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Study Design: In this study, we decided to change the activity of periaqueductal gray (PAG)'s metabotropic glutamate receptors subtype 8 (mGluR8) by means of its specific agonist, (S)-3,4-dicarboxyphenylglycine (DCPG), and by knock downing it with mGluR8 siRNA. We then evaluated the changes in animal pain threshold levels in the face of painful thermal stimuli (thermal hyperalgesia).Purpose: Although several mechanisms have been examined for central neuropathic pain, researchers have so far failed to find the precise mechanism for the development and progression of this type of pain. Hyperalgesia is one of the most important complications of central neuropathic pain and there is not a consensus among researchers about the exact cause of this complication. In this study, we investigated the effect of activation of the PAG region mGluR8 on the threshold of pain response to thermal noxious stimulus in rats and measured mGluR8 expression.Overview of Literature: Spinal cord injury (SCI) produces an decrease in mGluR2/3 expression in the injured and vehicle-treated groups compared to normal levels, APDC and L-AP4 treated groups had higher expression levels of mGluR2/3. These findings suggesting that the level of mGluR expression after SCI may modulate nociceptive responses.Methods: Male Wistar rats were randomly assigned to five groups (n=10 per group). The clip compression injury model was used to induce chronic central neuropathic pain. Three weeks after SCI, DCPG, siRNA, or normal saline were administered to the intra-ventrolateral PAG region. Withdrawal threshold to the noxious thermal stimulus (e.g., heat hyperalgesia) was assessed through the tail-flick test. In order to assure involvement of this receptor, pain responses were compared with mice that received GRM8 siRNA.Results: We found that the mGluR8 agonist DCPG increased lead to an increased expression of mGluR8 in the PAG region. We also found that SCI can decrease the threshold of response to painful thermal stimuli; however, activation of mGluR8 with DCPG agonist did not significantly improve the tail-flick response.Conclusions: The results revealed that activation of mGluR8 in PAG is not capable of improving the thermal hyperalgesia threshold. Based on the decreased expression of mGluR8 after SCI induced by clip compression injury and its significant increase after treatment of siRNA against mGluR8, this method might still hold promise as an effective treatment of neuropathic pain. It can be concluded that increased expression of mGluR8 is due to the fact that DCPG prevents the death of neurons that express these receptors.

Treatments for the positive and negative symptoms of schizophrenia have been explored for decades, but no completely successful therapy has been found as yet. Metabotropic glutamate receptor 5 (mGluR5), which potentiates N-methyl-D-aspartate receptors in brain regions implicated in schizophrenia, has become a novel drug target in the treatment of schizophrenia, especially for the mGluR5-positive allosteric modulators. Individuals with schizophrenia show deficits in prepulse inhibition (PPI), which is an operational measurement of sensorimotor gating. In this review, we focus on pharmacological, neurodevelopmental, and genetic animal models of disrupted PPI, with the aim of showing the potential role of mGluR5 in modulating the activity of N-methyl-D-aspartate receptors and their contributions toward the treatment of schizophrenia. As, the impairment of attentional modulation of PPI, but not that of baseline PPI, in individuals with schizophrenia is correlated with their symptom severity, this review also highlights that investigation of attentional modulation of PPI is critical for studying both cognitive impairments and glutamatergic dysfunctions of schizophrenia.

This review summarizes data on the interaction of effects arising as a result of activation of receptors for the main neurotransmitters in the CNS – glutamate and GABA. Reports on the structures and functions of the receptors for these signal substances are presented, and questions of their colocalization in synapses and interactions between the effects of activation of both ionotropic and metabotropic receptors for these neurotransmitters at the postsynaptic level are discussed.

