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The mGluR5 antagonist, MPEP was shown to exert anxiolytic-like effect in several anxiety-like behaviour tests, including elevated-plus maze, social exploration, fear-potentiated startle, Vogel-conflict and light-dark box test [ - ]. In addition, MTEP exerted anxiolytic-like effects in contextual fear conditioning following acute or subchronic treatment, indicating that tolerance does not develop to the anxiolytic effect of MTEP [ ]. Furthermore, it has been suggested that mGluR5 antagonism exerts its anxiolytic effect in the conditioned emotional response paradigm by a mechanism different from that of diazepam [ ].

In the chronic mild stress model, a validated model to screen for antidepressant activity, increased expression of hippocampal mGluR5 has been reported [ ]. It has been demonstrated that the mGluR5 antagonists, MPEP and MTEP, shortened the immobility time in the tail-suspension test and forced-swim test in mice [ , - ], indicative of an antidepressant-like effect. Interestingly, it has been reported that mGluR5 knockout mice display an antidepressant-like behavioural phenotype [ ].

In these mice imipramine, but not MPEP, exerted an antidepressant effect [ ]. In the same study a synergy of MPEP and imipramine was observed in the mouse forced-swim test. The above studies indicate that mGluR1 and mGluR5 antagonists may have therapeutic potential in the treatment of MDD and anxiety disorders. Moreover, the antidepressant efficacy of tricyclic antidepressants and SSRIs might be enhanced by concomitant treatment with mGluR5 negative modulators. Variations in GRM3 have been found to affect prefrontal glutamatergic neurotransmission and cognitive functions [ ].

However, the functional consequences of these alterations are unknown. Chronic treatment with MGS, furthermore, increased hippocampal neurogenesis [ ], a mechanism demonstrated for some of the current antidepressants [ ]. In the forced-swim test, the two compounds increased swimming behaviour without affecting climbing behaviour [ ].

Those antidepressants that increase serotonergic neurotransmission predominantly increase swimming behaviour whereas those that increase catacholaminergic neurotransmission increase climbing behaviour [ ]. However, in the same study LY had no effects in the elevated plus maze and stress-induced hyperthermia tests in mice or on punished drinking. Chronic treatment with citalopram, but not imipramine, decreased immunoreactivity of mGluR7 but not mGluR4 in the rat hippocampus and cerebral cortex [ ].

The lack of effect of chronic imipramine on mGlu4R expression in the rat brain has also been observed by another group [ ]. Pharmacological studies of group III mGluRs have been limited due to lack of subtype-selective compounds. Moreover, mGluR7 knockout mice displayed an antidepressant-like phenotype in the forced-swim test and the tail suspension test [ ].

In line with the latter study, the selective mGluR7 agonist AMN induced a dose-dependent decrease in the immobility time in the forced swim test and tail suspension test, supporting the hypothesis of antidepressant-like potency of mGluR7 agonists [ ]. In the same study, AMN did not change the behaviour of mGluR7 knockout mice in the tail suspension test, whilst imipramine significantly reduced their immobility, indicating an mGluR7-dependent mechanism of the antidepressant-like activity of AMN ACPT-I, a group III mGluR agonist, produced anxiolytic-like effect after central administration [ ] as assessed by the stress-induced hyperthermia and elevated plus-maze tests in mice, and the Vogel test in rats.

Currently, little is known about the dysfunction of the mGluR8.

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A recent study evaluated the behaviour of mGluR8 knockout mice in different behavioural tasks commonly used in neuropsychiatric research [ ]. These mice expressed no anxiogenic phenotype in unconditioned anxiety models, including elevated plus maze, elevated zero maze and light-dark box test. However, a contextual fear deficit was observed in the mGluR8 knockout mice, indicating that these receptors may be implicated in some anxiety disorders, such as generalised anxiety [ ]. Despite the limited number of studies on selective group III mGluR ligands the present studies indicate that compounds belonging to this group may possess antidepressant and anxiolytic properties.

It is characterized by motor symptoms such as rigidity, tremor, bradykinesia, postural instability and gait disturbances. PD is a progressive neurodegenerative disease affecting dopaminergic neurons in the substantia nigra pars compacta selectively. The resulting loss of dopaminergic innervation in the striatum is believed to be the primary event underlying the motor symptoms of PD.

This loss of dopaminergic tone within the striatum leads to secondary disturbances in the two efferent striatal systems arising from the medium spiny neurons, termed the direct and indirect pathways [ ]. Accordingly, stimulation of these two pathways oppositely regulates the main basal ganglia output pathway, the nigrothalamic pathway. In this respect, a loss of dopamine tone in the striatum is assumed to induce an unbalance between the two pathways, namely a disinhibition of striatopallidal neurons and an inhibition of striatonigral neurons, ultimately resulting in an increased activity of the GABAergic nigrothalamic pathway [ ].

It is generally believed that restoration of a normal level of activity within the indirect pathway would provide symptomatic effect in PD patients. Within this pathway, the subthalamic nucleus seems to play a critical role since it displays a continuous abnormal bursting mode of activity in PD patients [ , ]. Interestingly, similar findings have also been reported in rodent models based on the use of a neurotoxin, e. In the clinic, long-term use of L-DOPA, the most prescribed anti-Parkinsonian drug, often results in a loss of efficacy and the apparition of dyskinesias [ ].

It is thus essential to develop novel pharmacotherapies exhibiting a sustained symptomatic effect in the advanced stage of the disease, but also the potential to delay or stop the progression of the disease in its early stage. Activation of group I mGluRs has been shown to enhance NMDA currents in striatal neurons [ ], as well as induce overactivity of the striatopallidal pathway as measured by proenkephalin mRNA expression [ ]. Based on these and other evidence, it was hypothesized that blockade of group I mGluRs might induce antiparkinsonian-like effects in vivo.

Several studies have used subtype-selective antagonists of group I mGluRs to further dissect out the contribution of mGluR1 and mGluR5 to a potential antiparkinsonian-like effect in relevant animal models. In addition, the selective mGluR1 antagonist EMQMCM, was shown to slightly inhibit haloperidol-induced catalepsy, while it was devoid of effect on hypoactivity induced by a lower dose of haloperidol [ ].

