved among the eight mGlu receptor subtypes.Now, after 25 years from the discovery of mGlu receptors, a numberof potent and subtype-selective ligands of mGlu receptors areunder clinical development and are among the most promisingdrugs in the treatment of neurological and psychiatric disorders.

2. Structure and activation mechanism of mGluRs

Sequence analysis of most class CG-protein coupled receptors(GPCRs), including the 8 mGlu receptor subtypes, the Ca2þ-sensingreceptor, the taste T1R receptors, and the basic amino acid receptorGPCR6a, revealed that these receptors have a large extracellulardomain made of a Venus Fly Trap (VFT) domain similar to theperiplasmic bacterial leucine/isoleucine/valine binding protein(LIVBP) linked to the first TM domain via a cysteine-rich domain(CRD) containing 9 highly conserved cysteine residues (Fig. 1c). Anumber of 3D modeling studies (O’Hara et al., 1993), but mostimportantly, the resolution of a crystal structure of the mGlu1extracellular domain (Kunishima et al., 2000; Tsuchiya et al., 2002)confirmed that the glutamate binding domain is structurally similarto LIVBP-like proteins (Fig. 1a). Later on, the structures of mGlu3

and mGlu7 receptor VFTs were reported (Muto et al., 2007). TheVFT domain is composed of two lobes, each made of a-helicesaround a large b-sheet, with the glutamate binding site located inthe cleft between the two lobes. Structural analysis of the bindingpocket revealed 5 residues that directly contact the amino acidmoiety and are conserved in a large variety of amino acid bindingLIVBP-like proteins. The structure of the CRD was solved togetherwith the VFT of the mGlu3 receptor (Muto et al., 2007), andrevealed a domainmade of two subdomains, each composed of 4 b-strands stabilized by 2 disulfide bridges. This domain is furtherlinked to the VFT via an additional highly conserved disulfide bond,likely rigidifying the connection between the VFT and the CRD. The7-TM domain of mGlu receptors shows very low sequence simi-larity with the 7-TM domain of other GPCRs. However, the 7-TMdomains of mGlu receptors and other GPCRs share a similar generalfold, with a relatively central helix 3, and a possible amphipathic

Table 1Conformations of the Venus Fly Traps of mGlu receptor subtypes bound to agonistsor antagonists.

Receptor Ligand Ligand activity Conformation PDB entry

mGlu1 e e Dimer Roo 1EWTe e Dimer Aco 1EWVGlu Agonist Dimer Aco 1EWKGlu þ Gd3þ Agonist Dimer Acc 1ISRMCPG Antagonist Dimer Roo 1ISSLY341495 Antagonist Dimer Aoo 3KS9

mGlu5 Glu Agonist Dimer Acc 3LMK

mGlu3 Glu Agonist Dimer Rcc 2E4UDCG-IV Agonist Dimer Rcc 2E4V1S,3S-ACPD Agonist Dimer Rcc 2E4W1S,3R-ACPD Agonist Dimer Rcc 2E4X2R,4R-APDC Agonist Dimer Rcc 2E4Y

mGlu7 e e Dimer Roo 2E4ZLY341495 Antagonist Monomer open 3MQ4

Glu ¼ Glutamate; R ¼ resting; A ¼ active; o ¼ open; c ¼ closed.

Table 2Subtype-selective mGlu receptor ligands.

Subtype Orthostericagonists

Orthostericantagonists

PAMs NAMs

mGlu1 DHPG(group-selective)

LY367385,AIDA,MATIDA

Ro-0711401,Ro-674853,Ro-677476, VU71

CPCCOEt,BAY367620,JNJ6259685

mGlu5 DHPG(group-selective)CHPG

None DFB, CPPHA,CDPPB, VU29ADX47273,ADX63365

MPEP, SIB1757,SIB1893,Fenobam,AFQ056,AZD2516,AZD2066,STX107,ADX10059,ADX48621

mGlu2 LY354740,LY379268,LY404039

LY341495,MGS0039

LY566332,LY487379, BINA

mGlu3 MCPG Antagonist Dimer Roo 1ISSLY341495 Antagonist Dimer Aoo 3KS9

mGlu5 Glu Agonist Dimer Acc 3LMK

mGlu3 Glu Agonist Dimer Rcc 2E4UDCG-IV Agonist Dimer Rcc 2E4V1S,3S-ACPD Agonist Dimer Rcc 2E4W1S,3R-ACPD Agonist Dimer Rcc 2E4X2R,4R-APDC Agonist Dimer Rcc 2E4Y

mGlu7 e e Dimer Roo 2E4ZLY341495 Antagonist Monomer open 3MQ4

F. Nicoletti et al. / Neuropharmacology 60 (2011) 1017e1041 1019

helix 8 (Pin et al., 2003). Indeed, when the 7-TM domain alone isexpressed in cells (after deletion of both the extra and intracellularparts), it folds correctly, and can be directly activated by ligandsknown as positive allosteric modulators (PAMs) of the full lengthreceptors (Goudet et al., 2004), indicating that a change inconformation in such an isolated domain is sufficient for G-proteinactivation. In addition, as observed in many rhodopsin-like GPCRs,an ionic interaction between residues at the intracellular side ofhelices 3 and 6 is important to maintain the receptor in an inactiveconformation (Binet et al., 2007). Lastly, as observed in otherGPCRs, both the intracellular loops 2 and 3, as well as the helix 8 areimportant in G-protein coupling, being also involved in couplingselectivity (Pin et al., 2003).

Not only are mGlu receptors complex proteins because of themodular structural organization, but also because they form dimersstabilized by an intersubunit disulfide bond (Romano et al., 1996a).Such a dimeric organizationwas shown not only in transfected cells,but also in the brain. Using energy transfer technologies, togetherwith systems to control receptor subunit composition, it was shownthat mGlu receptors form dimers but not larger complexes, asopposed, for example, to the related GABAB receptor (Maurel et al.,2008). Early studies suggested that mGlu receptors only formhomodimers, then limiting the number of possible mGlu receptorsin the brain to the eight major subtypes (not taking into account thesplice variants). However, a recent report by Doumazane et al.(2010) demonstrates that, similarly to GABAB receptors and sweetand umami taste receptors, mGlu receptor subtypes can form het-erodimers. Subtypes of the same group of mGlu receptors can formintragroup heterodimers (e.g., mGlu1 with mGlu5 and mGlu2 withmGlu3 receptors), and, interestingly, group-II and group-III mGlureceptors can form intergroup heterodimers (e.g., mGlu2 withmGlu4 receptors). No heterodimers can be formed between group-Iand group-II/III mGlu receptors (e.g., mGlu1 and mGlu2 or mGlu4),suggesting that only mGlu receptor subtypes coupled to the same Gprotein can form heterodimers. Of interest, different mGlu receptorsubunits have been colocalized in specific subdomains in neurons,suggesting the existence of mGlu receptor heterodimers in thebrain. Further work is however necessary before the functionalsignificance of such heterodimeric receptor entities is identified.

The dimeric organization of the mGlu receptors raises thequestion of how receptor function is influenced by ligand bindingstoichiometry. Kniazeff et al. (2004a) have shown that a singleagonist per dimer (i.e. a single VFT stabilized in the closed state) issufficient for receptor activation, although the presence of twoagonist molecules (i.e. both VFTs in the closed state) leads toa 3-fold higher coupling efficiency. It has even been suggested thatthe two states (one or two VFTs in the closed state) activatedifferent signalling pathways, e.g. mGlu1 receptor coupling to Gsand Gq, respectively (Tateyama and Kubo, 2006). How can gluta-mate, by interacting into the cleft of the VFT, induce the necessarychange in conformation at the 7-TM level to activate G-proteins? Afirst important step was discovered through the resolution of theVFT structure occupied either by an agonist or an antagonist (Fig.1a,and Table 1) (Kunishima et al., 2000; Tsuchiya et al., 2002). Indeed,as observed for most LIVBP-like domains, ligand binding stabilizesthe VFT domain in a closed conformation. This is well illustrated bythe observation that many structures with bound agonists are inthe closed form (Tables 1 and 2). Although open conformationswith bound agonist have been identified for mGlu1 receptors, thismay simply reflect the ability of this domain to oscillate betweena closed and an open state, as already reported for many otherLIVBP-like proteins. In contrast, all antagonist bound structurescorrespond to open VFTs. Of note, removing the steric or ionichindrance that prevents VFT closure by site directed mutagenesiswas found sufficient to convert the group-III mGlu receptor

antagonists, (S)-2-amino-2-methyl-4-phosphonobutanoic acid(MAP4) and (1S,3R,4S)-1-aminocyclopentane-1,3,4-tricarboxylicacid (ACPT-I) into full agonists, consistent againwith the close statecorresponding to the active state (Bessis et al., 2002). As a furthersupport to this conclusion, the fully activated state of the relatedGABAB receptor was obtained by inserting a disulfide bond expec-ted to lock the VFT in its closed state (Kniazeff et al., 2004b).

The structures of mGlu1 VFT solved in the presence of agonistsand antagonists suggested that the dimeric organization playsa pivotal role in the activation process. Indeed, an important reor-ientation of the VFTs in the dimer, from resting (R) to active (A)(Fig. 1b) was observed when at least one VFT was in a closed state(Fig. 1b) (Kunishima et al., 2000; Tsuchiya et al., 2002). However,recent new structures of dimeric mGlu VFTs cast some doubts onthis proposed activation mechanism. Indeed, the active orientation

Fig. 2. Proteineprotein interactions involving group-I mGlu receptors in the post-synaptic densities. Long isoforms of Homer proteins allows the formation of multi-molecular complexes including mGlu1 and mGlu5 receptors. Interactions with NMDAreceptors, TrpC ion channels, inositol-1,4,5-trisphosphate receptors (InsP3R), or PIKE-Lare shown. Short Homer1a lacking the coiled-coil domain disrupts the formation of themultimolecular complex, thereby affecting mGlu1/5 receptor signalling.

F. Nicoletti et al. / Neuropharmacology 60 (2011) 1017e10411020

was observed with the dimeric mGlu1 receptor VFTs bound withthe antagonist, (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (LY341495) (unpublished observa-tion, pdb accession number 3KS9), and the resting orientation wassystematically observed with the mGlu3 receptor VFT dimer boundwith 5 different agonists (Muto et al., 2007). Although a change inthe relative position between the VFTs is expected, as suggested bya study performed on the related GABAB receptor (Rondard et al.,2008), the movement may not necessarily be as important as thatobserved in the crystal structures. As shown in Fig. 1c, it is notpossible to have both 7-TM domains of a dimeric mGlu receptor tobe in close proximity according to the solved structure of themGlu3receptor extracellular domain composed of both the VFT and theCRD. This appears surprising and not consistent with the FRET dataobtained with GFP fusion mGlu receptor subunits (Marcaggi et al.,2009; Tateyama et al., 2004). A relative movement between themGlu receptor subunits during activation is indeed supported byFRET measurements between their intracellular sides (Marcaggiet al., 2009; Tateyama et al., 2004). However, whether the changewith FRET is solely due to a change in the distance between thefused GFPs, or to a change in their relative orientation due toconformational changes of the intracellular loops remains unclear.Whatever the real mechanism, it leads to the activation of only one7TM within the dimer (Hlavackova et al., 2005), which stronglysuggests a direct contact between the 7TMs in the dimer. Furtherwork is necessary to understand how agonist binding leads to theactivation of the 7TM.

3. Detailed description of mGlu receptor subtypes

3.1. mGlu1 receptor

Gene name: GRM1 (human); Grm1 (rat, mouse). Accessionnumbers: NP_000829 (human); NP_058707 (rat); NP_058672(mouse). Chromosomal location: 6q24 (human); 1p13 (rat); 10A2(mouse) (Masu et al., 1991; Kuramoto et al., 1994; Desai et al., 1995;Stephan et al., 1996).

3.1.1. Splice variants (Ferraguti et al., 2008)mGlu1a or mGlu1a (longest isoform): 1199 and 1194 amino

acids in rodents and humans, respectively. C-terminus intracellulardomain formed by 360 amino acids. mGlu1b1 or mGlu1b: 906amino acids. C-terminus domain: 68 amino acids. mGlu1b2 ormGlu1f: 906 amino acids. C-terminus domain: 68 amino acids.mGlu1g or mGlu1d: 908 amino acids. C-terminus domain: 70amino acids. mGlu1d or mGlu1E55: 321 amino acids. Possiblesecreted protein.