Emerging evidence indicates that dysfunctional glutamate neurotransmission is critical in the initiation and development of alcohol and drug dependence. Alcohol consumption induced downregulation of glutamate transporter 1 (GLT-1) as reported in previous studies from our laboratory. Glutamate is the major excitatory neurotransmitter in the brain, which acts via interactions with several glutamate receptors. Alcohol consumption interferes with the glutamatergic signal transmission by altering the functions of these receptors. Among the glutamatergic receptors involved in alcohol-drinking behavior are the metabotropic receptors such as mGluR1/5, mGluR2/3, and mGluR7, as well as the ionotropic receptors, NMDA and AMPA. Preclinical studies using agonists and antagonists implicate these glutamatergic receptors in the development of alcohol use disorder (AUD). Therefore, the purpose of this review is to discuss the neurocircuitry involving glutamate transmission in animals exposed to alcohol and further outline the role of metabotropic and ionotropic receptors in the regulation of alcohol-drinking behavior. This review provides ample information about the potential therapeutic role of glutamatergic receptors for the treatment of AUD.

2-Arachidonoylglycerol and anandamide are the main endocannabinoids, which act through cannabinoid type-1 and type-2 receptors. Among its many functions, anandamide modulates anxiety-like behaviors in the ventromedial prefrontal cortex. The role of 2-arachidonoylglycerol in this region, however, has remained unclear. Here, we verified whether intra- ventromedial prefrontal cortex injection of 2-arachidonoylglycerol or URB602, a monoacylglycerol lipase inhibitor (responsible for 2-arachidonoylglycerol hydrolysis), induce anxiolytic-like effects in Wistar rats. Since activation of metabotropic glutamate receptor type 5 promotes diacylglycerol lipase-α-mediated 2-arachidonoylglycerol synthesis, we also verified if the blockade of this receptor impairs the anxiolytic-like effect induced by URB 602. 2-Arachidonoylglycerol reduced anxiety-like response in rats exposed to the Elevated Plus Maze test, an effect mimicked by URB602. Cannabinoid type-1 and type-2 receptor antagonists prevented these effects. The pre-treatment with an ineffective dose of MPEP, a metabotropic glutamate receptor type 5 antagonist, also attenuated the anxiolytic-like effect of URB602. Moreover, immunofluorescence microscopy revealed co-expression of metabotropic glutamate receptor type 5 and diacylglycerol lipase-α in several neurons in slices from the ventromedial prefrontal cortex. Altogether, our results implicate 2-arachidonoylglycerol and both cannabinoid receptors on anxiety-related behaviors mediated by ventromedial prefrontal cortex. Further, these data support a role for the coupling between metabotropic glutamate receptor type 5 activation and 2-arachidonoylglycerol signalling as a mechanism modulating aversive responses.

Metabotropic glutamate receptors (mGluRs) are important modulators of excitatory neurotransmission, and have been implicated in addiction to alcohol and anxiety-related behaviors. However, the behavioral consequence and contribution of individual subtypes are not known yet. This study determined the effects of mGluR8 activation on anxiety-like behavior, voluntary ethanol intake and ethanol-induced conditioned reward. To this aim, anxiety and spontaneous behavior were measured in C57BL/6J mice using the elevated plus maze (EPM), open field (OF) and light-dark box (LDB) tests after systemic injection of the selective mGluR8 agonist (S)-3,4-dicarboxyphenylglycine ((S)-3,4-DCPG). In addition, the anti-alcohol properties of mGluR8 were studied using a two-bottle choice continuous access drinking paradigm and ethanol-conditioned place preference (CPP). Results have shown that, compared to vehicle, DCPG produced an anxiolytic-like effect in the LDB, and OF tests. Furthermore, DCPG-injected mice displayed significantly lower intake and preference for ethanol [2.5-20% (v/v) escalating over 2weeks] in a two-bottle choice paradigm, with no significant difference observed with saccharin [0.04 & 0.08% (w/v)] nor on quinine [20 & 40μM (w/v)]. Interestingly, DCPG administration attenuated ethanol-induced acquisition, but not expression, of CPP. More importantly, these effects were significantly attenuated when mice were pre-injected with the group III mGluR-specific antagonist (S)-2-amino-2-methyl-4- phosphonobutyric (MAP4). These data demonstrate that activation of the mGluR8 reduces voluntary ethanol intake in male mice and eliminates place preference acquisition suggesting that mGluR8 signaling may contribute to the rewarding properties of ethanol. Taken together, these findings demonstrate that mGluR8-targeted pharmacotherapies may be beneficial for the treatment of anxiety and alcoholism.