Interestingly, an antiparkinsonian-like profile has been reported for another non-competitive mGluR5 antagonist, MPEP [ ]. In a more recent study, it was shown that the increased metabolic activity in the subthalamic nucleus of dopamine-depleted rats, as detected by cytochrome oxidase staining, was reversed in animals chronically treated with MPEP [ ].

Taken together, these data indicate that mGluR5 blockade would normalize the hyperactive state of the subthalamic nucleus, most likely indirectly through modulation of striatopallidal neurons [ ], thereby leading to antiparkinsonian-like effects. In line with this assumption, local injections of MPEP into the subthalamic nucleus attenuated motor asymmetries in unilateral 6-OHDA-lesioned rats [ ]. In summary, mGluR5 antagonism may offer symptomatic improvement based on the reported antiparkinsonian-like effects in animal models, whereas mGluR1 antagonism holds less promise.

Besides a potential symptomatic effect, group I mGluR antagonism has been suggested to be of potential interest with respect to alleviation of L-DOPA-induced dyskinesias. These data suggest that mGluR5 antagonism can prevent priming of dyskinesias, as well as reverse the expression of dyskinesias in primed animals, an effect attributed to the normalization of an excessive GABA overflow in the substantia nigra reticulata [ ].

Taken together, these findings strongly suggest a potential benefit of mGluR5 antagonism in the alleviation of L-DOPA-induced dyskinesias typically observed after long-term treatment in patients. One of the caveats in the latter studies is related to the fact that MPEP also acts as a NMDA receptor antagonist depending on the concentration used, which may account for the observed neuroprotective effect. Taken together, preclinical findings indicate that mGluR5, and possibly mGluR1 antagonism, may offer neuroprotective benefit slowing down the progression of the disease in its early stages.

For instance, intraventricular administration of DCG-IV reversed reserpine-induced akinesia in rats [ ]. However, more studies would be needed especially with respect to motor improvement as contradictory data have been reported in the literature. Group III mGluRs are presynaptically localized on GABAergic and glutamatergic terminals in several basal ganglia nuclei, including globus pallidus and substantia nigra, and therefore represent potential targets for reduction of abnormal activity associated with PD [ ].

Several preclinical studies support a possible therapeutic benefit of mGluR4 agonism, while only few studies have investigated the role of other subtypes, e. Early preclinical studies have shown that the selective group III agonist L-AP4 produced symptomatic improvement in both acute and chronic rodent models of Parkinson's disease, including haloperidol-induced catalepsy, reserpine-induced akinesia, and forelimb asymmetry in unilateral 6-OHDA-lesioned rats [ ]. It was further reported in the same study that L-AP4 modulated glutamatergic transmission at the striato-pallidal synapse through activation of mGluR4, as indicated by the loss of effect in brain slices from mGluR4 knockout mice.

This mechanism was also suggested to contribute to the observed behavioral improvements. In line with this hypothesis, intrapallidal administration of L-AP4 was later reported to alleviate 6-OHDA-induced akinesia assessed in a reaction time task in rats [ ]. A selective allosteric potentiator of mGluR4, PHCCC, was also reported to reverse reserpine-induced akinesia in rats, an effect again attributed to the modulation of striatopallidal glutamate transmission [ ].

Recently, a novel mGluR4-preferring agonist, LSP, was shown to reverse akinesia assessed by a reaction time task in 6-OHDA-lesioned rats after intrapallidal injection, and block haloperidol-induced catalepsy after systemic administration [ ]. Furthermore, LSP reduced glutamate transmission at the striatopallidal sysnapse by a presynaptic mechanism, as shown for L-AP4. In neuroprotection studies, both acute and subchronic intranigral injections of L-AP4 are found to prevent dopaminergic cell loss induced by 6-OHDA in rats [ , ]. Subchronic intranigral injections of L-AP4 were further shown to slow down dopaminergic neurodegeneration in 6-OHDA-lesioned rats already undergoing degeneration [ ].

In addition, L-AP4 was also reported to protect cultured dopaminergic neurons against rotenone toxicity [ ]. Based on the glutamate excitotoxicity hypothesis of dopaminergic degeneration, mGluR4 activation on glutamatergic terminals of subthalamonigral neurons have been suggested to contribute to such a neuroprotective effect. In fact, L-AP4 was shown to inhibit excitatory transmission in the substantia nigra pars compacta, and the effect was potentiated by PHCCC, further involving a selective effect of mGluR4 [ ].

These studies suggest that a decrease in excitatory glutamatergic transmission from the subthalamic nucleus may contribute to a possible neuroprotective benefit of mGluR4 positive modulation. However, more selective and brain penetrant compounds would be needed to strengthen this assumption. Recently, the selective allosteric mGluR7 agonist, AMN, was shown to reverse haloperidol-induced catalepsy in rats after intrastriatal or systemic administration [ ]. The same anticataleptic effect of AMN was also found in wild-type, but not in mGluR7 knockout mice, indicative of a selective mGluR7-mediated effect.

Additional studies are needed to address whether a neuroprotective potential can also be achieved. Fragile X syndrome FXS is the most common form of inherited mental retardation and is characterized by intellectual disabilities, autistic features, hyperactivity, audiogenic seizures, and certain physical features, e. It is usually caused by a mutation of the fragile X mental retardation-1 gene FMR1 , leading to either decreased levels or complete loss of the FMR1 gene product fragile X mental retardation protein FMRP [ , ].

FMRP is an RNA binding protein that controls for instance synthesis of certain components of the postsynaptic density PSD in both the neocortex and hippocampus, as well as translational efficiency of dendritic mRNAs in response to stimulation of mGluRs [ - ]. Fmr1 knockout mice display physical and behavioural phenotypes comparable to those of the human counterpart, such as macroorchidism, increased locomotor activity, audiogenic seizures, and impaired fear-conditioned memory [ - ].

Similarly to post-mortem observations in FXS patients [ - ], Frm1 knockout mice showed altered morphology of cortical and hippocampal dendritic spines, e. These observation suggest that FMRP plays a role in spine development and stabilisation [ ], and a loss of FRMP function may result in impaired synaptic activity underlying mental retardation [ ]. In line with this hypothesis, it has been demonstrated that Fmr1 knockout mice display an increased occurrence of mGluR-LTD [ ], while NMDA receptor-LTD has been found to be normal in the Fmr1 knockout mice in the hippocampus and cerebellum [ 61 , ].