3.1.2. Receptor signalling and interacting proteinsmGlu1 receptors are primarily coupled to Gq/G11 proteins

(Masu et al., 1991). Receptor activation stimulates phospholipase Cb(PLCb), the enzyme that cleaves phosphatidylinositol-4,5-bisphos-phate with the ensuing formation of the intracellular secondmessengers, inositol-1,4,5-trisphosphate (Ins-1,4,5-P3) and diac-ylglycerol (DAG). Ins-1,4,5-P3 releases Ca2þ from intracellularstores, whereas DAG activates protein kinase C. Stimulation ofcAMP formation, arachidonic acid release, the mitogen-activatedprotein kinase (MAPK) pathway, and L-type voltage-sensitive Ca2þ

channels has also been reported in response to mGlu1 receptoractivation (reviewed by Ferraguti et al., 2008). The mGlu1 receptornegatively modulates a variety of Kþ channels, including M-typevoltage-gated Kþ channels (Ikeda et al., 1995) and the “tandem-pore” TASK and TREK Kþ channels (Talley et al., 2000; Chemin et al.,2003). In cultured neurons, mGlu1 (and mGlu5) receptors nega-tively modulate voltage-sensitive Ca2þ channels via mechanisms

that involve pertussis toxin (PTX)-sensitive and PTX-insensitive Gproteins and are regulated by Homer proteins (Choi and Lovinger,1996; Kammermeier et al., 2000).

Different isoforms of G-protein coupled receptor kinases (GRKs),including GRK2, GRK4, and GRK5, mediate homologous desensiti-zation of mGlu1 receptors (Dale et al., 2000; Sallese et al., 2000;Iacovelli et al., 2003). GRK4 is required for desensitization ofnative mGlu1 receptors in cerebellar Purkinje cells (Sallese et al.,2000). The Regulator of G-protein Signalling, RGS-4, whichincreases the GTPase activity of Gaq, inhibits mGlu1 receptor sig-nalling (Saugstad et al., 1998).

A number of proteins have been shown to interact with mGlu1receptors and to modify their surface expression and intracellularsignal transduction. Homer proteins, which contain both PDZ (fromPSD-95, DlgA, and Zo-1 proteins) and EVH-1 (from Ena/VaspHomology-1) domains, bind to a proline-rich motif in theC-terminal tail of mGlu1a and mGlu5 receptors (Brakeman et al.,1997; Kato et al., 1998; Xiao et al., 1998; Tu et al., 1998). Allmembers of the Homer family, with the exception of Homer1a,contain a C-terminal coiled-coil domain, which allows multi-merization (Kato et al., 1998; Tu et al., 1998). Thus, Homer proteinsform a linking bridge between mGlu1a receptors and otherproteins that are involved in receptor signalling, such as PLCb3 and-4, the InsP3 receptor, and the TrpC1 channel (reviewed by Ferragutiet al., 2008) (Fig. 2). The latter likely behaves as a store-operatedchannel, providing a potential route to restore intracellular Ca2þ

stores after the opening of InsP3-gated ion channels. mGlu1areceptors can also activate the phosphatidylinoisol-3-kinase(PtdIns-3-K) pathway via the interaction with Homer protein, andthe PtdIns-3-K enhancer, PIKE-L (Rong et al., 2003) (Fig. 2). All theseinteractions are disrupted by the short Homer isoform, Homer1a,which is rapidly induced in response to synaptic activation andshares with other Homers the ability to interact with mGlu1areceptors, but cannot form multimeric complexes. mGlu1a recep-tors can also associate with tamaline (Kitano et al., 2002), thecytoskeletal protein, 4.1G (Lu et al., 2004), and the ubiquitin ligase,Siah-1A (Seven In Ansentia Homologue-1A) (Ishikawa et al., 1999;Kammermeier and Ikeda, 2001). The mGlu1 receptor co-immuno-precipitates and functionally interacts with ephrin-B2 (Calò et al.,2005), a member of the ephrin/Eph receptor family of trans-membrane proteins, which mediate processes of cell-to-cell inter-action during development and in the adult life. Activation ofephrin-B2 by its receptor partner, Eph-B1, amplifies mGlu1receptor signalling in brain tissue and cultured neurons. This

F. Nicoletti et al. / Neuropharmacology 60 (2011) 1017e1041 1021

interaction might have interesting implications for processes ofdevelopmental plasticity (Calò et al., 2005, 2006).

3.1.3. Functional anatomyExpression of mGlu1 receptors is extensive in cerebellar Pur-

kinje cells and in themitral/tufted cells of the olfactory bulb. Strongexpression is also found in the pars compacta of the substantianigra, lateral septum, globus pallidum, and thalamic relay nuclei(Martin et al., 1992; Shigemoto et al., 1992; Baude et al., 1993).Neuroendocrine regions of the hypothalamus express higher levelsof mGlu1b thanmGlu1a receptors (Mateos et al., 1998; Van den Pol,1994). The subcellular localization of the mGlu1 receptor has beenconsistently associated with postsynaptic specialization of excit-atory synapses, where the receptor appears to be concentrated inperisynaptic and extrasynaptic areas. Thus, mGlu receptors arerecruited by high concentrations of glutamate that escape theclearance mechanisms and spread to the sides of the synaptic cleft(Ferraguti et al., 2008 and references therein).

The function of the mGlu1 receptor has been most extensivelystudied in the cerebellar cortex, where receptor activation isrequired for the induction of long-term depression (LTD) of excit-atory neurotransmission at parallel fibre-Purkinje cell synapses.This particular form of synaptic plasticity underlies motor learning,vestibulo-ocular reflex adaptation, and eye-blink conditioning(reviewed by Kano et al., 2008). Activation of mGlu1 receptors inPurkinje cells leads to formation of diacylglycerol, which is thencleaved by diacylglycerol lipase into 2-arachidonylglycerol (2-AG),the major endocannabinoid species of the CNS. 2-AG diffuses backto parallel fibre nerve terminals, where it activates type-1 canna-binoid receptors, thereby inhibiting glutamate release (reviewed byKano et al., 2008). Gene-targeted deletion of mGlu1 receptorsimpairs LTD at parallel fibers-Purkinje cell synapses resulting intoa severe motor incoordination (Aiba et al., 1994; Conquet et al.,1994). Selective re-introduction of mGlu1a receptors in Purkinjecells restores LTD and corrects motor impairment (Ichise et al.,2000). In addition, mice lacking mGlu1 receptors show a defect inthe elimination of supranumerary climbing fibers innervatingPurkinje cells that physiologically occurs in the developing cere-bellum (Kano et al., 1997). Thus, the presence of mGlu1 receptors isessential for the correct development of the cerebellar cortex. Inaddition to a role in synaptic plasticity, mGlu1 receptors alsomediate a slow EPSP at synapses made between parallel fibers andPurkinje cells (Batchelor et al., 1997). Therefore, mGlu1 receptorsare involved in both acute and long-term regulation of synaptictransmission. While this synaptic response is induced by repetitivestimuli, it can be induced by as few as 3 stimuli (Batchelor andGarthwaite, 1997) which demonstrates that synaptically releasedL-glutamate can readily access these receptors. The mGlu1-receptormediated EPSC is subject to pronounced synaptic plasticity. Thus, itwas shown that depolarization of Purkinje cells by climbing fibrestimulation elicits near complete inhibition of this synaptic current(Jin et al., 2007). These various functions of mGlu1 receptors (role insynaptic transmission, expression of synaptic plasticity, trigger forsynaptic plasticity) could all contribute to the role of these recep-tors in physiological and pathological processes.

3.1.4. Pharmacology3,5-Dihydroxyphenylglycine (DHPG) binds to the glutamate

recognition site ofmGlu1 receptors behaving as an orthosteric agonist.However, this drug is not subtype selective, and also activates mGlu5receptors. To our knowledge, there are no orthosteric agonistsselective for mGlu1 receptors. (S)-2-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine (Ro67-7476), (9H-xanthene-9-carbonyl)-carba-mic acid butyl ester (Ro-674853), diphenyl-acetyl-carbamic acid ethylester (Ro-01-6128), and 4-nitro-N-(1,4-diphenyl-1H-pyrazol-5-yl)

benzamide (VU71) are examples of selectivemGlu1 receptor PAMs (or“enhancers”), which require the presence of an orthosteric agonist tobe active (reviewed by Niswender and Conn, 2010). These drugs, ifgiven alone, exclusively recruit mGlu1 receptors that are activated byendogenous glutamate, i.e. their action is activity-dependent. 4-(Amino-carboxy-methyl)-3-methyl-benzoic acid (LY367385), 1-ami-noindane-1,5,-dicarboxylic acid (AIDA), and its derivative, a-amino-5-carboxy-3-methyl-2-thiopheneacetic acid (3-MATIDA) are orthostericantagonists of mGlu1 receptors with little or no activity at mGlu5receptors (reviewed by Schoepp et al., 1999). 7-(Hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt) is theprototype of a growing list of drugs acting as negative allostericmodulators (NAMs) of mGlu1 receptors (reviewed by Niswender andConn, 2010). Some of these drugs, including (3aS,6aS)-hexahydro-5-methylene-6a-(2-naphthalenylmethyl)-1H-cyclopenta[c]furan-1-one(BAY367620) (Carroll et al., 2001) and (3,4-dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-(cis-4-methoxycyclohexyl)-methanone (JNJ16259685)(Lavreysen et al., 2004), display high receptor affinity and aresystemically active.

3.1.5. Relevance to human disorders3.1.5.1. Inherited ataxia and autoimmune cerebellar disorders. Animalstudies suggest that inherited ataxia can be associated witha defective expression or function of mGlu1 receptors in Purkinjecells. Ataxic transgenic mice show mutations of the Grm1 gene ora reduced expression/activity of mGlu1 receptors or downstreameffector molecules in Purkinje cells (Conti et al., 2006; Sachs et al.,2007; Kurnellas et al., 2007). Interestingly, in conditional spino-cerebellar ataxia type 1 (SCA1) mutant mice, recovery from thedisease after stopping transgene expression correlates with locali-zation of the mGlu1a receptor to the Purkinje cell-parallel fibresynapse (Zu et al., 2004). Although these data suggest that theGRM1 is a candidate gene for inherited cerebellar disorders, itshould be highlighted that no causative mutations in the GRM1gene have been found in childrenwith idiopathic early-onset ataxia(Rossi et al., 2010). In three patients, cerebellar ataxia has beenassociated with the presence of autoantibodies directed againstmGlu1 receptors. Two of these patients had Hodgkin’s lymphomawith paraneoplastic cerebellar ataxia (Sillevis Smitt et al., 2000).The third patient had a primary autoimmune disorder (Marignieret al., 2010). mGlu1 receptor PAMs are potential candidates forthe treatment of those forms of ataxia that are associated withdefective mGlu1 receptors. Mice developing experimental auto-immune encephalomyelitis (EAE) after immunization with themyelin oligodendrocyte glycoprotein (MOG) show a reducedexpression of mGlu1a receptors in Purkinje cells and an impairedmotor coordination at the rotarod test. Motor impairment is cor-rected by a systemic treatment with a selective mGlu1 receptorPAM (Fazio et al., 2008).

3.1.5.2. Malignant melanomas. Suzy Chen and her associates(Pollock et al., 2003) showed that insertional mutant mice predis-posed to develop malignant melanomas had a deletion of 70 kb inintron 3 of Grm1, resulting into an ectopic expression of mGlu1receptors in melanoma cells. Mutant mice in which expression ofthe Grm1 gene is driven by the promoter of dopachrome tauto-merase (an enzyme specifically expressed in melanocytes) alsodevelop multiple melanomas. Expression of mGlu1 receptors hasbeen detected in human melanomas, but not in benign nevi(Pollock et al., 2003). The oncogenic activity of mGlu1 receptors inmelanoma cells depends on the activation of multiple transductionpathways that include PKC-3, the MAPK pathway, and the PtdIns-3-K/Akt pathway (Marín et al., 2006; Shin et al., 2010). Treatment ofhuman melanoma cells with mGlu1 receptor NAMs or with rilu-zole, which inhibits glutamate release, reduces cell proliferation

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(Namkoong et al., 2007). No clinical data with mGlu1 receptorantagonists are available, as yet. However, data from a phase0 clinical trial show that a 14-day treatment with riluzole inhibitsmGlu1 receptor signalling and metabolic activity in post-treatmenttumor samples (Yip et al., 2009).