Microinjection of kainic acid into rat hippocampus causes excitotoxic neuronal damage predominantly in the CA3 and CA1 fields. These lesions can be significantly reduced by simultaneous administration of MPEP, a negative allosteric modulator of type 5 metabotropic glutamate receptors, and LY354740, an agonist of type 2 metabotropic glutamate receptors. The decrease in neuronal death in the hippocampus during pharmacological modulation was paralleled by adaptive changes in gene expression. In the hippocampus, gene expression of type 5 postsynaptic metabotropic glutamate receptor was close to the control level, and in the frontal cortex expression of the gene of α1-subunit of the GABAA receptor returned to normal. In the frontal cortex, a reciprocal relationship was observed for type 2 metabotropic glutamate receptor: expression of the corresponding gene decreased in response to pharmacological activation.

The neuronal K+/Cl- symporter, KCC2, shapes synaptic responses mediated by Cl--permeant GABAA receptors. Moving from the evidence that excitatory neurotransmission drives changes in KCC2 expression in cerebellar neurons, we studied the regulation of KCC2 expression by group-I metabotropic glutamate (mGlu) receptors in the cerebellum of adult mice. Mice lacking mGlu5 receptors showed a large reduction in cerebellar KCC2 protein levels and a loss of KCC2 immunoreactivity in Purkinje cells. Similar changes were seen in mice treated with the mGlu5 receptor antagonist, MPEP, whereas treatment with the mGlu5 receptor positive allosteric modulator (PAM), VU0360172, increased KCC2 expression. In contrast, pharmacological inhibition of mGlu1 receptors with JNJ16259685 enhanced cerebellar KCC2 protein levels and KCC2 immunoreactivity in Purkinje cells, whereas treatment with the mGlu1 receptor PAM, RO0711401, reduced KCC2 expression. To examine whether the reduction in KCC2 expression caused by the absence or the inhibition of mGlu5 receptors could affect GABAergic transmission, we performed electrophysiological and behavioral studies. Recording of extracellular action potentials in Purkinje cells showed that the inhibitory effect of the GABAA receptor agonist, muscimol, was lost in cerebellar slices prepared from mGlu5-/- mice or from mice treated systemically with MPEP, in line with the reduction in KCC2 expression. Similarly, motor impairment caused by the GABAA receptor PAM, diazepam, was attenuated in mice pre-treated with MPEP. These findings disclose a novel function of mGlu5 receptors in the cerebellum and suggest that mGlu5 receptor ligands might influence GABAergic transmission in the cerebellum and affect motor responses to GABA-mimetic drugs. This article is part of the Special Issue entitled 'Metabotropic Glutamate Receptors, 5 years on'.

Slow excitatory postsynaptic currents (EPSCs) mediated by metabotropic glutamate receptors (mGlu receptors) have been reported in several neuronal subtypes, but their presence in hippocampal pyramidal neurons remains elusive. Here we find that in CA1 pyramidal neurons a slow EPSC is induced by repetitive stimulation while ionotropic glutamate receptors and glutamate-uptake are blocked whereas it is absent in the VGLUT1 knockout mouse in which presynaptic glutamate is lost, suggesting the slow EPSC is mediated by glutamate activating mGlu receptors. However, it is not inhibited by known mGlu receptor antagonists. These findings suggest that this slow EPSC is mediated by a novel mGlu receptor, and that it may be involved in neurological diseases associated with abnormal high-concentration of extracellular glutamate. This article is part of the Special Issue entitled ‘Metabotropic Glutamate Receptors, 5 years on’.