Since both LTD and long-term potentiation LTP are believed to contribute to learning and memory [ ], an increased mGluR-LTD may interfere with the establishment and maintenance of strong synapses required for memory formation. In recent years, pharmacological studies using mGluR5 antagonists have been performed in animal models of FXS. It was demonstrated that the non-competitive antagonist MPEP increased inhibitory phosphorylation of glycogen synthase kinase-3 GSK3 in Fmr1 knockout mice, but not in wild type mice [ ]. Interestingly, it was reported that Fmr1 knockout mice display impaired inhibitory serine-phosphorylation of GSK3, and inhibition of GSK-3 by lithium ameliorated behavioural deficits in models of FXS.

Taken together, these studies indicate that increased mGluR signalling in Fmr1 knockout mice may contribute to the deficit in inhibitory control of GSK3.

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In line with this hypothesis, studies in primary cortical neurons have shown that FMRP acted as a repressor of the translation of Shank1 mRNAs, which controls dendritic spine morphology, and that DHPG-mediated mGluR stimulation enhanced the translation of Shank1 [ ]. Furthermore, McBride et al. Courtship behaviour activity was recovered in larvae and adults treated with MPEP, suggesting that the observed effects did not result from the prevention of developmental defects.

In a follow up study, it was shown that learning deficits, which appeared at an older age than the deficits in training and memory, were rescued by the same mGluR antagonists as used previously [ ]. Interestingly, the learning deficits were rescued with treatment during development alone. However, the loss of mushroom bodies could not be restored in older flies. In a zebrafish model of FXS, MPEP has been shown to either completely or partially rescue the phenotypes, including craniofacial and neurite branching abnormalities [ ]. In Fmr1 knockout mice, MPEP has been demonstrated to rescue heightened audiogenic seizures susceptibility, abnormal center-field behaviour [ ], and impaired pre-pulse inhibition [ ].

In addition, both MPEP and fenobam rescued the protrusion morphology observed in hippocampal neurons of Fmr1 knockout mice [ ]. The mGluR5 antagonist, fenobam, has been demonstrated to reduce hyperactivity and anxiety in patients suffering from FXS in a small clinical trial [ ]. However, this effect was not always well-correlated with subjective clinical improvement nor with the pharmacokinetics of fenobam, which showed great inter-individual differences. In preclinical studies, fenobam and other mGluR5 antagonists, including MTEP, have been reported to produce impairments in various cognitive tests, including water maze and passive avoidance tests [ , ], while other studies have not found any effect of fenobam on working memory or spatial learning at therapeutic relevant doses [ ].

In line with a potential effect on cognitive function, MPEP has been demonstrated to suppress theta and gamma oscillations and impair LTP in the dentate gyrus, whereas enhanced LTP was observed in the CA1 region of rats [ ]. Currently, no preclinical or clinical evidence supporting a role of selective group II or II modulators in the treatment of FXS has been published.

Since the Fmr1 gene has been identified as an autism-related gene and the most common cause of autism [ ], modulation of mGluRs for the treatment of FXS might also be beneficial for autism, which is also supported by the observation that MPEP blocked repetitive features in a mice model of autism [ ]. In conclusion, reduction in mGluR5 signalling may represent a promising target for treating many of the aspects of FXS.

However, possible adverse effects of mGluR5 antagonism on cognitive function remain to be further adressed. Symptoms generally start appearing between mid thirties and middle age, and patients usually die 15 to 20 years after the symptomatic onset [ , ]. The neurodegeneration occurs preferentially in the striatum, extends at later stages to other brain regions including the deep layers of cortex, globus pallidus, thalamus, subthalamic nuclei, substantia nigra and gliosis formation appears [ ]. In the striatum, the neuronal loss selectively affects GABAergic medium spiny neurons, whereas large aspiny cholinergic neurons are spared [ , ].

As for fragile X syndrome, HD is caused by a mutation in the gene encoding the protein huntingtin Htt [ , ]. Even though Htt is expressed throughout the nervous system, the neurodegeneration remains limited to specific brain areas even at late stages of HD. Some studies have suggested that Htt is required for cell survival, and loss of its function may therefore be involved in neurodegeneration [ ].

Glutamate excitotoxicity has been proposed to play a central role in the pathogenesis of HD [ ], and the involvement of the NMDA receptors in glutamate-mediated excitotoxicity has been especially investigated [ ]. However, there is emerging evidence that mGluRs may also play a role in glutamate-mediated excitotoxicity [ ].

More precisely, the identification of proteins interacting with both Htt and mGluR signalling indicates that Htt might indeed be involved in the regulation of mGluR signaling [ , ]. These data suggest that a reduction in mGluR signalling may have neuroprotective effects. Further characterization of the precise receptor subtypes involved is unfortunately lacking. They also display decreased expression of several neurotransmitter receptors including striatal mGluR1, mGluR2 and mGluR3.

The decrease in the mGluR2 has been suggested to contribute to glutamate-mediated excitotoxicity by increasing glutamate release from corticostriatal terminals [ ]. These data suggest that decreasing glutamatergic transmission through modulation of mGluRs may provide symptomatic relief as well as slow down the progression of the disease.

However, riluzole has since been demonstrated to lack efficacy in HD patients [ ], which may be due to non-specific effects on other transmitter systems. In conclusion, mGluRs modulation may provide therapeutic benefits in HD. However, more studies aimed at elucidating the precise molecular mechanisms underlying the disease would be needed to further support a role of specific mGluR subtypes.

Glutamatergic pathways have been implicated in the pathophysiology of AD [ ]. Furthermore, a reduction of mGluR1 has been found in the frontal cortex of patients with AD, and this reduction was correlated with the progression of the disease [ ]. Pharmacological activation of Group II and III mGluR has been shown to reduce neuronal death in vitro , an effect attributed to reduced glutamate release [ , ]. Thus, mGluR2 might play a key role in the pathogenesis of AD [ ]. Interestingly, agonists of mGluRs induced Tau phosphorylation, and several lines of evidence suggest that the differential expression of glutamate receptors in specific populations of neurons may account for specific neuronal vulnerability [ ].

In conclusion, there is limited information about the role of mGluRs in the pathogenesis of AD, but it is likely that mGluRs may play a significant role in the pathophysiology of this disease. However, there is a lack of published reports, showing efficacy with mGluR ligands in AD models.