3.1.5.3. Neurodegeneration/neuroprotection. mGlu1 receptor antag-onists protect hippocampal neurons against “post-ischemic”degeneration in both hippocampal slices exposed to oxygeneglucose deprivation and in vivo models of transient global ischemia(reviewed by Pellegrini-Giampietro, 2003). Pharmacologicalblockade of mGlu1 receptors enhances GABAergic transmission inthe hippocampus by preventing the mGlu1-receptor mediatedformation of endocannabinoids and the ensuing activation ofinhibitory CB1 receptors localized on GABAergic nerve terminals(Landucci et al., 2009). In contrast, it is the activation of mGlu1receptors that mediates the mechanism of ischemic toleranceobserved with the paradigm of “ischemic preconditioning” inhippocampal slices (Werner et al., 2007), whereas activation of bothmGlu1 and mGlu5 receptors mediates mechanisms of “ischemicpost-conditioning” (Scartabelli et al., 2008). In cultured neuronschallenged with excitotoxins mGlu1 receptor antagonists areconsistently neuroprotective, whereas agonists can be neurotoxic orneuroprotective depending on the experimental paradigm(reviewed by Nicoletti et al., 1999). Michel Baudry and his associateshave shown that mGlu1a receptors activate two pathways thatdifferentially affect neurodegeneration: (i) a protective pathwaymediated by the activation of PtdIns-3-K; and (ii) a toxic pathwaymediated by intracellular Ca2þ release. The calpain-mediated trun-cation of mGlu1a receptors prevents the activation of the PtdIns-3-Kpathway, leaving the Ca2þpathway intact (Xu et al., 2007). Recentevidence also indicates that mGlu1a may produce dual neuro-protective and neurotoxic signalling in cerebellar and corticalneurons (Pshenichkin et al., 2008) exhibiting the properties ofa dependence receptor by inducing apoptosis in the absence ofglutamate, while promoting neuronal survival in its presence. Themechanism of the proapoptotic action has not been elucidated,but, similarly to other dependence receptors, it may involve anagonist-independent interaction of the C-terminal receptor domainwith intracellular targets. Instead, the prosurvival action of mGlu1occurs via a novel, G-protein independent, mechanism mediatedby b-arrestin1-dependent, persistent, activation of the MAPKpathway (Emery et al., 2010) with a pharmacology indicating thepresence of a ligand bias whereby glutamate, but not quisqualatecan activate the signal transduction mechanism. This suggestsa role for receptor desensitization and internalization e that crit-ically depend on the extent and duration of agonist exposure e inmechanisms of neurodegeneration/neuroprotection. Moreover, theproapoptotic action of mGlu1a may play a role in developmentalapoptosis in the CNS.

3.1.5.4. Schizophrenia. Recent evidence corroborates the hypoth-esis that inhibition of mGlu1 receptors could be a novel treatmentfor schizophrenia. Indeed, mGlu1 receptor antagonists were shownto selectively improve prepulse inhibition in DBA/2J mice (Hikichiet al., 2010), an animal model for impaired sensorimotor gating.Sensorimotor gating is a fundamental form of information pro-cessing that is deficient in patients with schizophrenia (Braff et al.,1992) and which can be modeled in animals using acoustic pre-pulse inhibition of the startle (PPI). Deficits in PPI were alsoobserved in mice with gene-targeted deletion of the mGlu1receptor, which was evident as early as 6 weeks postnatal andremained impaired till adulthood (Brody et al., 2003). Moreover,allosteric mGlu1 receptor antagonists reduced methamphetamine-induced hyperlocomotion (Satow et al., 2009) and behave similarly

to the atypical antipsychotic, clozapine, in activating neurons in thenucleus accumbens and medial prefrontal cortex (Suzuki et al.,2010). Although these findings are still at a relatively early stage,mGlu1 receptor antagonists hold promise as novel putative anti-psychotic drugs.

3.2. mGlu5 receptor

Gene name: GRM5 (human); Grm5 (rat, mouse). Accessionnumbers: NP_000833 (human); NP_058708 (rat); NP_001074883(mouse). Chromosomal location: 11q14.2 (human); 1q32 (rat); 7D3(mouse) (Abe et al., 1992; Kuramoto et al., 1994).

3.2.1. Splice variantsmGlu5a: 1212 amino acids in humans; 1203 amino acids in rats;

highly and diffusely expressed in the rat brain during early post-natal development (Romano et al., 1996b).

mGlu5b: a variant that contains a 32 amino acid fragmentinserted into the cytoplasmic tail 50 residues after the 7th TM;more abundant in the adult brain (Joly et al., 1995; Minakami et al.,1995; Romano et al., 1996b).

mGlu5d: identified in human cerebellum and hippocampus;C-terminus domain 267 amino acids shorter than human mGlu5areceptors (Malherbe et al., 2002).

3.2.2. Receptor signalling and interacting proteinsThe mGlu5 receptor is coupled to Gq/G11 protein and its acti-

vation stimulates PI hydrolysis. In recombinant cells, activation ofmGlu5 receptors induces oscillatory increases in intracellular Ca2þ

release, as a result of a PKC-mediated receptor phosphorylation(Kawabata et al., 1996). Both mGlu5a and mGlu5b receptors arecharacterized by a long C-terminus domain that allows the inter-action with Homer proteins similarly to mGlu1a receptors. In thepostsynaptic elements, mGlu5 receptors are physically linked to theNR2 subunit of NMDA receptors via a chain of interacting proteins,which include PSD-95, Shank, and Homer (Tu et al., 1999) (Fig. 2).Calcium ions that enter the cell via the NMDA-gated ion channelactivate protein phosphatase 2B, which dephosphorylates mGlu5receptors thereby limiting mGlu5-receptor desensitization(Alagarsamy et al., 2005). In addition, a large body of evidenceindicates that activation of mGlu5 receptors enhances NMDAreceptor function (Doherty et al., 1997; Ugolini et al., 1999; Awadet al., 2000; Attucci et al., 2001; Mannaioni et al., 2001; Pisaniet al., 2001). The neuron-specific protein, Norbin, physically inter-acts with mGlu5 receptors in vivo and increases both membranelocalization and signalling of mGlu5 receptors (Wang et al., 2009).The mGlu5 receptors are selectively desensitized by members ofthe GRK2 family (GRK2 and GRK3), through a mechanism thatinvolves phosphorylation of the Threo 840 residue (Sorensen andConn, 2003).

3.2.3. Functional anatomyThemGlu5a receptor is highly expressed in the CNS during early

postnatal life, and likely mediates the robust PI response to excit-atory amino acids found in all brain regions early after birth(Casabona et al., 1997). The mGlu5b receptor is abundant in theadult hippocampus, corpus striatum, and cerebral cortex (Romanoet al., 1996b), and is therefore the main target for pharmacologicalintervention in the adult brain. Partly, because of their functionalinteraction with NMDA receptors (Collett and Collingridge, 2004),mGlu5 receptors are involved in the regulation of synaptic plas-ticity (Bortolotto et al., 2005; Manahan-Vaughan and Braunewell,2005; Bikbaev et al., 2008). Mice with genetic deletion of mGlu5receptors show a mild deficit in long-term potentiation (LTP) in thehippocampus and an impaired spatial learning (Jia et al., 1998).

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However, pharmacological inhibition of mGlu5 receptors does notaffect LTP in this pathway, suggesting that the deficit in theknockout has a developmental origin (Bortolotto et al., 2005).

Pharmacological activation of mGlu5 receptors induces a robustform of LTD at the Schaffer collateral-CA1 pyramidal cell synapse inthe hippocampus (Palmer et al., 1997). This form of synaptic plas-ticity can also be induced by synaptic activity and has been shownto be dependent on dendritic protein synthesis under certaincircumstances (Huber et al., 2000) but independent of proteinsynthesis under others (Moult et al., 2008). A selective amplifica-tion of mGlu5-receptor mediated LTD in the hippocampus has beensuggested to underlie cognitive dysfunction in Fragile-X mutantmice and represents a promising target for therapeutic intervention(see below). A variety of different signalling mechanisms have beenfound to be involved in mGluR-LTD in the hippocampus, includingthe activation of p38 MAPK (Bolshakov et al., 2000; Rush et al.,2002) and tyrosine phosphatases (Moult et al., 2008), includingthe Striatal Enriched tyrosine Phosphatase, STEP (Zhang et al.,2008a,b).

In addition to direct roles in LTP and LTD at CA1 synapses, mGlu5receptors have been demonstrated to play a crucial role in someforms of metaplasticity. Metaplasticity is the plasticity of synapticplasticity and comes in many varieties (Abraham, 2008). One ratherunusual manifestation of metaplasticity has been termed themolecular switch, whereby the induction of LTP makes the induc-tion of subsequent LTP at the same pathway resistant to inhibitionby a-methyl-4-carboxyphenylglycine (MCPG) (Bortolotto et al.,1994). This conditioning effect of the first tetanus relies on activa-tion of mGlu5 receptors since it is blocked by 2-methyl-6-(phenyl-ethynyl)-pyridine (MPEP) and is absent in the mGlu5 knockoutmouse (Bortolotto et al., 2005). Like the activation of the slow EPSCin cerebellar Purkinje cells described above, the setting of themolecular switch by activation of mGlu5 receptors can be achievedby very few synaptic responses (Bortolotto et al., 2008). This onceagain demonstrates that mGlu receptors can be activated relativelyeasily, despite their more peripheral location at synapses. A secondform of metaplasticity at these synapses, that may utilise similarmechanism, is where prior stimulation of group-I mGlu receptorsleads to a greater magnitude LTP (Cohen et al., 1998). The mecha-nisms bywhich activation of mGlu5 results is metaplasticity are notfully understood but might involve both Ca2þ/calmodulin-depen-dent protein kinase II (CaMKII) (Bortolotto and Collingridge, 1998)and PKC (Bortolotto and Collingridge, 2000).

The expression and function of mGlu5 receptors in the basalganglia motor circuits and in the pain neuraxis is described below.Interestingly, mGlu5 receptors are also expressed in non-neuronalcells, including astrocytes, oligodendrocytes, and microglia, stem-progenitor cells, and a variety of peripheral cells. Expression andfunction of mGlu5 receptors in astrocytes is highly plastic andchanges dramatically in response to cell activation or under path-ological conditions (Miller et al., 1996; Balázs et al., 1997; Aronicaet al., 2000, 2003; Geurts et al., 2003). Mice expressing a mutatedform of human superoxide dismutase associated with amyotrophiclateral sclerosis (ALS) show astrocytic degeneration in the ventralhorns of the spinal cord, which likely depends on the activation ofmGlu5 receptors by endogenous glutamate. Blocking mGlu5receptors in vivo delays the onset of motor neuron disease andincreases survival of these mice (Rossi et al., 2008). Embryonic stem(ES) cells (pluripotent stem cells derived from the inner mass of theblastocysts) grown under proliferating conditions express mGlu5receptor and no other mGlu receptor subtypes. Pharmacologicalblockade of mGlu5 receptors inhibits self-renewal of ES cells andpromotes cell differentiation towards mesoderm and endodermlineages (Cappuccio et al., 2005). mGlu5 receptors are alsoexpressed by neural stem cells, i.e. stem cells resident in the CNS,

which can give rise to neurons, astrocytes, and oligodendrocytes.Mice lacking mGlu5 receptors have a lower number of proliferatingneuroprogenitors in zones of active neurogenesis of the adult brain(Di Giorgi-Gerevini et al., 2005). A recent review (Julio-Pieper et al.,in press) highlights the role of mGlu receptors in peripheral organs.The regulation of the lower esophageal sphincter by mGlu5receptor is of great relevance from a therapeutical standpoint (seebelow). mGlu5 receptors are also found in the liver, and hepato-cytes lacking mGlu5 receptors are less sensitive to hypoxic damage(Storto et al., 2004). In addition, pharmacological blockade ofmGlu5 receptors reduces liver damage caused by lipopolysaccha-ride (Jesse et al., 2009) or acetaminophen (Storto et al., 2003).mGlu5 receptors are expressed in many other peripheral cells,including cells of the male germinal line, insulinoma cell lines,immune cells, and brain endothelial cells, where their precisefunction remains to be determined (Julio-Pieper et al., in press).

3.2.4. PharmacologyThere are no selective orthosteric agonists of mGlu5 receptors

with theexceptionof (RS)-2-chloro-5-hydroxyphenylglycine (CHPG),which displays lowaffinity and is active in the highmicromolar range(reviewed by Schoepp et al., 1999). A number of mGlu5-receptorenhancers have been developed, which include [(3-fluorophenyl)methylene]hydrazone-3-fluorobenzaldehyde (DFB), N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydrox-ybenzamide (CPPHA), (S)-(4-fluorophenyl)-(3-[3-(4-fluoro-phenyl)-[1,2,4]-oxadiazol-5-yl]piperidin-1-yl)methanone (ADX47273), 3-cy-ano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB), 4-nitro-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (VU29), and ADX63365behave as mGlu5-receptor enhancers (reviewed by Niswender andConn, 2010), whereas MPEP, 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine hydrochloride (MTEP), 6-methyl-2-(phenylazo)-3-pyridinol(SIB-1757), and (E)-2-methyl-6-(2-phenylethenyl)pyridine (SIB-1893) are the prototypes of a growing list of mGlu5 receptors NAMs,which also includes fenobam, AFQ056, AZD2516, AZD2066, STX107,ADX10059, and ADX48621. Many of these drugs are systemicallyactive and are under clinical development.