Parkinson's disease is the slow-progressing chronic neurodegenerative disease. It caused by the progressive destruction and death of neurons that produce the neurotransmitter dopamine, primarily in the substantia nigra and also in other parts of the Central nervous system. Insufficient production of dopamine leads to the activating influence of the basal ganglia to the cerebral cortex. Guiding symptoms are muscle rigidity, hypokinesia, tremor, postural instability. Modern medicine has not yet found methods of curing disease, however, the existing methods of conservative and surgical treatment significantly improve the patient’s quality of life and slow the progression of the disease. There is an assumption of the key role of glutamate receptors excessive activation in the pathogenesis of Parkinson's disease. It can be expected that glutamate receptors may be a new therapeutic target in the treatment of this pathology. The study of glutamate receptors blockers is an important task in the search for new pharmacological agents in the treatment of Parkinson's disease. Experiments on animal models suggest the change in the activity of these receptors can facilitate the primary motor symptoms of Parkinson's disease and also side effects caused by the levodopa replacement therapy. AMPA- NMDA receptors antagonists have shown the ability to reverse motor symptoms and levodopa-induced dyskinesia in preclinical models of Parkinson's disease. Metabotropic glutamate receptors antagonists are even more promising in the treatment of Parkinson's disease due to more "accurate" work in the synapse. These drugs also reduce motor deficits, as well as protecting the patient from neurodegeneration. Thus glutamate receptors are a promising target for the development of new pharmacological treatments of Parkinson's disease.

Metabotropic glutamate receptors (mGluRs) are mainly known for regulating excitability of neurons. However, mGluR6 at the photoreceptor-ON bipolar cell synapse mediates sign inversion through glutamatergic inhibition. Although this is currently the only confirmed function of mGluR6, other functions have been suggested. Here we present Tg(mglur6b:EGFP)zh1, a new transgenic zebrafish line recapitulating endogenous expression of one of the two mglur6 paralogs in zebrafish. Investigating transgene as well as endogenous mglur6b expression within the zebrafish retina indicates that EGFP and mglur6b mRNA are not only expressed in bipolar cells, but also in a subset of ganglion and amacrine cells. The amacrine cells labeled in Tg(mglur6b:EGFP)zh1 constitute a novel cholinergic, non-GABAergic, non-starburst amacrine cell type described for the first time in teleost fishes. Apart from the retina, we found transgene expression in subsets of periventricular neurons of the hypothalamus, Purkinje cells of the cerebellum, various cell types of the optic tectum, and mitral/ruffed cells of the olfactory bulb. These findings suggest novel functions of mGluR6 besides sign inversion at ON bipolar cell dendrites, opening up the possibility that inhibitory glutamatergic signaling may be more prevalent than currently thought. J. Comp. Neurol. 524:2363-2378, 2016. © 2016 Wiley Periodicals, Inc.

The interface of receptor-mediated regulation of cellular signaling and neurological outputs remains an active field of investigation. The metabotropic G protein-coupled glutamate receptors, and in particular, the group II cyclic adenosine mono-phosphate (cAMP)-lowering metabotropic glutamate receptors 2 and 3 (mGlu2/3 glutamate receptors), have gained interest as therapeutic targets in different forms of neurological disorders. This review explores mGlu2/3 glutamate receptors expression, pharmacological activation, and signaling links to anxiety, as assessed in animal models and in clinical trials.