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The mechanisms underlying pain remain unclarified. However, it is thought that continuous activation of peripheral afferent fibers by noxious stimulation results in sensitization of dorsal horn neurons, which would subsequently produce aberrant activity in primary afferent fibers [ ]. As a result, peripheral and central mechanisms contribute to a cycle of persistent nociception.

Persistent activation of peripheral afferents may result in central changes in neurotransmitter release or receptor states, resulting in chronic nociceptive activation. Glutamate is released in the spinal dorsal horn, in which it acts via activation of ionotropic glutamate receptors as well as mGluRs [ 1 , ]. Increasing evidence supports a specific role of mGluRs in nociceptive transmission, given the wide expression of these receptors along the nociceptive neuroaxis, such as the dorsal root ganglia, midbrain periaqueductal grey region, spinal cord, thalamus and amygdala [ ].

For instance, Group I mGluRs are expressed both at the spinal and supra-spinal levels, including the thalamus, a brain area critically involved in the signaling of nociceptive information [ ]. Moreover, Group I and II mGluRs are expressed by peripheral terminals and in the soma of dorsal root ganglia neurons [ ]. Almost all mGluR subtypes are expressed in the spinal cord [ 10 , 12 , 16 , 17 , , ]. Besides being expressed in neurons, mGluRs are also found in glial cells, which may play a role in neuropathic pain [ ], but this topic will not be reviewed here.

Other studies inactivating the mGluR1 by a selective antibody have shown that intrathecal blockade of mGluR1 reduced nociceptive behaviors in several models of inflammatory and neuropathic pain, including complete Freund's adjuvant CFA -induced chronic inflammatory pain, formalin-induced persistent nociception, nerve injury-induced neuropathic pain and DHPG-induced spontaneous nociceptive behaviours in rodents [ - ]. In line with an involvement of mGluR1 in pain mechanisms, up-regulation of mGluR1 was also demonstrated in spinal dorsal horn in response to persistent inflammatory hyperalgesia [ ].

Several mGluR1 antagonists, e. In addition, systemic administration of the non-competitive mGluR1 antagonist, A, has been reported to reverse inflammatory and neuropathic pain in rodents, further supporting a therapeutic potential of mGluR1 antagonism in the treatment of chronic pain states [ , ]. Several other non-competitive mGluR1 antagonists, such as A, A, A and A, have also been reported to attenuate spontaneous nociception in a pre-clinical model of postoperative pain [ ].

Beside these pharmacological evidences, antisense knockdown of mGluR1 receptors has been reported to decrease spinal nociceptive neurotransmission and neuropathic hyperalgesia [ , , ], further strengthening the antinociceptive potential of mGluR1 blockade. A large body of literature supports the assumption that mGluR5 modulates pain and that mGluR5 antagonism may be used in the treatment of chronic pain conditions.

As described for mGluR1, mGluR5 are also expressed both at the spinal and supra-spinal levels where they control nociceptive transmission. At the supra-spinal level, pharmacological blockade of mGluR1 by MPEP prevented the nociceptive response of sensory neurons in the rat thalamus [ ]. At the behavioural level, the selective mGluR5 antagonist, SIB, fully reversed hyperalgesia in a neuropathic pain model in rats [ ].

In addition, two other mGluR5 antagonists, MPEP and MTEP, have been shown to produce antinociceptive effects in a wide range of rat nociceptive assays, including CFA-induced chronic inflammatory pain, hyperalgesia induced by formalin and mechanical allodynia following spinal nerve ligation [ 32 , 34 , , , ]. MPEP was also reported to prevent the increased nociceptive reaction induced by the cannabinoid receptor agonist WIN 55, in rats [ ]. Moreover, MPEP abolished acetic acid-induced writhing activity in mice, and was shown to reduce mechanical allodynia and thermal hyperalgesia in a model of post-operative hypersensitivity [ ].

Taken together, preclinical studies support the concept of mGluR5 antagonism for the treatment of chronic pain. The role of group III mGluRs in nociceptive processing has not been thoroughly investigated, but some evidence may indicate a therapeutic potential of certain subtypes. It was indeed reported that activation of group III mGluRs with l-AP4 attenuated allodynia in spinal nerve-ligated rats, but did not affect pain threshold in normal rats [ ].

In addition, intrathecal injection of another group III mGluRs agonist, ACPT-I, inhibited the nociceptive responses to formalin as well as the mechanical hyperalgesia associated with inflammatory pain in carrageenan-treated and monoarthritic rats or neuropathic pain in mononeuropathic and vincristine-treated rats, while it did not affect pain threshold to mechanical or thermal stimuli in normal rats [ ]. Similar antinociceptive effects were also observed following intrathecal injection of PHCCC, a mGluR4 positive allosteric modulator [ ].

At the cellular level, activation of the group III mGluRs by L-AP4 reduced pain-related synaptic plasticity in the amygdala under normal conditions as well as in a model of arthritis pain [ ]. Recently, Palazzo et al. In their study, activation of mGluR7 by the selective agonist AMN was found to have pro-nociceptive effects under normal conditions, but not in the arthritic pain model, while activation of mGluR8 by the selective receptor agonist S-3,4-DCPG exhibited antinociceptive effects in arthritic, but not in normal rats [ ].

However, more studies using subtype selective compounds would be needed in order to identify which of group III mGluRs would be most promising. In conclusion, mGluRs modulation may represent a promising strategy for the treatment of different types of pain, including inflammatory and neuropathic pain. At present, there are very few effective and well-tolerated therapies for neuropathic pain.

Current medications include opioids, antidepressants and anticonvulsants. Modulation of mGluRs may offer better efficacy and more importantly better side-effect profile than current therapies, since the use of opioids in neuropathic pain remains controversial, and both antidepressants and anticonvulsants are associated with side-effects. Glutamate is widely implicated in the mechanisms underlying epilepsy [ , ]. Therefore, targets that potentially control glutamatergic transmission are of special interest to investigate as candidates to prevent epileptogenesis. In rodent models of epilepsy changes in glutamate receptor or glutamate transporter expression were shown to affect epileptic seizures [ ].

Independent of the primary cause, synaptically released glutamate appears to play a major role in the initiation and spread of seizure activity. Antagonists of ionotropic glutamate receptors reduced seizures in several animals models of epilepsy [ - ]. However, these drugs failed early in clinical trials due to multiple side effects, including motor and cognitive impairment [ , ]. With the more recent discovery of mGluRs, there is a renewed interest in targeting glutamate receptors for the treatment of epilepsy. Long-lasting functional enhancement of group I mGluR activity has been reported in amygdala-kindled rats, and up-regulation of mGluR5 immunoreactivity has been described in temporal lobe epilepsy and in focal cortical dysplasia patients [ ].