3.2.5. Relevance to human disorders and clinical perspectives3.2.5.1. Fragile-X syndrome (FXS). FXS is the most frequent inheri-ted cause of mental retardation (incidence ¼ 1:3600 in males and1:4000e6000 in females) caused by the transcriptional silencing ofthe FMR1 gene, which encodes the fragile X mental retardationprotein (FMRP) (Pieretti et al., 1991). Prominent signs and symp-toms include cognitive dysfunction, autism, behavioural problems,seizures, dysmorphic features, and macroorchidism. Currentmedications include antipsychotic, anticonvulsant, antidepressant,and psychostimulant drugs, which, however, do not correctcognitive impairment associated with FXS (reviewed by Dölen andBear, 2008). Fmr1 knockout mice show a selective amplification ofmGlu5-receptor mediated LTD in the Schaffer collateral-CA1 pyra-midal cell synapses in the hippocampus. Remarkably, other formsof synaptic plasticity, including the more classical NMDA-receptordependent LTD, showno abnormalities in the hippocampus of Fmr1knockout mice (Huber et al., 2002; reviewed by Waung and Huber,2009). The mGlu5-receptor mediated LTD is, under certaincircumstances, dependent of protein synthesis occurring in thedendrites of CA1 pyramidal neurons as a result of local mRNAtranslation. FMRP is one of the dendritic proteins synthesized inresponse tomGlu5-receptor activation and has the specific functionof acting as a translational suppressor of other LTD-associatedproteins, such as PostSynaptic Density-95 (PSD-95), the amyloidprecursor protein, microtubule-associated protein 1b (MAP1b), theelongation factor 1a, and the cytoskeleton-associated protein, Arc.In the absence of FMRP, these proteins are constitutively and highly

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expressed, and this makes the mGlu5-receptor mediated LTDinsensitive to protein synthesis inhibitors (reviewed byWaung andHuber, 2009). A series of recent elegant studies have characterizedthe signalling pathways leading to dendritic protein synthesis inresponse to mGlu5-receptor activation. This includes the associa-tion of mGlu5 receptors with Homer proteins, and the activation ofupstream regulators of dendritic mRNA translation, such as theERK/MAPK-interacting kinase (Mnk1)/eukaryotic initiation factor4E (eIF4E) pathway, and the PtdIns-3-K/mammalian target ofrapamycin (mTOR)/p70S6K pathway. Many steps along thesepathways are abnormal in Fmr1 knockout mice (Giuffrida et al.,2005; Ronesi and Huber, 2008; Sharma et al., 2010). The lack ofone of the two Grm5 alleles as well as systemic treatment withMPEP or other mGlu5-receptor antagonists corrects most of thephenotypes associated with the lack of FMRP, including cognitivedysfunction, epileptic seizures, and morphological abnormalities(Yan et al., 2005; Tucker et al., 2006; Dölen et al., 2007; de Vrij et al.,2008). Most of the mGlu5-receptor NAMs listed in the previousparagraph are under clinical development for the treatment of FXS.Interestingly, non-sedative doses of MPEP block repetitive self-grooming behavior in BTBR T þ tfJ mice, which show multiplebehavioural traits with face validity for the diagnostic symptoms ofautism (Silverman et al., 2010). This raises the possibility that formsof autism other than FXS may be amenable of treatment withmGlu5-receptor antagonists.

3.2.5.2. Parkinson’s disease and L-DOPA-induced dyskinesia. mGlu5receptors are highly expressed in the basal ganglia motor circuitand are involved in the regulation of motor behavior (Smith et al.,2000; Paquet and Smith, 2003; reviewed by Conn et al., 2005).Seminal work by the groups of David Lovinger and Paolo Calabresi,Antonio Pisani and other associates have shed lights into the role ofgroup-I mGlu receptors in processes of striatal synaptic plasticityunderlying habit memory and motor learning (reviewed byGubellini et al., 2004; Bonsi et al., 2008; Lovinger, 2010). The neo-striatum (caudate nucleus and putamen), which is the primaryinput region of the basal ganglia, is connected to output nuclei(internal globus pallidus and substantia nigra pars reticulata) bya “direct” inhibitory GABAergic pathway, and by an “indirect”pathway, which includes a striatal GABAergic projection to theexternal globus pallidus, an additional GABAergic projection fromthe external globus pallidus to the subthalamic nucleus, and anexcitatory glutamatergic projection from the subthalamic nucleusto the output nuclei. Dopamine released from the nigro-striatalpathway stimulates the direct pathway acting at D1 receptors andinhibits the indirect pathway acting at D2 receptors. The progres-sive loss of nigro-striatal neurons associated with Parkinson’sdisease leads to a decreased activity of the direct pathway and anincreased activity of the indirect pathway, which lead to inhibitionof thalamocortical neurons and motor dysfunction (bradykinesia,rigidity, and resting tremor). Dopamine replacement therapy withL-3,4-dihydroxyphenylalanine (L-DOPA) is highly effective inrelieving parkinsonian symptoms in the first few years of treatment(the “honeymoon”). Afterwards, L-DOPA treatment is complicatedby loss of efficacy and the occurrence of stereotyped involuntarymovements (monophasic and diphasic L-DOPA-induced dyskine-sias), which likely depends on a hyperactivity of the direct pathway(Cenci, 2007). mGlu5 receptors are expressed in the neostriatum bymedium spiny projection neurons and interneurons (Smith et al.,2000), and are also found in output nuclei and in nuclei of theindirect pathway (reviewed by Conn et al., 2005). In striatalprojection neurons of the indirect pathway, mGlu5 receptors arefunctionally linked to NMDA receptors and A2A adenosine recep-tors, forming a receptor complex that counteracts the activity of D2receptors (Ferré et al., 2002; Nishi et al., 2003). In striatal projection

neurons of the direct pathway, mGlu5 receptors affect synapticresponses to dopamine by modulating the activity of dopamine-and cAMP-regulated phosphoprotein, DARPP-32 (Liu et al., 2001).mGlu5 receptors inhibit neurons of the external globus pallidus bya mechanism of cross-desensitizationwith mGlu1 receptors (Poisiket al., 2003), whereas their activation produces membrane depo-larization and an increase in burst firing in neurons of the sub-thalamic nucleus (Awad et al., 2000). A growing body of evidenceindicates that systemic treatment with mGlu5-receptor NAMs ishighly effective in relieving motor symptoms and L-DOPA-induceddyskinesias in rodent and primatemodels of parkinsonism (Breysseet al., 2002, 2003; Mela et al., 2007; Yamamoto and Soghomonian,2009; Ouattara et al., 2009; Ambrosi et al., 2010; Johnston et al.,2010; Rylander et al., 2010). The mGlu5 NAMs, AFQ056, AZD2516,and ADX48621, are currently in phase I/II of clinical developmentfor the treatment of Parkinson’s disease and L-DOPA-induceddyskinesias. Remarkably, genetic deletion of mGlu5 receptors orsystemic treatment with mGlu5-receptor blockers is neuro-protective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP) and methamphetamine mouse models of toxicologicalparkinsonism (Battaglia et al., 2002, 2004). Although these areacute models of nigro-striatal degeneration, the possibility thatmGlu5-receptor blockade attenuates the progressive loss of nigralneurons associated with Parkinson’s disease is attractive andwarrants further investigation.

3.2.5.3. Chronic pain. Chronicization of pain reflects the develop-ment of “nociceptive sensitization”, i.e. the amplification of paintransmission that occurs along the entire pain neuraxis andunderlies the hallmark features of chronic pain, such as primaryand secondary hyperalgesia, mechanical and thermal allodynia,and spontaneous pain (reviewed by Basbaum et al., 2009). All mGlureceptor subtypes (with the exception of mGlu6 receptors) arewidely distributed in pain centers of the brain and spinal cord, andare implicated in the induction, expression, and maintenance ofnociceptive sensitization (Neugebauer, 2001; Varney and Gereau,2002; Goudet et al., 2009; Chiechio et al., 2010). In peripheralnociceptors (the peripheral terminals of dorsal root ganglianeurons) mGlu1 and mGlu5 receptors respond to ambient gluta-mate by triggering a cascade of reactions leading to sensitization ofTrpV1 channels, which sense noxious heat and also respond toinflammatory molecules and capsaicin (Bhave et al., 2001; Hu et al.,2002). In nociceptive neurons of the dorsal horns of the spinal cord,the mGlu5 receptor is activated by glutamate released fromprimary afferent fibers or by local excitatory interneuronsexpressing PKC-g. Activation of mGlu5 receptors leads to inhibitionof Kv4.2 voltage-sensitive potassium channels via a phosphoryla-tion mechanism mediated by the MAPK pathway (Hu et al., 2007).The resulting increase in neuronal excitability contributes to noci-ceptive sensitization in spinal cord neurons. mGlu5 receptors arealso found in supraspinal brain centers, such as dorsal raphe nucleiand amygdala, where their activation sustains chronic pain (deNovellis et al., 2005; Ansah et al., 2009, 2010). Pharmacologicalblockade of mGlu5 receptors is analgesic inmodels of inflammatoryand neuropathic pain, and inhibits the development of tolerance tothe analgesic activity of morphine (Fisher et al., 2002; Kozela et al.,2003; de Novellis et al., 2004; Smith et al., 2004; Varty et al., 2005;Han and Neugebauer, 2005; Sevostianova and Danysz, 2006;Osikowicz et al., 2008; Montana et al., 2009). Based on thesepreclinical data, mGlu5-receptor NAMs such as AZD2516 andAZD2066 are under clinical development for the treatment ofneuropathic pain (pain originating from structural or functionallesions of the pain pathways). In a phase IIa clinical trial, themGlu5-receptor NAM, ADX100159, has shown better efficacy thanplacebo in the treatment of acute pain associated with migraine.

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3.2.5.4. Drug addiction. Drug addiction or “substance dependence”(Diagnostic and Statistical Manual of Mental Disorders, fourthedition, 1994) is a chronic, relapsing disorder characterized bycompulsive drugs seeking behavior, loss of control in taking thedrug, and emergence of a negative emotional state when access tothe drug is prevented (reviewed by Koob and Le Moal, 2008). Froma therapeutic standpoint, it is helpful to subdivide the addictionprocess into three phases: (i) an “intoxication phase” (e.g. a cocainebinge), dominated by the reinforcing properties of the drug; (ii) anabstinence phase, in which mechanisms of negative reinforcementsustain drug craving; and (iii) a phase of enduring vulnerability todrug intake, in which drug reinstatement may be induced by stress,drug priming, or environmental cues previously paired with drugintake. Activation of the dopaminergic mesolimbic system, pro-jecting from the ventral tegmental area (VTA) to the shell of nucleusaccumbens, mediates the reinforcing properties of drugs of abuse(Di Chiara and Imperato,1988), whereas a dysregulation of synapticplasticity in the nucleus accumbens contributes to the phase ofenduring vulnerability to drug intake (reviewed by Kauer andMalenka, 2007; Kalivas, 2009). Chiamulera et al. (2001) haveshown that mice lacking mGlu5 receptors fail to self-administercocaine without showing a defect in the ability of cocaine toincrease extracellular dopamine levels in the nucleus accumbens.Data obtained with MPEP in experimental paradigms measuringacute drug reward (e.g., self-administration of drugs of abuse,measurements of brain reward thresholds, and conditioned-placepreference) indicate that activation of mGlu5 receptors is requiredfor incentive motivation for the reinforcer (reviewed by Kenny andMarkou, 2004; Kenny et al., 2005). mGlu5-receptor NAMs exertanti-reinforcing effects at multiple levels including VTA neurons,where group-I mGlu receptors are involved in mechanisms ofsynaptic plasticity underlying reward-based conditioning and thedevelopment of drug addiction (Kauer and Malenka, 2007; Ahnet al., 2010). Accordingly, cocaine-mediated synaptic potentiationis absent in VTA neurons from mGlu5-defient mice (Bird et al.,2010). mGlu5-receptor blockade in the nucleus accumbens iseffective in preventing relapse to drug seeking as well as neuro-chemical changes associated with drug reinstatement (Bespalovet al., 2005; Schroeder et al., 2008). mGlu5-receptor NAMs holdpromise in the treatment of drug addiction, and AFQ056 is underclinical development for the treatment of tobacco smoking (Kenny,2009). However, it should be highlighted that mGlu5-receptorblockade increases somatic signs and reward deficits associatedwith nicotine withdrawal (Liechti and Markou, 2006), suggestingthat mGlu5-receptor NAMs should be associated with drugs thatlower the reward threshold (e.g., bupropion) in the acute phase ofnicotine withdrawal.