Motor dysfunction is a hallmark of Parkinson’s disease (PD); however, non-motor symptoms such as gastrointestinal dysfunction often arise prior to motor symptoms. Alterations in the gut microbiome have been proposed as the earliest event in PD pathogenesis. PD symptoms often demonstrate sex differences. Glutamatergic neurotransmission has long been linked to PD pathology. Metabotropic glutamate receptors (mGlu), a family of G protein-coupled receptors, are divided into three groups, with group III mGlu receptors mainly localized presynaptically where they can inhibit glutamate release in the CNS as well as in the gut. Additionally, the gut microbiome can communicate with the CNS via the gut-brain axis. Here, we assessed whether deficiency of metabotropic glutamate receptor 8 (mGlu8), group III mGlu, modulates the effects of the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), on behavioral and cognitive performance in female and male mice. We studied whether these effects are associated with changes in striatal tyrosine hydroxylase (TH) levels and the gut microbiome. Two-week sub-chronic MPTP increased activity of female and male wild-type (WT) and mGlu8 knockout (KO) mice in the open field. MPTP also showed genotype- and sex-dependent effects. MPTP increased the time WT, but not KO, females and males spent exploring objects. In WT mice, MPTP improved sensorimotor function in males but impaired it in females. Further, MPTP impaired cued fear memory in WT, but not KO, male mice. MPTP reduced striatal TH levels in WT and KO mice but these effects were only pronounced in males. MPTP treatment and genotype affected the diversity of the gut microbiome. In addition, there were significant associations between microbiome α-diversity and sensorimotor performance, as well as microbiome composition and fear learning. These results indicate that specific taxa may directly affect motor and fear learning or that the same physiological effects that enhance both forms of learning also alter diversity of the gut microbiome. MPTP’s effect on motor and cognitive performance may then be, at least in part, be mediated by the gut microbiome. These data also support mGlu8 as a novel therapeutic target for PD and highlight the importance of including both sexes in preclinical studies.

The present study aimed to determine the role of metabotropic glutamate receptor 8 (mGluR8) in tumor biology. Using various molecular approaches (RNAi or GRM8 cDNA), cell clones with downregulated (human neuroblastoma SH-SY5Y and human glioma LN229) or overexpressed (human glioma U87-MG and LN18 cell lines) mGluR8 were generated. Next, comparative studies on cell proliferation and migration rates, induction of apoptosis and chemosensitivity were performed among these clones. The mGluR8-downregulated SH-SY5Y clones proliferated faster and were more resistant to cytotoxic action of staurosporine, doxorubicin, irinotecan and cisplatin when compared to control cells. Moreover, these clones were characterized by a lower activity of caspases, calpains and some kinases (GSK-3β, Akt and JNK). The mGluR8-downregulated LN229 clones migrated faster and were less prone to cell-damaging effect of staurosporine and irinotecan when compared with relevant control cells. In contrast, in GRM8-overexpressing U87-MG and LN18 clones, a decreased cell proliferation, increased apoptosis and elevated vulnerability to some cytotoxic agents were found. Altogether, our in vitro data for the first time evidenced a tumor suppressor and chemosensitizing role of mGluR8.

Glutamate serves as the primary excitatory neurotransmitter in the nervous system. Previous studies have identified a role for glutamate and group I metabotropic receptors as targets for study in peripheral inflammatory pain. However, the coordination of signaling events that transpire from receptor activation to afferent neuronal sensitization has not been explored. Herein, we identify that scaffolding protein A-Kinase Anchoring Protein 79/150 (AKAP150) coordinates increased peripheral thermal sensitivity following group I metabotropic receptor (mGluR5) activation. In both acute and persistent models of thermal somatosensory behavior, we report that mGluR5 sensitization requires AKAP150 expression. Furthermore, electrophysiological approaches designed to record afferent neuronal activity reveal that mGluR5 sensitization also requires functional AKAP150 expression. In dissociated primary afferent neurons, mGluR5 activation increases TRPV1 responses in an AKAP dependent manner through a mechanism that induces AKAP association with TRPV1. Experimental results presented herein identify a mechanism of receptor-driven scaffolding association with ion channel targets. Importantly, this mechanism could prove significant in the search for therapeutic targets that repress episodes of acute pain from becoming chronic in nature.