Moreover, these two compounds were also shown to reduce seizures in genetically epilepsy prone rats GEPR [ , ] and attenuate PTZ- [ , ] and DHPG- [ , ] induced seizures in rodents. AIDA further attenuated KA-induced seizures in immature rats [ ] as well as kindling-related learning deficits [ ]. Following evidence that S C3HPG exhibited anticonvulsant activity, compounds with preferential action on group II mGluRs have been tested in several models of epilepsy. The lack of optimal subtype selective compounds has hampered the investigation of the role of individual group III mGluRs in epileptogenesis.

However, knockout animals have implicated an important role for mGluR7 in seizure activity [ , ], and a down-regulation of mGluR8 has been described in pilocarpine-epileptic rats [ ]. In addition, the use of various mouse strains with differential susceptibility to pilocarpine-induced epilepsy has indicated that mGluR4 expression levels in the dentate gyrus of the hippocampus were inversely correlated with seizure susceptibility [ ].


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Pharmacological studies using activation of group III mGluR have yielded mixed results in animal models of epilepsy. Cortical energy metabolite changes associated with clonic-tonic seizures were also either normalized measured as a decrease of glucose and glycogen or markedly reduced measured as a an accumulation of lactate [ ]. Suppression of SWD has been shown with some mGluR modulators in lethargic mice, a model predictive of clinical efficacy in absence seizures [ ]. Spontaneous seizures following status epilepticus induced by KA or pilocarpine in rats are regarded as models of human temporal lobe epilepsy.

In these models, the effects of mGluR modulators have not been thoroughly investigated and mixed results have been observed. In conclusion, the existing preclinical data positively support the therapeutic potential of mGluR ligands in epilepsy. However, studies using subtype specific agents in different models are still required.

Earlier attempts to target ionotropic glutamate receptors for the treatment of central nervous system disorders have failed due to severe side effects that included, among others, cognitive and motor impairments. As outlined in this review, targeting glutamatergic neurotransmission through modulation of the mGluR family of receptors holds great promise for the treatment of a number of central nervous system disorders, with the advantage of potential fewer side effects. From the collection of evidence presented here, one can extract that the therapeutic effects of drugs targeting mGluRs involve, in the majority of cases, a reduction in the excitatory drive either through antagonism of Group I mGluRs or activation of Group II and III mGluRs.

One clear exception is the use of mGluR5 positive modulators for the treatment of cognitive deficits associated with schizophrenia. Obviously, the final result will depend on whether the targeted glutamatergic pathways are directly or indirectly involved in the pathological condition of interest, and the clinical efficacy may reside in an indirect potentiation of GABAergic, dopaminergic or other neurotransmitter systems.

In addition, targeting mGluRs may also have therapeutic actions independent of glutamatergic signalling altogether, since non-glutamatergic terminals also express mGluRs. In recent years, an intense effort has been concentrated in the synthesis and characterization of novel, more selective drugs acting on selective subtypes of mGluRs.


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Many of the drugs discussed here have shown promising performance in preclinical studies. Several clinical trials of subtype-selective mGluR modulators are ongoing for the treatment of schizophrenia, anxiety and depression among others. The outcome of these clinical studies will be met with great interest, since they will reveal whether targeting subtypes of mGluRs is a viable stragegy for the treatment of various central nervous system disorders both in terms of therapeutic benefits as well as side-effect liability.

National Center for Biotechnology Information , U. Journal List Curr Neuropharmacol v. Published online Mar. P Montezinho , 1 P. S Pinheiro , 2 K. F Sotty 1 Department of Neurophysiology, H. P Montezinho 1 Department of Neurophysiology, H. F Herrik 1 Department of Neurophysiology, H. Author information Article notes Copyright and License information Disclaimer. This is an open access article distributed under the terms of the Creative Commons Attribution License http: This article has been cited by other articles in PMC.

Abstract Glutamate is the main excitatory neurotransmitter in the central nervous system CNS and is a major player in complex brain functions. Classification, Structure, and Function Metabotropic glutamate receptors belong to the superfamily of G-protein-coupled receptors. Open in a separate window. Expression Pattern and Subcellular Localization Group I mGluRs Immunohistochemical studies have shown that high levels of mGluR1 are present in the hippocampus, globus pallidus, substantia nigra, thalamus, cerebellum and the olfactory bulb [ 7 , 8 ].

Group III mGluRs The mGluR4s show a widespread brain distribution, but high distribution levels are only reported in the hippocampus and cerebellar cortex, while the expression of mGluR6s is limited to the retina [ 23 ]. Molecular Mechanisms of Action The mGluRs generally exert modulatory roles although some members of the family have been found to mediate synaptic transmission directly via activation of slow postsynaptic potentials [ 41 ]. Modulation of Synaptic Plasticity The mGluRs have been implicated in a number of synaptic plasticity phenomena, including short-term modification of synaptic strength, long-term depression LTD and long-term potentiation LTP.

Long-Term Depression Activation of Group I mGluRs, either synaptically or pharmacologically, has been shown to induce long-term depression of synaptic transmission [ 58 - 64 ]. Selective Group I Modulation Based on the purported disinhibition of pyramidal glutamatergic output as a core feature of schizophrenia, modulation of glutamate signalling at the postsynaptic levels via group I metabotropic receptors, and in particular mGluR5s, has gained interest as a potential promising therapeutic strategy.

Selective Group I Modulation mGluR1 Only a few preclinical studies have investigated the effect of selective mGluR1 negative allosteric modulators on drug-related behaviours. Selective Group III Modulation Similarly to metabotropic receptors of group II, subtypes belonging to group III are also located presynaptically, where they act as autoreceptors, regulating synaptic glutamate release. Selective Group I Modulation Group I mGluR activation in rat hippocampus by DHPG was decreased after subchronic treatment with the antidepressant treatments, electroconvulsant stimulation and imipramine [ , ].