3.2.5.5. Anxiety. Drugs that block mGlu5 receptors consistentlyshow anxiolytic-like activity in a variety of animal models such asfear potentiated startle, contextual fear conditioning, elevated plusmaze, conflict tests, and stress-induced hyperthermia (Spoorenet al., 2000; Tatarczy�nska et al., 2001; Busse et al., 2004; Roppeet al., 2004; Pietraszek et al., 2005; Stachowicz et al., 2007;Spanka et al., 2010). Mice lacking mGlu5 receptors also showa reduced stress-induced hyperthermia (Brodkin et al., 2002).Remarkably, fenobam, a clinically validated anxiolytic drug, behavesas a potent and selective mGlu5-receptor NAM (Porter et al., 2005).A critical issue is whether mGlu5-receptor antagonists showa better profile of safety and tolerability than benzodiazepines andselective serotonin reuptake inhibitors (SSRIs), which are widelyprescribed for the treatment of generalized anxiety disorders andpanic attacks. A potential advantage with respect to benzodiaze-pines is that, at least in preclinical models, mGlu5-receptor NAMsretain their anxiolytic activity after repeated dosing (i.e. there is no

development of tolerance) (Nordquist et al., 2007). As opposed todiazepam, MPEP produces a robust anxiolytic effect in rat conflicttests at doses that do not impair working memory and spatiallearning (Ballard et al., 2005). Fenobam, however, was shown in onestudy to produce anxiolytic activity at doses that impaired spatiallearning (Jacob et al., 2009). Finally, little is known on the interac-tion between mGlu5-receptor NAMs and drug metabolizingenzymes (e.g. the various isotypes of cytochrome-P450) and drugefflux pumps. Thus, the development of mGlu5-receptor NAMs asnovel anxiolytic agents warrants further investigations.

3.2.5.6. Schizophrenia. The interest for mGlu5 receptors in schizo-phrenia stems fromthe evidence thatmGlu5-receptorknockoutmiceshow a disruption in PPI, which reflects a defect in sensory-motorgating (Kinney et al., 2003; Brody et al., 2004). mGlu5-receptorblockade enhances the psychotomimetic effect of phencyclidine(Campbell et al., 2004), and mice with genetic deletion of Norbin,which enhances mGlu5-receptor signalling, also show a defect in PPI(Wang et al., 2009). GRM5 has been mapped to 11q15 neighbouringa translocation that segregates with schizophrenia in a large Scottishfamily (Devon et al., 2001). mGlu5 and NMDA receptors may actsynergistically in regulatingneuronal activity in the prefrontal cortex,a region that is critically involved in the pathophysiology of cognitivedysfunction in schizophrenic patients. Accordingly, pretreatmentwith a selective mGlu5-receptor enhancer prevents the abnormalityin neuronal firing induced by NMDA receptor blockade in themedialprefrontal cortex (Lecourtier et al., 2007). The prediction thatamplification of mGlu5-receptor function could be beneficial in thetreatment of schizophrenia led to the development of a series ofmGlu5-receptor PAMs (reviewed by Conn et al., 2009). Among these,CDPPB and ADX47273 are active in preclinical models that predictefficacy in the treatment of positive symptoms and cognitivedysfunction associated with schizophrenia (Liu et al., 2008;Schlumberger et al., 2009a,b; Vardigan et al., 2010), and ADX63365is currently developed for the treatment of schizophrenia. It shouldbe highlighted that the therapeutic activity of conventional anti-psychotics on cognitive dysfunction associatedwith schizophrenia isnegligible, and therefore, the use of mGlu5-receptor PAMs mayrepresent a new avenue in the treatment of schizophrenicsyndromes.

3.2.5.7. Gastroesophageal reflux disorder (GERD). GERD isa common disorder affecting 3e7% of the U.S. population, which iscaused by an abnormal reflux of stomach acid to the esophagus dueto a transient relaxation of the lower esophageal sphincter (LES).The most common symptoms are regurgitation, heartburn, anddysphagia. In some cases, GERD causes injury of the esophagealepithelium leading to esophagitis, esophageal strictures, meta-plastic changes in the esophageal epithelium (Barrett’s esophagus),and esophageal adenocarcinoma. Proton pump inhibitors arecommonly used in the treatment of GERD. These drugs, however,inhibit acid secretion without affecting LES tone. Interestingly,glutamate is a potent activator of the vagal pathway mediating LESrelaxation (Partosoedarso and Blackshaw, 2000), and mGlu recep-tors, includingmGlu5, are expressed by gastric vagal afferents (Pageet al., 2005). Preclinical studies have shown that mGlu5-receptorNAMs such as MPEP and MTEP increase basal LES pressure andinhibit LES relaxation (Frisby et al., 2005; Jensen et al., 2005). Ina clinical study, treatment with the mGlu5 NAM, ADX100159,reduced the number and duration of symptomatic reflux episodesas well as nocturnal and postprandial esophageal acid exposure(Keywood et al., 2009). A modified release formulation ofADX100159 showed a better profile of tolerability and is thereforeparticular suitable for long-term treatments in patients with GERD(Zerbib et al., 2010).

Fig. 3. Synaptic distribution of group-II and group-III mGlu receptors. Note thatpresynaptic mGlu2/3 receptors are located in the pre-terminal regions of the axons,where they can be activated by glutamate released from astrocytes via the cystine/glutamate antiporter. In contrast, presynaptic mGlu4/7/8 receptors are located near tothe active zone of neurotransmitter release. Glial mGlu3 receptors induce the forma-tion and secretion of TGF-b. The presence of mGlu5 receptors in glial cells is alsoshown.

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3.3. mGlu2 and mGlu3 receptors

3.3.1. mGlu2 receptorGene name: GRM2 (human); Grm2 (rat, mouse). Accession

numbers: NP_000830 (human); NP_001099181 (rat); NP_001153825(mouse). Chromosomal location: 3q21.31 (human); 8q32 (rat); 9(mouse) (Tanabe et al., 1992; Kuramoto et al., 1994; Flor et al., 1995a;Martí et al., 2002).

3.3.2. mGlu3 receptorGene name: GRM3 (human); Grm3 (rat, mouse). Accession

numbers: NP_000831 (human); NP_001099182 (rat); NP_862898(mouse). Chromosomal location: 7q21.1eq21.2 (human); 4q32(rat); 5A1-h (mouse) (Tanabe et al., 1992; Kuramoto et al., 1994;Scherer et al., 1996; Emile et al., 1996; Corti et al., 2000).

3.3.2.1. Splice variants. Three splice variants of GRM3 have beenreported in human brain and B lymphoblasts. The most abundantvariant lacks exon 4 (GRM3D4) and encodes for a 60 kDa proteinlacking the 7-TMdomain ofmGlu3 receptors (Sartorius et al., 2006).

3.3.2.2. Signal transduction and interacting proteins. mGlu2 andmGlu3 receptors are coupled to Gi/Go proteins in heterologousexpression systems (reviewed by Tanabe et al., 1992). Their acti-vation inhibits cAMP formation, inhibits voltage-sensitive Ca2þ

channels, activates Kþ channels, and can also activate the MAPKand PtdIns-3-K pathways (reviewed by Pin and Duvoisin, 1995).mGlu2/3 receptor agonists do not stimulate PI hydrolysis on theirown, but amplify the stimulation of PI hydrolysis mediated bymGlu1/5 receptors in brain slices (Genazzani et al., 1994; Schoeppet al., 1996). Recent findings suggest that mGlu2 and mGlu3receptors show a different sensitivity to processes of homologousdesensitization mediated by GRK2/b-arrestin, with mGlu2 recep-tors being resistant to desensitization. However, this difference isvisible only when inhibition of cAMP formation is measured asa read-out of mGlu2/3 receptor activation (Iacovelli et al., 2009).Group-II mGlu receptors were shown to interact with calmodulin,protein phosphatase 2C, and the Ran binding protein in themicrotubule-organizing center (RanBPM) (reviewed by Niswenderand Conn, 2010).

3.3.2.3. Functional anatomy. mGlu2 and mGlu3 receptors arediffusely expressed in the CNS. mGlu2 receptors are uniquelylocalized in neurons and particularly in the pre-terminal region ofaxons, far from the active zone of neurotransmitter release (Lujánet al., 1997; Tamaru et al., 2001), whereas mGlu3 receptors arefound at both presynaptic and postsynaptic sites as well as in glialcells (Ohishi et al., 1993a,b; 1994; Neki et al., 1996; Petralia et al.,1996; Ferraguti and Shigemoto, 2006). Presynaptic mGlu2/3receptors can be activated by an excess of synaptic glutamate, or,alternatively, by the glutamate released from astrocytes via thecystineeglutamate membrane antiporter (see Kalivas, 2009)(Fig. 3). Changes in the expression and/or activity of the cys-tineeglutamate antiporter may affect the function of mGlu2/3receptors in brain regions that are critically involved in drugaddiction (see below). A major function of presynaptic mGlu2/3receptor is to inhibit neurotransmitter release. Both receptors havean established role in the regulation of synaptic plasticity, partic-ularly in the induction of LTD of excitatory synaptic transmission(Yokoi et al., 1996; Manahan-Vaughan, 1998; Kahn et al., 2001;Kilbride et al., 2001; Renger et al., 2002; Robbe et al., 2002; Grueterand Winder, 2005; Nicholls et al., 2006; Altinbilek and Manahan-Vaughan, 2009).

A particular form of synaptic plasticity has been described in themouse accessory olfactory bulb, where activation of mGlu2

receptors relieves the GABAergic inhibition of mitral cells, thuspermitting the formation of a specific olfactory memory thatfaithfully reflects the memory of male pheromones formed atmating (Hayashi et al., 1993; Kaba et al., 1994). mGlu3 receptorswere also found in embryonic stem cells and glioma-initiating cells,where their activation limits cell differentiation by negativelyregulating type-4 bone-morphogenetic protein (BMP-4) receptorsignalling (reviewed by Melchiorri et al., 2007).

3.3.2.4. Pharmacology. There are no marketed orthosteric agonistsor antagonists that can differentiate between mGlu2 and mGlu3receptors, with the exception of N-acetylaspartateglutamate (NAAG),which selectivelyactivatesmGlu3 receptors (Wroblewska et al.,1997;but see also Chopra et al., 2009). Orthosteric agonists of mGlu2 andmGlu3 receptors include 2R,4R-APDC, and the carbox-ycyclopropylglycine derivatives, DGC-IV and L-CCG-I. DCG-IV is activein the nanomolar range, but lacks specificity because it also activatesNMDA receptors. L-CCG-I also activates group-I mGlu receptors(reviewed by Schoepp et al., 1999). LY354740 and LY379268 areconformationally constrained glutamate analogues in which theglutamate backbone is locked into a fully extended state by incor-poration into a bicycle[3.1.0] hexane ring system. Both compoundsbehave as potent mGlu2/3 receptor agonists and are systemicallyactive (reviewed by Schoepp et al., 1999). (�)-(1R,4S,5S,6S)-4-Amino-2-sulfonylbicyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY404-039), which is pharmacologically similar to LY379268, is underclinical development for the treatment of schizophrenia (see below).LY341495 is an orthosteric antagonist with nanomolar affinity formGlu2 and mGlu3 receptors, but is not subtype selective and mayrecruit other mGlu receptor subtypes (reviewed by Schoepp et al.,1999). (3-(3,4-Dichlorobenzyloxy)-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid) MGS0039 (Nakazato et al., 2004), isa potent and selective mGlu2/3 receptor antagonist, which holdspromise as a potential antidepressant drug (see below). 2,2,2-Trifluoro-N-[4-(2-methoxyphenoxy)phenyl]-N-(3-pyridinylmethyl)

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ethanesulfonamide hydrochloride (LY487379) and 30-([(2-cyclo-pentyl-6-7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methy-l)biphenyl l-4-carboxylate (BINA) are prototypes of selective mGlu2receptor PAMs (reviewed by Niswender and Conn, 2010), which arealso under development in the treatment of schizophrenia (seebelow). No mGlu3 receptor enhancers are currently available.