l-Glutamate (l-Glu) plays an essential role in the central nervous system (CNS) as an excitatory neurotransmitter, and exerts its effects by acting on a large number of ionotropic and metabotropic receptors. These receptors are also expressed in several peripheral tissues, including the kidney. This review summarizes the general properties of ionotropic and metabotropic l-Glu receptors, focusing on N-methyl-d-aspartate (NMDA) and Group 1 metabotropic glutamate receptors (mGluRs). NMDA receptors are expressed in the renal cortex and medulla, and appear to play a role in the regulation of renal blood flow, glomerular filtration, proximal tubule reabsorption and urine concentration within medullary collecting ducts. Sustained activation of NMDA receptors induces Ca(2+) influx and oxidative stress, which can lead to glomerulosclerosis, for example in hyperhomocysteinemia. Group 1 mGluRs are expressed in podocytes and probably in other cell types. Mice in which these receptors are knocked out gradually develop albuminuria and glomerulosclerosis. Several endogenous agonists of l-Glu receptors, which include sulfur-containing amino acids derived from l-homocysteine, and quinolinic acid (QA), as well as the co-agonists glycine and d-serine, are present in the circulation at concentrations capable of robustly activating ionotropic and metabotropic l-Glu receptors. These endogenous agonists may also be secreted from renal parenchymal cells, or from cells that have migrated into the kidney, by exocytosis or by transporters such as system x(-)(c), or by transporters involved in ammonia secretion. l-Glu receptors may be useful targets for drug therapy, and many selective orally-active compounds exist for investigation of these receptors as potential drug targets for various kidney diseases.

Whereas the ionotropic glutamate receptors are the major mediator in glutamatergic transmission, the metabotropic glutamate receptors (mGluRs) usually play a modulatory role. Whereas the entorhinal cortex (EC) is an essential structure involved in the generation and propagation of epilepsy, the roles and mechanisms of mGluRs in epilepsy in the EC have not been determined. Here, we studied the effects of activation of group II metabotropic glutamate receptors (mGluRs II) on epileptiform activity induced by picrotoxin or deprivation of extracellular Mg2+ and neuronal excitability in the medial EC. We found that activation of mGluRs II by application of the selective agonist, LY354740, exerted robust inhibition on epileptiform activity. LY354740 hyperpolarized entorhinal neurons via activation of a K+ conductance and inhibition of a Na+ -permeable channel. LY354740-induced hyperpolarization was G protein-dependent, but independent of adenylyl cyclase and protein kinase A. However, the function of Gβγ was involved in mGluRs II-mediated depression of both neuronal excitability and epileptiform activity. Our results provide a novel cellular mechanism to explain the antiepileptic effects of mGluRs II in the treatment of epilepsy.

We report the discovery and SAR of two novel series of imidazopyrimidinones and dihydroimidazopyrimidinones as metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs). Exploration of several structural features in the western and eastern part of the imidazopyrimidinone core and combinations thereof, revealed compound 4a as a mGlu5 PAM with good in vitro potency and efficacy, acceptable drug metabolism and pharmacokinetic (DMPK) properties and in vivo efficacy in an amphetamine-based model of psychosis. However, the presence of CNS-mediated adverse effects in preclinical species precluded any further in vivo evaluation.

The fast actions of the excitatory neurotransmitter glutamate are mediated by glutamate-gated ion channels (ionotropic Glu receptors). Metabotropic glutamate receptors (mGlus) are coupled to second messenger pathways via G proteins and modulate glutamatergic and GABAergic neurotransmission. Of the eight different types of mGlus (mGlu1-mGlu8), mGlu4, mGlu6, mGlu7 and mGlu8 are members of group III. Except for mGlu6, group III receptors are generally located presynaptically and regulate neurotransmitter release. Because of their role in modulating excitatory neurotransmission, mGlus are attractive targets for therapies aimed at treating anxiety disorders.In this review, the authors discuss the role of mGlu4 and mGlu8 in anxiety disorders. They also discuss how mGlu4 and mGlu8 have distinct expression patterns in the brain, which might have related functions. Finally, the authors discuss how compounds that target more than one mGlu receptor might be therapeutically more effective.mGlu4 might compensate for mGlu8 deficiency, and deficiency of both receptors might result in a more pronounced phenotype than deficiency of either receptor alone. The distinct and overlapping anatomical distribution and functions of mGlu4 and mGlu8 suggest that both receptors, either individually or combined, are attractive therapeutic targets in anxiety disorders, post-traumatic stress disorder, Parkinson's disease, and multiple sclerosis.