Selective Group III Modulation Chronic treatment with citalopram, but not imipramine, decreased immunoreactivity of mGluR7 but not mGluR4 in the rat hippocampus and cerebral cortex [ ]. Selective Group I Modulation mGluR1 and mGluR5 are located postsynaptically to glutamatergic terminals in almost all striatal medium spiny neurons, as well as in the globus pallidus, subthalamic nucleus and substantia nigra reticulate [ ], and are therefore in key positions to modulate neuronal activity within the indirect pathway.

Selective Group III Modulation Group III mGluRs are presynaptically localized on GABAergic and glutamatergic terminals in several basal ganglia nuclei, including globus pallidus and substantia nigra, and therefore represent potential targets for reduction of abnormal activity associated with PD [ ]. Selective Group I Modulation Bear et al. Pharmacology and functions of metabotropic glutamate receptors. Pin J P, Duvoisin R.

The metabotropic glutamate receptors: Neuroprotective and behavioral effects of the selective metabotropic glutamate mGlu 1 receptor antagonist BAY Sequence and expression of a metabotropic glutamate receptor. Ionotropic and metabotropic glutamate receptor structure and pharmacology. Psychopharmacology Berl ; 1: Cellular localization of a metabotropic glutamate receptor in rat brain. Differential localization of phosphoinositide-linked metabotropic glutamate receptor mGluR1 and the inositol 1,4,5-trisphosphate receptor in rat brain. Perisynaptic location of metabotropic glutamate receptors mGluR1 and mGluR5 on dendrites and dendritic spines in the rat hippocampus.

Immunohistochemical localization of a metabotropic glutamate receptor, mGluR5, in the rat brain. Co-localization and functional interaction between adenosine A 2A and metabotropic group 5 receptors in glutamatergic nerve terminals of the rat striatum. Distribution of metabotropic glutamate receptor mGluR5 immunoreactivity in rat brain. Differential plasma membrane distribution of metabotropic glutamate receptors mGluR1 alpha, mGluR2 and mGluR5, relative to neurotransmitter release sites.

Ferraguti F, Shigemoto R. The metabotropic glutamate receptors, mGluR2 and mGluR3, show unique postsynaptic, presynaptic and glial localizations. Role of a metabotropic glutamate receptor in synaptic modulation in the accessory olfactory bulb. Pre- and postsynaptic localization of a metabotropic glutamate receptor, mGluR2, in the rat brain: Metabotropic glutamate receptors mGluR2 and mGluR5 are expressed in two non-overlapping populations of Golgi cells in the rat cerebellum.

Immunohistochemical localization of metabotropic glutamate receptors, mGluR2 and mGluR3, in rat cerebellar cortex. Molecular characterization of a novel retinal metabotropic glutamate receptor mGluR6 with a high agonist selectivity for Laminophosphonobutyrate. Metabotropic glutamate receptors depress afferent excitatory transmission in the rat nucleus tractus solitarii.

High level of mGluR7 in the presynaptic active zones of select populations of GABAergic terminals innervating interneurons in the rat hippocampus. Immunoreactivity for the group III metabotropic glutamate receptor subtype mGluR4a in the superficial laminae of the rat spinal dorsal horn. Metabotropic glutamate receptors in superficial laminae of the rat dorsal horn.

Distribution of metabotropic glutamate receptor 7 messenger RNA in the developing and adult rat brain. Localization of a metabotropic glutamate receptor, mGluR7 in axon terminals of presumed nociceptive, primary afferent fibers in the superficial layers of the spinal dorsal horn: Presynaptic localization of a metabotropic glutamate receptor, mGluR7, in the primary afferent neurons: Peripheral group I metabotropic glutamate receptors modulate nociception in mice. Colocalization of metabotropic glutamate receptors in rat dorsal root ganglion cells.

Stimulation of microglial metabotropic glutamate receptor mGlu2 triggers tumor necrosis factor alpha-induced neurotoxicity in concert with microglial-derived Fas ligand. Activation of group II metabotropic glutamate receptors underlies microglial reactivity and neurotoxicity following stimulation with chromogranin A, a peptide up-regulated in Alzheimer's disease. Role of metabotropic glutamate receptors in oligodendrocyte excitotoxicity and oxidative stress. Alpha 1-adrenergic modulation of metabotropic glutamate receptor-induced calcium oscillations and glutamate release in astrocytes.

Expression and functional role of mGluR3 and mGluR5 in human astrocytes and glioma cells: Activation of metabotropic glutamate receptor 3 enhances interleukin IL -1beta-stimulated release of IL-6 in cultured human astrocytes. Metabotropic glutamate receptors mediate excitatory transmission in the nucleus of the solitary tract. Pinheiro P S, Mulle C. An ion channel locus for the protein kinase C potentiation of transmitter glutamate release from guinea pig cerebrocortical synaptosomes. Glutamate exocytosis and MARCKS phosphorylation are enhanced by a metabotropic glutamate receptor coupled to a protein kinase C synergistically activated by diacylglycerol and arachidonic acid.

Retrograde inhibition of presynaptic calcium influx by endogenous cannabinoids at exci-tatory synapses onto Purkinje cells. Calmodulin dependence of presynaptic metabotropic glutamate receptor signaling. G protein betagamma subunit-mediated presynaptic inhibition: G protein betagamma directly regulates SNARE protein fusion machinery for secretory granule exocytosis. Noradrenaline modulates transmission at a central synapse by a presynaptic mechanism. Metabotropic glutamate receptors contribute to the induction of long-term depression in the CA1 region of the hippocampus.

Postsynaptic induction and presynaptic expression of hippocampal long-term depression. Kemp N, Bashir Z I. Metabotropic glutamate receptor-induced homosynaptic long-term depression and depotentiation in the dentate gyrus of the rat hippocampus in vitro. Activation of group I metabotropic glutamate receptors induces long-term depression in the hippocampal CA1 region of adult rats in vitro. Selective involvement of mGlu1 receptors in corticostriatal LTD. Presynaptic long-term depression at the hippocampal mossy fiber-CA3 synapse. Time-dependent reversal of long-term potentiation by low-frequency stimulation at the hippocampal mossy fiber-CA3 synapses.

Extinction of cued fear memory involves a distinct form of depotentiation at cortical input synapses onto the lateral amygdala. Long-term depression in hippocampal interneurons: Metabotropic glutamate receptor-mediated long-term depression: Metabotropic glutamate receptor-dependent long-term potentiation.