3.3.2.5. Relevance to human disorders and clinical perspectives3.3.2.5.1. Anxiety. mGlu2/3 receptors regulate synaptic trans-

mission and plasticity in the amygdala (Wang and Gean, 1999; Linet al., 2000, 2005), a brain region that encodes fear memory and iscritically involved in the pathophysiology of anxiety disorders.Systemic treatment with the mGlu2/3 receptor agonist, LY354740,enhances Fos protein expression e a non-specific marker of cellactivation e in GABAergic neurons of the lateral portion of centralamygdala (CeL) (Linden et al., 2005, 2006). Thus, activation ofmGlu2/3 receptors inhibits GABA release at basolateral amygdala(BLA)-CeL synapses, leading to an increased activity of GABAergicinterneurons in the CeL. This, in turn, reduces the activity of outputneurons in the medial central amygdala, which project to brainregions mediating the motor, autonomic, and endocrine features ofanxiety. Treatment with LY354740 is highly effective in severalanimal models of anxiety and panic disorders with no reductions ofactivity on repeated dosing (reviewed by Swanson et al., 2005). Theanxiolytic activity of LY354740 requires the presence of bothmGlu2and mGlu3 receptors (Linden et al., 2005), and, as predicted by theabove mechanism, is reversed by the benzodiazepine antagonist,flumazenil (Ferris et al., 2001). LY354740 has progressed into phaseII clinical trials with demonstration of good efficacy in the treat-ment of generalized anxiety disorder before discontinuation basedon findings of convulsions in preclinical studies (Dunayevich et al.,2008). If convulsions represent an off-target effect of LY354740 orrather develop as a result of chronic activation (or desensitization)of mGlu2 or mGlu3 receptors remains to be determined.

3.3.2.5.2. Schizophrenia. The development of mGlu2/3 receptoragonists as antipsychotic drugs moved from the observation thatLY354740 inhibits glutamate release (Battaglia et al., 1997), allow-ing for testing the hyperglutamatergic theory in schizophrenia(Aghajanian and Marek, 1999). Moghaddam and Adams (1998)found that LY354740 attenuates the disruptive effect of phencycli-dine on working memory, locomotion, stereotypies, and corticalglutamate efflux. Since then, a number of mGlu2/3 receptoragonists have shown robust activity in models that are used topredict efficacy of potential antipsychotic agents (Schoepp andMarek, 2002; Conn et al., 2008, 2009). A pioneer phase II clinicalstudy has shown that the a 21-day treatment with LY2140023, theoral prodrug of the potent and selective mGlu2/3 receptor agonist,LY404039, was nearly as effective as treatment with the antipsy-chotic olanzapine in reducing both positive and negative symptomsin schizophrenic patients (Patil et al., 2007). As opposed to olan-zapine, LY2140023 did not increase body weight and bloodtriglyceride levels, two effects that seriously limit the use of atypicalantipsychotic drugs in the treatment of schizophrenia (Patil et al.,2007). The antipsychotic activity of mGlu2/3 receptor agonistshas been proposed to involve a negative interaction betweenmGlu2/3 receptors and 5-HT2A receptors. 5-HT2A receptors areactivated by hallucinogenic drugs, such as lysergic acid dieth-ylamide, psilocin, and (�)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and are antagonized by clozapine and otheratypical antipsychotics. Pharmacological activation of mGlu2/3receptors attenuates 5-HT2A-receptor-mediated excitatory post-synaptic currents recorded in layer V pyramidal neurons of theprefrontal cortex (Marek et al., 2000), and reduces electrophysio-logical and behavioural effects of hallucinogens (Gewirtz andMarek, 2000; Winter et al., 2004; K1odzinska et al., 2002; Zhai

et al., 2003; Benneyworth et al., 2007). Variations in the GRM3gene (encoding human mGlu3 receptors) have been consistentlyassociated with the risk of schizophrenia as well as with theresponse to antipsychotic medication (Egan et al., 2004; Bishopet al., 2005, 2007; Nicodemus et al., 2007; Fijal et al., 2009;Jönsson et al., 2009). However, preclinical studies suggest that itis the mGlu2 receptor that specifically mediates the antipsychoticactivity of mGlu2/3 receptor agonists. González-Maeso et al. (2008)have shown that mGlu2 and 5-HT2A receptors form a heterodimericcomplex in the cell membrane, and that activation of mGlu2receptors inhibits a particular signalling pathway activated by 5-HT2A receptors in response to hallucinogens. In addition, selectivemGlu2 receptor PAMs mimic the action of mGlu2/3 receptoragonists in inhibiting 5-HT2A receptor function (Zhai et al., 2003;Benneyworth et al., 2007). In one paper, however, the ability ofmGlu2/3 agonists to inhibit DOI-stimulated PI hydrolysis in vivo ispreserved in both mGlu2 and mGlu3 receptor knockout mice,although it is lost in double mGlu2/3 knockout mice (Molinaroet al., 2009). In line with these findings, an altered dimerizationof mGlu3 receptors was detected in the prefrontal of schizophrenicpatients (Corti et al., 2007a). Whether or not dual mGlu2/3 receptoragonists and selective mGlu2 receptor PAMs are comparable interms of efficacy and tolerability in the treatment of schizophreniais an interesting issue that warrants further investigation.

3.3.2.5.3. Depression. Multiple classes of drugs are available inthe treatment of major depression, yet no drug has a fast onset ofantidepressant activity, and a substantial percentage of depressedpatients are resistant to medication. Dr. Chaki and his associateshave shown that systemic treatment with the selective mGlu2/3receptor antagonist, MGS0039, exerts antidepressant effects inmodels that are predictive of clinical efficacy, such as the learnedhelplessness paradigm, the forced swim test, and the tail suspen-sion test (Chaki et al., 2004; Yoshimizu et al., 2006; reviewed by Pilcet al., 2008). Treatment with MGS0039 increases dopamine releasein the nucleus accumbens and neurogenesis in the hippocampaldentate gyrus (Yoshimizu and Chaki, 2004; Karasawa et al., 2006),two effects that are consistent with an antidepressant activity. Incombination studies, low doses of the mGlu2/3 receptor agonist,LY379268, shorten the temporal latency of classical antidepressantsin reducing the expression of b1-adrenergic receptors in thehippocampus (a classical biochemical marker of antidepressant-induced neuroadaptation) and reducing the immobility time in theforced swim test (Matrisciano et al., 2005, 2007).Whether repeateddosing of LY379268 potentiate the activity of classical antidepres-sants by desensitizing mGlu2/3 receptors remains to bedetermined.

3.3.2.5.4. Drug addiction. mGlu2 receptors negatively regulatesthe activity of the reward pathway (i.e. the mesolimbic dopami-nergic system) as shown by the increased reinforcing properties ofcocaine shown bymGlu2 receptor knockout mice (Morishima et al.,2005). As predicted from this finding, pharmacological activation ofmGlu2/3 receptors reduces self-administration of nicotine andcocaine (Liechti and Markou, 2006; Adewale et al., 2006), butprecipitates the deficit in brain reward function associated withnicotine withdrawal (Kenny et al., 2003). Thus, mGlu2/3 receptoragonists may be valuable in the treatment of the “intoxication”phase of nicotine or cocaine addiction, but may increase drugcraving during the early phase of drug withdrawal. Interestingly,however, mGlu2/3 receptor agonists reduce the somatic signs ofopiate withdrawal and the associated hyperactivity of locuscoeruleus neurons (Fundytus and Coderre, 1997; Vandergriff andRasmussen, 1999), suggesting that activation of mGlu2/3 recep-tors differentially affects various aspects of drug withdrawal(reviewed by Kenny and Markou, 2004). An elegant series ofexperiments by Peter Kalivas and his associates has linked

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a defective activation of mGlu2/3 receptors to abnormalities ofsynaptic plasticity in the core of nucleus accumbens underlying theenduring vulnerability to drug reinstatement in addiction(reviewed by Kalivas, 2009). Rats withdrawn from chronic cocaineself-administration fail to develop LTP in the nucleus accumbenscore after in vivo stimulation of the prefrontal cortex because ofa pre-existing potentiation of synaptic transmission, which resultsform a reduced ability of presynaptic mGlu2/3 receptors to nega-tively regulate glutamate release. This derives (i) from a reducedexpression of the xCT subunit of the glial cystineeglutamate anti-porter transport system Xc

�, which releases the glutamate neces-sary for the activation of presynaptic mGlu2/3 receptors, and (ii)from a reduced expression of type-3 Activator of G-protein Sig-nalling (AGS3), which, in spite of its name, negatively regulatesmGlu2/3 receptor signalling. Treatment with N-acetylcysteine,which provides the cystine substrate for residual cys-tineeglutamate exchangers, restores synaptic plasticity in thenucleus accumbens core and prevents cocaine relapse via theactivation of mGlu2/3 receptors (Moran et al., 2005; Moussawiet al., 2009; reviewed by Kalivas, 2009). N-Acetylcysteine is underclinical development for the treatment of nicotine and cocaineaddiction (LaRowe et al., 2006, 2007; Mardikian et al., 2007; Karilaet al., 2008; Knackstedt et al., 2009). Curiously, N-acetylcysteine ismarketed as an expectorant, and is also helpful in improvingbronchial secretions associated with tobacco smoking.

3.3.2.5.5. Chronic pain. mGlu2/3 receptors are found in manystations of the pain neuraxis, from peripheral nociceptors to theamygdala, which encodes the emotional aspects of pain. In noci-ceptors, activation of mGlu2/3 receptors negatively regulate TrpV1channels via the inhibition of cAMP formation (Yang and Gereau4th, 2002; Carlton et al., 2009), whereas activation of presynapticmGlu2/3 receptors localized on primary afferent fibers inhibitsneurotransmitter release in the dorsal horns of the spinal cord(review by Chiechio et al., 2010). Systemic treatment with mGlu2/3receptor agonists consistently produces analgesia in animal modelsof acute and chronic pain, but their use is limited by the develop-ment of tolerance in response to repeated dosing (Jones et al.,2005). This limitation can be overcome by a novel analgesicstrategy based on the transcriptional activation of the Grm2 gene.L-Acetylcarnitine (LAC), a drug marketed for the treatment ofneuropathic pain, induces the expression of mGlu2 receptors indorsal root ganglia and in the dorsal horns of the spinal cord byenhancing acetylation of the p65/Rel subunit of the NFkB family oftranscription factors. Remarkably, LAC-induced analgesia requiresmultiple dosing and is abolished by the mGlu2/3 receptor antago-nist, LY341495 (Chiechio et al., 2002, 2006). Identical results areobtained with inhibitors of histone deacetylase, which also causeanalgesia by inducing mGlu2 receptors in the spinal cord (Chiechioet al., 2009). Transcriptional regulation of mGlu2 receptors hasbeen highlighted as an epigenetic path to novel treatments forchronic pain (Chiechio et al., 2010).

3.3.2.5.6. Brain tumors. Grade III and IV gliomas (anaplasticastrocytoma and glioblastoma multiforme, respectively) are highlyinfiltrating malignant brain tumors that represent the 3rd largestcause of all cancer-related deaths. It is generally believed thatglioblastoma multiforme arises from a particular population oftransformed neural stem cells named “glioma stem cells”, whichsustain tumor growth and are intrinsically resistant to radiotherapyand chemotherapy (reviewed by Stiles and Rowitch, 2008). Purifiedglioma stem cells express mGlu3 receptors, the activation of whichrestrains the pro-differentiating activity of type-4 bone-morpho-genetic protein (BMP-4) via a mechanism of receptorereceptorinteraction. Systemic treatment with the preferential mGlu2/3receptor antagonist, LY341495, reduces the growth of brain tumorsoriginating from U87MG glioma cells (Arcella et al., 2005) or

human glioma stem cells (Ciceroni et al., 2008) inmice. More recentfindings suggest thatmGlu3 receptor antagonists act synergisticallywith DNA-alkylating agents in killing glioma stem cells (Ciceroni C.et al., unpublished). The possibility that mGlu3 receptor blockade isused as a strategy for the treatment of malignant gliomas isattractive and warrants further investigation.

3.3.2.5.7. Neurodegenerative disorders. The role of mGlu2/3receptors in mechanisms of neurodegeneration/neuroprotection ishighlighted in a previous review (Bruno et al., 2001). It is disap-pointing that the robust neuroprotective activity of mGlu2/3receptor agonists found in cell cultures (Bruno et al., 1995; Copaniet al., 1995) is only partially seen in in vivo models of acute orchronic neurodegenerative disorders (Bond et al., 1999, 2000;Murray et al., 2002; Battaglia et al., 2003). The use of knockoutmice unravelled distinct roles for mGlu2 and mGlu3 receptors inmechanisms of neurodegeneration/neuroprotection, with neuro-protection being entirely mediated by glial mGlu3 receptors incultures challenged with mGlu2/3 receptor agonists (Corti et al.,2007b). In contrast, the lack of mGlu2 receptors in neurons atten-uates excitotoxic death (Corti et al., 2007b), and treatment ofneuronal cultures with a selective mGlu2 receptor enhanceramplifies b-amyloid toxicity (Caraci F. et al., unpublished). Activa-tion of glial mGlu3 receptors enhances the production of trans-forming growth-factor-b (TGF-b) (Fig. 3), which acts as a paracrineprotective factor on neighbour neurons (Bruno et al., 1998;D’Onofrio et al., 2001). Interestingly, systemic treatment with themGlu2/3 receptor agonist, LY379268, prevents neurodegenerationand increases the expression of TGF-b2 in the entorhinal cortex ofrats exposed to an alcohol binge (Cippitelli et al., 2010). Glial mGlu3receptors are promising targets for the treatment of Alzheimer’sdisease (AD) because TGF-b protects neurons against b-amyloidtoxicity (reviewed by Caraci et al., 2009), and type-2 TGF-b recep-tors are defective in the AD brain (Tesseur et al., 2006). In addition,abnormalities in the mGlu3/TGF-b axis might contribute to thepathophysiology of Huntington’s disease (HD) because TGF-b1levels are reduced in the plasma and brain tissue of HD patients,and activation of mGlu3 receptors fails to enhance the productionof TGF-b1 in brain tissue of HD mutant mice (Battaglia et al., 2010).Production of nerve growth factor (NGF), brain-derived neuro-trophic factor (BDNF), and glial-derived neurotrophic factor (GDNF)is also positively regulated by mGlu3 receptors (Ciccarelli et al.,1999; Battaglia et al., 2009; Di Liberto et al., 2010). GDNF isa potent prosurvival factor for nigral dopaminergic neurons (Linet al., 1993), and intraputaminal infusion of GDNF attenuatedparkinsonian symptoms in two phase-I clinical trials (Gill et al.,2003; Slevin et al., 2005). Thus, drugs that selectively activatemGlu3 receptors might produce neuroprotective effects in all majorneurodegenerative disorders of the CNS.

3.4. mGlu4, mGlu7, and mGlu8 receptors

3.4.1. mGlu4 receptorGene name: GRM4 (human); Grm4 (rat, mouse). Accession

numbers: NP_000832 (human); NP_073157 (rat); NP_001013403(mouse). Chromosomal location: 6p21.3 (human); 20p12 (rat);17A3.3 (mouse) (Tanabe et al., 1992; Kuramoto et al., 1994; Floret al., 1995b; Barbon et al., 2000a).

3.4.2. mGlu7 receptorGene name: GRM7 (human); Grm7 (rat, mouse). Accession

numbers: NP_000835 (human); NP_112302 (rat); NP_796302(mouse). Chromosomal location: 3p26.1ep25-1 (human); 4q42(rat); 6E3 (mouse) (Okamoto et al., 1994; Saugstad et al., 1994;Barbon et al., 2000b).

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3.4.3. mGlu8 receptorGene name: GRM8 (human); Grm8 (rat, mouse). Accession

numbers: NP_000836 (human); NP_071538 (rat); NP_032200(mouse). Chromosomal location: 7q31.3eq32 (human); 4q22 (rat);6A3 (mouse) (Duvoisin et al., 1995; Saugstad et al., 1997; Schereret al., 1996, 1997).

3.4.3.1. Splice variants. There are no variants of mGlu4 receptors.Five splice variants of mGlu7 receptors have been described so far(mGlu7aee). In mGlu7b, alternative splice originates from an out-of-frame insertion in the C-terminus domain, which results in thereplacement of the last 16 amino acids of mGlu7a with 23 aminoacids (Flor et al., 1997; Corti et al., 1998). Expression of mGlu7receptors in non-neuronal tissue (see below) is restricted to vari-ants mGlu7c and mGlu7d (Schulz et al., 2002). A splice variant ofmGlu8 receptors (mGlu8b) has been described in rats and humans,in which an out-of-frame insertion of 55 bp results in the substi-tution of the last 16 amino acids of mGlu8a with 16 different aminoacids (Corti et al., 1998; Malherbe et al., 1999). An additional varianthas been described in the human mGlu8 receptor, in which aninsertion of 74 bp introduces a frame shift in the predicted trans-lation resulting in termination of the polypeptide before the 7-TMregion (Malherbe et al., 1999).

3.4.3.2. Signal transduction and interacting proteins. mGlu4, mGlu7,and mGlu8 receptors are coupled to Gi/Go proteins in heterologousexpression systems (reviewed by Pin and Duvoisin, 1995;Niswender and Conn, 2010). Activation of the MAPK and PtdIns-3-K pathways mediated by native mGlu4 receptors has beenreported in cultured cerebellar granule cells (Iacovelli et al., 2002).mGlu7 receptors bind to a number of interacting proteins thatinclude filamin A, protein phosphatase 1C, protein interacting withprotein kinase C 1 (PICK1), syntenin, the bg subunits of G proteins,and MacMARCKS (macrophage myristoylated alanine rich C kinasesubstrate) (Boudin et al., 2000; El Far et al., 2001; Enz and Croci,2003; Bertaso et al., 2006). Proteins interacting with mGlu8receptors include Band 4.1, which facilitates cell surface receptorexpression and inhibits mGlu8-receptor signalling (Rose et al.,2008), and Pias-1 and other proteins of the sumoylation cascade(Tang et al., 2005).

3.4.3.3. Functional anatomy. mGlu4, mGlu7, and mGlu8 receptorsare localized presynaptically at the active zone of neurotransmitterrelease. Synaptic glutamate can therefore activate all three receptorsubtypes, thus negatively regulating its own release (reviewed byNiswender and Conn, 2010). However, glutamate binds with rela-tively high affinity tomGlu4 andmGlu8 receptors, but displays verylow affinity for mGlu7 receptors (reviewed by Schoepp et al., 1999).This suggests that mGlu7 receptors can only be recruited by highconcentrations of glutamate released under conditions of highsynaptic activity. Not surprisingly, mice lacking mGlu7 receptorsshow an increased susceptibility to epileptic seizures (Sansig et al.,2001). A presynaptic integration exists among mGlu7 receptors,GABAB receptors and A1 adenosine receptors, which functionallyinteract in reducing glutamate release mediated by N-type voltage-sensitive Ca2þ channels (Martín et al., 2008). However, repeatedagonist exposure discloses a facilitatory mGlu7 signal on glutamaterelease, which is mediated by stimulation of PI hydrolysis andtranslocation of munc-13-1, a protein that is essential for priming ofsynaptic vesicles (Martín et al., 2010). Thus, the regulation ofglutamate release by mGlu7 receptors is not univocal and is strictlyactivity-dependent.

The mGlu4 receptor is highly expressed in the cerebellum,where its activation inhibits glutamate release at the synapsebetween parallel fibers (the axons of cerebellar granule cells) and

Purkinje cells. High-to-moderate levels of expression are also foundin the thalamus, basal ganglia, and olfactory bulb. mGlu4 receptorsfound in nerve terminals of striatal projection neurons innervatingthe external globus pallidus are particularly relevant from a clinicalstandpoint (see below). A truncated form of mGlu4 receptorslacking a great portion of the glutamate binding domain has beenfound in taste buds (Chaudhari et al., 2009). mGlu4 receptors werealso present in medulloblastoma cells (Iacovelli et al., 2006),immune cells (see below), and in pancreatic a-cells, where theyinhibit glucagons secretion (Uehara et al., 2004). mGlu7 are highlyexpressed in the CNS, and are also found in peripheral organs.mGlu7 receptors are found in hair cells and in spiral ganglion cellsof the inner ear, and common single nucleotide polymorphisms(SNPs) of GRM7 are strongly associated with the risk of developingage-related hearing impairment (presbycusis), the most prevalentsensory impairment in the elderly (Friedman et al., 2009). Recentfindings suggest that mGlu7 receptors are expressed in the colonmucosa, where receptor activation increases fecal water content ina stress-induced defecation paradigm (Julio-Pieper et al., in press).It has been suggested that mGlu7 receptors play a role in functionaldisorders of the gut, such as the irritable bowel syndrome (IBS),which are often associated with chronic stress.

The mGlu8 receptor is widely, but unevenly, distributed in theCNS. For example, mGlu8-receptor expressing nerve terminalstarget specific subsets of GABAergic neurons in the hippocampus(Ferraguti et al., 2005).

3.4.3.4. Pharmacology. L-AP4 and L-SOP (an endogenous product ofphospholipids cleavage which accumulates in the Alzheimer’sbrain) are the prototypical, non-subtype-selective orthostericagonists of group-III mGlu receptors (reviewed by Schoepp et al.,1999). As outlined in the Historical background, these twocompounds are also able to block excitatory amino acid-stimulatedPI hydrolysis in brain slices (Nicoletti et al., 1986a). Whether thisparticular effect derives from an interaction between group-I andgroup-III mGlu receptors is unknown. (1S,3R,4S)-1-Amino-cyclopentane-1,3,4-tricarboxylic acid ACTP-I and (R,S)-4-phospho-nophenylglycine (PPG) also behave as non-subtype-selectiveorthosteric agonists of group-III mGlu receptors (reviewed bySchoepp et al., 1999). In spite of the new insights into the activationmechanisms of group-III mGlu receptors (Selvam et al., 2007; Frauliet al., 2007), there are only a few orthosteric agonists that candiscriminate between mGlu4 and mGlu8 receptors. (S)-3,4-dicar-boxyphenylglycine (DCPG) has�100 fold greater affinity for mGlu8receptors than for all other group-III mGlu receptor subtypes(Thomas et al., 2001), and is widely used as a tool to selectivelyactivate mGlu8 receptors. The available orthosteric antagonists ofgroup-III mGlu receptors display low receptor affinity or lackspecificity. For example, (R,S)-a-cyclopropyl-4-phosphonophenyl-glycine (CPPG), which is often used as an orthosteric antagonist ofgroup-III mGlu receptors, can also antagonize group-II mGlureceptors with nanomolar affinity (Toms et al., 1996). N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC) isthe prototype of a growing list of selective mGlu4 receptor PAMsthat hold promise for the treatment of Parkinson’s disease andother disorders (reviewed by Niswender and Conn, 2010). Becauseof its structure similarity with CPCCOEt, PHCCC can also have off-target effects by blocking mGlu1 receptors at high concentrations.The mGlu5-receptor NAMs, MPEP and SIB1893, also behave asmGlu4 receptor PAMs in the high micromolar range (Mathiesenet al., 2003). Only few drugs behave as selective ligands of mGlu7receptors. These include the “allosteric agonist” N,N0-Bis(diphe-nylmethyl)-1,2-ethanediamine dihydrochloride (AMN082), whichdirectly activatemGlu7 receptors by interactingwith a site differentfrom the glutamate binding site, and the putative mGlu7 receptor

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NAM, 6-(4-methoxyphenyl)-5-methyl-3-(4-pyridinyl)-isoxazolo[4,5]pyridine-4(5H)-one (MMPIP) (Mitsukawa et al., 2005; Suzukiet al., 2007). A bias inherent to the use of AMN082 is that thedrug induces a rapid internalization of mGlu7 receptors (Pelkeyet al., 2007). This may partly explain some unexpected findings inexperiments using AMN082 (see below).