Induction of LTP in the hippocampus needs synaptic activation of glutamate metabotropic receptors. Long-term potentiation selectively expressed by NMDA receptors at hippocampal mossy fiber synapses. The regulation of hippocampal LTP by the molecular switch, a form of metaplasticity, requires mGlu5 receptors.

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Naie K, Manahan-Vaughan D. Regulation by metabotropic glutamate receptor 5 of LTP in the dentate gyrus of freely moving rats: Motor deficit and impairment of synaptic plasticity in mice lacking mGluR1. Metabotropic glutamate receptor antagonist, R,S -alpha-methylcarboxyphenyglycine, blocks two distinct forms of long-term potentiation in area CA1 of rat hippocampus.

Characterization of long-term potentiation of primary afferent transmission at trigeminal synapses of juvenile rats: The induction of long-term plasticity of non-synaptic, synchronized ac-tivity by the activation of group I mGluRs. Grover L M, Yan C. Group I metabotropic glutamate receptor mGluR -dependent long-term depression mediated via p38 mitogen-activated protein kinase is inhibited by previous high-frequency stimulation and activation of mGluRs and protein kinase C in the rat dentate gyrus in vitro.

The pipeline and future of drug development in schizophrenia. Dopamine receptors and the dopamine hypothesis of schizophrenia. Receptor mechanisms in the treatment of schizophrenia. Lewis D A, Moghaddam B. Cognitive dysfunction in schizophrenia: Molecular mechanisms underlying glutamatergic dysfunction in schizophrenia: Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans.

Psychotomimetic perceptual cognitive and neuroendocrine responses. Effects of ketamine in normal and schizophrenic volunteers. Metabotropic glutamate receptor protein expression in the prefrontal cortex and striatum in schizophrenia. Disruption of prepulse inhibition in mice lacking mGluR1. Activation of type 5 metabotropic glutamate receptors enhances NMDA responses in mice cortical wedges.

Clozapine reverses schizophrenia-related behaviours in the metabotropic glutamate receptor 5 knockout mouse: Discovery of positive allosteric modulators for the metabotropic glutamate receptor sub-type 5 from a series of N- 1,3-diphenyl-1H- pyrazolyl benzamides that potentiate receptor function in vivo. Metabotropic glutamate mGlu5 receptor-mediated modulation of the ventral striopallidal GABA pathway in rats. Interactions with adenosine A 2A and dopamine D 2 receptors. Interaction of N-methyl-D-aspartate and group 5 metabotropic glutamate receptors on behavioral flexibility using a novel operant set-shift paradigm.

Homayoun H, Moghaddam B. Bursting of prefrontal cortex neurons in awake rats is regulated by metabotropic glutamate 5 mGlu5 receptors: Positive allosteric modulation of metabotropic glutamate 5 mGlu5 receptors reverses N-Methyl-D-aspartate antagonist-induced alteration of neuronal firing in prefrontal cortex. The genomic organisation of the metabotropic glutamate receptor subtype 5 gene, and its association with schizophrenia.

Expression of the human excitatory amino acid transporter 2 and metabotropic glutamate receptors 3 and 5 in the prefrontal cortex from normal individuals and patients with schizophrenia. In vivo inhibition of veratridine-evoked release of striatal excitatory amino acids by the group II metabotropic glutamate receptor agonist LY in rats.

Moghaddam B, Adams B W. Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Allosteric potentiators of the metabotropic glutamate receptor 2 mGlu2. Identification and biological activity of indanone containing mGlu2 receptor potentiators. Benzazoles as allosteric potentiators of metabotropic glutamate receptor 2 mGluR2: Biphenyl-indanone A, a positive allosteric modulator of the metabotropic glutamate receptor subtype 2, has antipsychotic- and anxiolytic-like effects in mice.

Effects of a metabotropic glutamate receptor group II agonist LY in animal models of positive schizophrenia symptoms and cognition. Preliminary evidence of attenuation of the disruptive effects of the NMDA glutamate receptor antagonist, ketamine on working memory by pretreatment with the group II metabotropic glutamate receptor agonist LY in healthy human subjects. Metabotropic glutamate receptor 2 and 3 gene expression in the human prefrontal cortex and mesencephalon in schizophrenia. A polymorphism of the metabotropic glutamate receptor mGluR7 GRM7 gene is associated with schizophrenia.

The schizophrenic faces of PICK1. Presynaptic metabotropic glutamate receptors regulate glutamatergic input to dopamine neurons in the ventral tegmental area. Metabotropic glutamate receptor 7 modulates the rewarding effects of cocaine in rats: Concomitant deficits in working memory and fear extinction are functionally dissociated from reduced anxiety in metabotropic glutamate receptor 7-deficient mice. Lack of the metabotropic glutamate receptor subtype 7 selectively impairs short-term working memory but not long-term memory. Lack of the metabotropic glutamate receptor subtype 7 selectively modulates Theta rhythm and working memory.

Altered short-term synaptic plasticity in mice lacking the metabotropic glutamate receptor mGlu7. Positive associations of polymorphisms in the metabotropic glutamate receptor type 8 gene GRM8 with schizophrenia. Evaluation of the mGlu8 receptor as a putative therapeutic target in schizophrenia. Intra-amygdala and systemic antagonism of NMDA receptors prevents the reconsolidation of drug-associated memory and impairs subsequently both novel and previously acquired drug-seeking behaviors.

Role of NMDA receptors in dopamine neurons for plasticity and addictive behaviors. Behavioral and neurochemical interactions between Group 1 mGluR antagonists and ethanol: Effects of group I metabotropic glutamate receptor antagonists on the behavioral sensitization to motor effects of cocaine in rats. Kotlinska J, Bochenski M. Pretreatment with Group I metabotropic glutamate receptors antagonists attenuates lethality induced by acute cocaine overdose and expression of sensitization to hyperlocomotor effect of cocaine in mice.

Effects of mGluR1 antagonism in the dorsal hippocampus on drug context-induced reinstatement of cocaine-seeking behavior in rats. Comparison of the effects of mGluR1 and mGluR5 antagonists on the expression of behavioral sensitization to the locomotor effect of morphine and the morphine withdrawal jumping in mice. Metabotropic glutamate receptor 5 mGluR5 regulation of ethanol sedation, dependence and consumption: Antagonism at metabotropic glutamate 5 receptors inhibits nicotine- and cocaine-taking behaviours and prevents nicotine-triggered relapse to nicotine-seeking.