3.4.3.5. Relevance to human disorders and clinical perspectives3.4.3.5.1. Parkinson’s disease. Activation of mGlu4 receptors

inhibits GABA release at the synapse between stratial projectionneurons and neurons of the external globus pallidus. This is the firstsynapse of the indirect pathway of the basal ganglia motor circuit,which is overactive in Parkinson’s disease (reviewed by Conn et al.,2005). Drugs that activate mGlu4 receptors including orthostericagonists and selective PAMs cause a robust depression of inhibitorysynaptic transmission in the external globus pallidus and relievemotor symptoms in animal models of parkinsonism (Marino et al.,2003; Valenti et al., 2003; Niswender et al., 2008; Beurrier et al.,2009). Because the inhibitory action of mGlu4 receptors onsynaptic transmission in the external globus pallidus is not affectedby dopamine loss, one can predict that mGlu4 receptor agonistsretain their therapeutic activity in Parkinsonian patients for a longtime without causing dyskinesias or other motor side effects thattypically develop in response to L-DOPA or other dopaminergicdrugs. It is now believed that during the early “compensated” phaseof Parkinson’s disease a number of mechanisms reduce the activityof the indirect pathway. These include an increased production ofendogenous opioids, which suppress synaptic transmission in theexternal globus pallidus by activating presynaptic m opioid recep-tors (Sandyk, 1988; Schroeder and Schneider, 2002). WhethermGlu4 receptors undergo plastic modification in this specificsetting is unknown. An early treatment with mGlu4 receptoragonists might reinforce the defensive mechanisms in the earlyphases of Parkinson’s disease, thus delaying the clinical onset of thedisorder. Activation of mGlu4 receptors might produce a dualbenefit in Parkinson’s disease by relieving motor symptoms andattenuating the progressive degeneration of nigro-striatal dopa-minergic neurons at the same time. In mice challenged with thetoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP),systemic treatment with PHCCC reduces the degeneration of nigro-striatal dopaminergic neurons. PHCCC retains its protective activitywhen locally injected in the external globus pallidus, suggestingthat inhibition of synaptic transmission in the external globuspallidus leads to a reduced activity of excitatory neurons of thesubthalamic nucleus, thereby inducing neuroprotection (Battagliaet al., 2004). However, mGlu4 receptors also reduce excitatorysynaptic transmission in the pars compacta of the substantia nigra,a mechanism that may contribute to restrain excitotoxic death ofnigral dopaminergic neurons (Valenti et al., 2005). Finally,preclinical data raise the interesting possibility that mGlu4 receptoragonists may be helpful for the prophylaxis of drug-inducedparkinsonism occurring in schizophrenic patients receiving first-generation antipsychotic drugs. These patients are usually treatedwith anticholinergic drugs, which, however, cause autonomicadverse effects and cognitive dysfunctions.

3.4.3.5.2. Absence epilepsy. Absence seizures, which are char-acterized by synchronous spike-and-wave discharges (SWDs) atthe EEG, are generated by an abnormal oscillatory activity ofa thalamocortical loop that comprises ventrobasal thalamic nuclei,the cerebral cortex, and the reticular thalamic nucleus (RTN)(reviewed by Blumenfeld, 2005). Drugs that block T-type voltage-sensitive Ca2þ channels, such as ethosuximide and valproate, aswell as clonazepam and lamotrigine are commonly used in thetreatment of absence epilepsy; however, these drugs cause class-related adverse effects as sedation and ataxia, and >20% of patients

with absence seizures are resistant to medication. Recent evidencesuggests that mGlu receptors in general, and group-III mGlureceptors in particular, are novel potential targets for treatment ofabsence epilepsy. Genetic deletion of mGlu4 receptors or intra-RTNinjection of a group-III mGlu receptor antagonist protects miceagainst absence seizures induced by low doses of pentylentetrazol(Snead et al., 2000). In addition, WAG/Rij rats, which spontaneouslydevelop SWDs after 2e3 months of age, show an increasedexpression of mGlu4 receptors in the RTN, and respond to phar-macological activation of mGlu4 receptors with an increasedfrequency of absence seizures (Ngomba et al., 2008). Interestingly,the GRM4 gene is localized within the EJM1 susceptibility focus forjuvenile myoclonic epilepsy (Wong et al., 2001; Izzi et al., 2003),which is characterized by absence seizures combined withmyoclonic and toniceclonic seizures. These data stimulate thesearch formolecules that selectively antagonizemGlu4 receptors aspotential anti-absence drugs.

Recent evidence indicates that absence seizures develop in miceunder conditions that disrupt the interaction of mGlu7 receptorswith PICK1 (Bertaso et al., 2008). In addition, mutant mice lackingthe PDZ domain in mGlu7 receptors (necessary for the interactionwith PICK1 and other proteins) are more sensitive to pentylente-trazol-induced absence seizures (Zhang et al., 2008a,b). Thissuggests that interaction between mGlu7 receptors and PICK1 isprotective against paroxysmal activity of the thalamocorticalnetwork underlying absence seizures.

3.4.3.5.3. Pain. Recent evidence suggests that group-III mGlureceptors regulate pain transmission and are potential targets foranalgesic drugs (reviewed by Goudet et al., 2009). However, the indi-vidual role of mGlu4, mGlu7, andmGlu8 receptors in the regulation ofpain threshold is not univocal. Intrathecal injection of PHCCC causesanalgesia in models of inflammatory or neuropathic pain (Goudetet al., 2008), suggesting that mGlu4 receptors in the spinal cordnegatively modulate pain transmission. The role of mGlu7 andmGlu8receptors has been investigated by experiments withmicroinfusion ofsubtype-selective ligands in two supraspinal centers that lie along thepain neuraxis, i.e. the amygdala and the periaqueductal grey. In bothregions, activation of mGlu7 receptors with the “allosteric agonist”AMN082 amplifies nocifensive behavior, whereas selective activationof mGlu8 receptors with DCPG produces opposite effects (Marabeseet al., 2007a; Palazzo et al., 2008). Systemic treatment with DCPGalso causes analgesia (Marabese et al., 2007b). Thus, compounds thatactivate mGlu4 and mGlu8 receptors but have no activity at mGlu7receptors can be developed as novel analgesic drugs.

3.4.3.5.4. Anxiety. A role for group-IIII mGlu receptors in anxietywas suggested by the evidence that intrahippocampal injection ofthe non-subtype-selective agonist, L-SOP, had an anticonflict effectin the rat Vogel test (Tatarczy�nska et al., 2001). Both mGlu8 andmGlu4 receptors appear to negatively modulate anxiety in rodents.mGlu8-receptor knockout mice exposed to the elevated plus mazetest showed anxiety-related behavior and a higher number of c-Fos-positive neurons in the centromedial thalamic nucleus as comparedto wild-type mice (Linden et al., 2002, 2003; Duvoisin et al., 2005).In addition, the mGlu8-receptor agonist, DCPG, and the novelmGlu8-receptor enhancer, AZ12216052, reduced anxiety-likebehavior in mice (Duvoisin et al., 2010; see Stachowicz et al., 2005for contrasting data). Selective activation of mGlu4 receptors inthe rat amygdala produced an anticonflict effect in the Vogel test(see Linden and Schoepp, 2006 for a comprehensive review). Therole of mGlu7 receptors in anxiety is uncertain because treatmentwith the mGlu7 receptor agonist, AMN082, relieves anxiety andgenetic deletion of mGlu7 receptors also relieves anxiety (reviewedby Lavreysen and Dautzenberg, 2008). Functional antagonism ofmGlu7 receptors by AMN082 resulting from receptor internaliza-tion (see above) may help reconcile these contrasting findings.

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3.4.3.5.5. Neuroinflammation and regulation of the immune sys-tem. A report by Fallarino et al. (2010) discloses a new mechanismthat highlights the cross-talk between the nervous and immunesystems. These authors have shown that activation of mGlu4receptors expressed on dendritic cells, a cell type crucial for sup-porting an immune response, drives the differentiation of antigen-specific T cells into T regulatory (Treg) cells at the expenses ofautoreactive TH17 cells, thus reinforcing mechanisms of immunetolerance. Mice lackingmGlu4 receptors immunized with a myelin-specific antigen develop a more severe experimental autoimmuneencephalomyelitis (EAE), whereas wild-type mice treated with themGlu4 receptor PAM, PHCCC, are protected against EAE. Remark-ably, PHCCC administered at the onset of motor symptoms reducesthe frequency and severity of relapses in a relapsing-remittingmodel of EAE. These data are particularly relevant to the treatmentof relapsing-remitting multiple sclerosis, a demyelinating disorderof the CNS mediated inter alia by autoreactive clones of and TH17cells. The central role of mGlu4 receptors in the immunologicalsynapses between dendritic cells and T lymphocytes (Fallarinoet al., 2010; see also Hansen and Caspi, 2010) suggests a thera-peutic activity of mGlu4 receptor enhancers in autoimmunedisorders other than multiple sclerosis.

3.4.3.5.6. SmitheLemlieOpitz syndrome and retinitis pigmento-sa. GRM8, the human gene encoding the mGlu8 receptor, encom-passes approximately 1000 kb of DNA at the boundary of theq31.3eq32.1 bands of chromosome 7, the same region where theSmitheLemlieOpitz syndrome and an autosomal form of retinitepigmentosa (Scherer et al., 1997). The SmitheLemlieOpitzsyndrome is a relatively rare developmental disorder due to defi-ciency of the enzyme 7-dehydrocholesterol reductase. Retinitepigmentosa is a group of genetic eye disorders characterized byabnormalities of photoreceptors or retinal pigment epithelium. Itshould be highlighted that the mGlu8 receptor has been firstidentified in the retina (Duvoisin et al., 1995), where it showsmultiple localizations (Quraishi et al., 2007). Interestingly, mGlu8receptors are found in photoreceptor nerve terminals, where theymodulate neurotransmitter release by interacting with calciumchannels (Koulen et al., 1999, 2005). Whether abnormalities ofmGlu8 receptors are related to the progressive blindness associatedwith autosomal retinite pigmentosa remains to be established.

Fig. 4. Localization and function of mGlu6 receptors in retinal ON-bipolar cells. mGlu6receptors are present in the dendrites of the ON-bipolar cells of the retina, where theiractivation negatively modulates TrpM1 channels through a chain of events that includeintracellular calcium release and activation of the protein phosphatase, calcineurin.

3.5. mGlu6 receptor

Gene name: GRM6 (human); Grm6 (rat, mouse). Accessionnumbers: NP_000834 (human); NP_075209 (rat); NP_775548(mouse). Chromosomal location: 5q35 (human); 10 (rat); 11B1.3(mouse) (Nakajima et al., 1993; Hashimoto et al., 1997; Laurie et al.,1997).

3.5.1. Splice variantsmGlu6 receptor variants have been identified in rats and

humans. The rat receptor variant is characterized by an additionalexon of 88 nucleotides which contains an in frame stop codon,resulting in a truncated protein of 508 amino acids. The two humanvariants lack 97 nucleotides of exon 6 and include 5 nucleotides ofintron 5, respectively. mRNAs of these two variants encode trun-cated proteins of 425 and 405 amino acids, respectively. All trun-cated variants lack the 7-TM and the C-terminus domain of thereceptor (Valerio et al., 2001).

3.5.2. PharmacologyThemGlu6 receptor exhibits the samepharmacological profile as

other group-III mGlu receptors, being activated by L-AP4, L-SOP, andPPG, and antagonized by CPPG, (RS)-a-methylserine-O-phosphate

(MSOP), and (S)-2-amino-2-methyl-4-phosphonobutanoic acid(MAP4).

3.5.3. Functional anatomy and relevance to human disordersThe mGlu6 receptor is exclusively localized in the dendrites of

ON-bipolar cells of the retina and responds to glutamate releasedfrom rod and cone photoreceptor cells in the dark (Nakajima et al.,1993; Nomura et al., 1994; Vardi et al., 2000). Activation of mGlu6receptors reduces excitability of ON-bipolar cells by negativelyregulating a membrane non-selective cation channel, which likelycorresponds to the TrpM1 channel (Shen et al., 2009; Morganset al., 2009; Koike et al., 2010). This effect is mediated by a Goprotein-dependent activation of the Ca2þ-stimulated proteinphosphatase, calcineurin (Dhingra et al., 2004; Nawy, 1999, 2000)(Fig. 4). Light reduces glutamate stimulation of mGlu6 receptors,leading to opening of cation channels and depolarization of ON-bipolar cells. The effect of light is amplified by inactivation of themGlu6 receptor signalling mediated by the transmembrane proteinR9AP, which facilitates the GTPase activity of RGS11 complexedwith the Gb5 subunit of Go (Cao et al., 2009; Masuho et al., 2010;Zhang et al., 2010). mGlu6 receptor knockout mice show a loss ofON responses but an unchanged response to light (Masu et al.,1995), and a mouse screened for the lack of the b-wave at theelectroretinogram showed a splice error in the Grm6 and the lack ofmGlu6 receptors in the retina (Maddox et al., 2008). The b-wave ofthe electroretinogram reflects the light-induced depolarization ofON-bipolar cells (Stockton and Slaughter, 1989). Interestingly,mutations in the gene encoding the mGlu6 receptor is associatedwith autosomal recessive congenital stationary night blindnesscharacterized by abnormal electroretinogram ON responses inhumans (Dryja et al., 2005; Zeitz et al., 2005; O’Connor et al., 2006).Mutations of the TrpM1 gene are also associated with autosomalrecessive congenital stationary night blindness (Van Genderenet al., 2009).

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In conclusion, these are exciting times for mGlu receptors. After25 years we can truly believe that subtype-selective mGlu receptorligands will soon enter the clinic. Perhaps the treatment of FXS willbe the launching platform for the use of mGlu drugs in highlyprevalent disorders, such as schizophrenia, Parkinson’s disease,chronic pain, and drug addiction. It is sad that Prof. Costawill not bea witness of the clinical era of mGlu receptors.

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