Attenuation of behavioral effects of cocaine by the Metabotropic Glutamate Receptor 5 Antagonist 2-Methyl phenylethynyl -pyridine in squirrel monkeys: Attenuation of cocaine self-administration in squirrel monkeys following repeated administration of the mGluR5 antagonist MPEP: Psychopharmacology Berl ; 2: Functional coexpression of excitatory mGluR1 and mGluR5 on striatal cholinergic interneurons. Neuropsychopharmacology; ; 34 4: Group III mGlu receptor agonists produce anxiolytic- and antidepressant- like effects after central administration in rats.

Potential anti-anxiety, anti-addictive effects of LY a selective group II glutamate metabotropic receptors agonist in animal models. Peters J, Kalivas P W.

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The group II metabotropic glutamate receptor agonist, LY, inhibits both cocaine- and food-seeking behavior in rats. Activation of group II metabotropic glutamate receptors in the nucleus accumbens shell attenuates context-induced relapse to heroin seeking. Activation of group II metabotropic glutamate receptors attenuates both stress and cue-induced ethanol-seeking and modulates c-fos expression in the hippocampus and amygdala.

A role of ventral tegmental area glutamate in contextual cue-induced relapse to heroin seeking. Glutamate receptor metabotropic 7 is cis-regulated in the mouse brain and modulates alcohol drinking. Genotype patterns that contribute to increased risk for or protection from developing heroin addiction. Westenberg H G, Sandner C.

Tolerability and safety of fluvoxamine and other antidepressants. Cassano P, Fava M. Tolerability issues during long-term treatment with antidepressants. Medical disorders affect health outcome and general functioning depending on comorbid major depression in the general population. Prevalence and effects of mood disorders on work performance in a nationally representative sample of U. Drug-induced actions on brain neurotransmitter systems and changes in the behaviors and emotions of depressed patients. Effects of amitriptyline and imipramine on brain amine neurotransmitter metabolites in cerebrospinal fluid.

The serotonin-1A receptor in anxiety disorders. Dual- and Triple-Acting agents for treating core and Co-morbid symptoms of major depression: He was also published by Shattinger Music in St. Louis, and many of his works went to Carl Fischer Music. One popular Philadelphia publication was the piece The Philadelphia Record March , of which arrangements were created for bands and piano rolls in short order.

It remains a favorite band march into the 21st Century. While it appears that Hans never actually recorded, a handful of his pieces did make it to piano rolls. To complicate matters concerning an accounting of all of his works, but also demonstrating that he was following a common dispersal practice, the amazingly prolific composer also wrote under the pseudonyms Heinrich Engel , Charles Lindsay and Pierre Renard , further increasing the scope of his known output. For the Federal census, Engelmann, Marie and Frances were shown living near downtown Philadelphia, and he listed in a crowded space the occupations of musician, composer and piano teacher.

Hans Engelmann died in at just Attempts to find a definitive cause of death have fallen short of an answer to date. A notice appeared in The Music Trade Review of May 16, , stating that "Hans Engelmann, composer of much meritorious music which has won a large vogue with teachers, died late last week in Philadelphia. While in the past they had only reported on his latest compositions or who was playing what in recitals, in June, then in August, there were several tributes to the prematurely deceased composer, starting with this one in the June issue:.

Composers, like poets, are born and not made. It is possible, of course, for a man to go through an elaborate course of harmony, counterpoint, musical form, etc. There are thousands of Doctors of Music in the world to whom the writing of such music is a simple matter. But natural musicians are more rare. Natural musicians are those to whom music is as the breath of life.

They think in tones as others think in words and can only find the true expression of their inmost thoughts in the language of music. A course in theory can only develop such gifts to a higher degree of technical perfection, it cannot supply them if they are missing. Hans Engelmann was unquestionably a natural musician. From him melodies gushed like water from a spring. Engelmann's music possesses at least one quality which no critic can afford to decry.

It possesses the quality of absolute sincerity. Engelmann entered into the life of the people around him and absorbed the life of the everyday world. This he gave out again in his music in good measure. He did what so many of us fail to do—the best he knew how under the circumstances in which he was placed. He interpreted the life he lived honestly into music, and in doing this he gave pleasure to hundreds of thousands—perhaps millions—of people, because he gave them tunes they could understand.

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Hans Engelmann is dead, and dead before his time, but some at least of his hundreds of melodies will live after him and serve to awaken in many a small heart the love of music which unites all Etude readers, however varied their tastes, in the bonds of true fellowship. He was obviously quite highly regarded for his work, as a number of testimonials poured in to The Etude over the summer, some of them making it into the August issue distilled for relevance here:.

There never has been in America such a prolific and melodious composer as the late Hans Engelmann. To speak from my personal experience I attended all the yearly meetings of the National and State Music Teachers' Associations to hear the works of American composers performed, the impression was that all the old forms should be thrown over board, and that no such commonplace as tune and rhythm should be employed. Those of us who have watched the outcome of the effort well know when it ended. Some composers have at once reached the hearts of the people by the simplicity of their melodies, others by the constant performance of them and the popularity of certain artists.

In the last finality what one needs to express his deepest feelings is not technique, or scientific contrapuntal examples and exercises, written by learned doctors or professors of music, but real inspirational melody; no matter who wrote it, whether it be a Schubert, Schumann or Engelmann. I have used and played many of Hans Engelmann's writings. About two years ago I purchased several of them for a large publishing house, and one of the numbers being too difficult, we asked him for an easier arrangement, or something of a different style.

It was only a few days until we received quite a bundle of new pieces and were requested to take our choice. The musical world has been uplifted and made to feel more keenly the tender and sympathetic qualities of the art in the works of Hans Engelmann. Time and use will put the stamp of approval on those writings of his which are to last, but among them will be "Melody of Love", and "When the Lights are Low".

In my estimation Hans Engelmann was one of the great, modern melodists, one of the few composers who never had to seek for a theme, for his supply of that rare product was inexhaustible, his gift in this respect was almost ethereal. None but a Child of Inspiration could have penned such melodies as he has left to the music-loving word.

Truly a magnificent monument. I am proud to have known him both as a friend and a musician, and deeply regret his early demise. I predict that posterity will be familiar with the name of Hans Engelmann. I was very much grieved to learn of the death of Hans Engelmann. Enabled Average Customer Review: Be the first to review this item Would you like to tell us about a lower price?

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