Two articles in this issue of Neuron (Yelshanskaya et al., 2016; Yi et al., 2016) explore the structural basis of allosteric inhibition in ionotropic glutamate receptors, providing key insights into how iGluRs function in the brain as well as how they might be pharmacologically modulated in neurological disorders and disease.

Background: The ability of metabotropic glutamate receptors to modulate the neurotransmission of glutamate has attracted great attention for its role in the pathophysiology of schizophrenia and also for its potential ability to be a target for the development of novel antipsychotics. Metabotropic glutamate receptor 7 has a wide expression in the cortex, hippocampus, and other forebrain regions. It has an important role in short-term plasticity and multiple learning processes. Exploring the molecular changes and cellular genetic expression of metabotropic glutamate receptor 7 gene is an essential step to know more about its real functioning in patients presenting with schizophrenia Aim: Measuring the genetic expression of metabotropic glutamate receptor 7 in patients presenting with schizophrenia and comparing it in healthy controls. Methods: Modeling of schizophrenia through human induced pleuripotent stem cells (hIPSc) through reprogramming of fibroblasts into pluripotent stem cells followed by neuronal differentiation. Real time Polymerase chain reaction was used for measurement of genetic expression. Results: There were lower means of metabotropic glutamate receptor 7 gene expression in the patients group (0.843) than the control group (1.051) but with no statistically significant difference between the 2 groups (P=0.241). Conclusion: There was no significant alteration of the genetic expression of metaboptric glutamate receptor in schizophrenic patients. However, further studies are needed with larger samples to verify its role in pathophysiology of schizophrenia.

The metabotropic glutamate receptors (mGluRs) are glutamate-activated G-protein-coupled receptors that are expressed throughout the central nervous system. The eight mGluR subtypes serve to modulate transmission at many synapses and are potential therapeutic targets for the treatment of many neurological and psychiatric diseases. In particular, their organization in multiple domains and subunits offers various possibilities for the development of new drugs that modulate mGluR activity. This review will show how recent and original approaches to study the mGluR structure, dynamics, and pharmacology have brought a new view of their mechanism of activation and the possibility of developing innovative ligands, such as light-regulated drugs, to control the physiological activity of mGluRs in animals.

Exactly three decades ago, metabotropic glutamate receptors (mGluRs) were discovered as glutamate receptors coupled to heterotrimeric G-proteins and able to induce polyphosphoinositide hydrolysis. Since then, eight different mGluRs have been identified, which activate a variety of second messenger systems and trigger complex physiological responses in nearly all brain areas. A participation of mGluRs in amygdala networks was shown to regulate emotional-affective behaviours. In this chapter, I will examine the localization of mGluRs in the amygdaloid complex and how genetic and/or pharmacological manipulation of these receptors affects different amygdala-dependent emotional behaviours including fear learning and extinction. Furthermore, I will discuss the growing literature addressing the influence of mGluRs on affective aspects of pain processing within the nociceptive amygdala. Finally, the potential of drugs acting at mGluRs as novel targets for neuropsychiatric disorders characterized by impaired amygdala functions will be examined.

Because of their modulatory role, cell-type-specific expression in the CNS, and anti-inflammatory properties, the metabotropic glutamate receptors (mGluRs) have generated significant interest as potential therapeutic targets for various brain disorders. In addition, preclinical studies in animal models of Parkinson’s disease have revealed that specific mGluR subtypes mediate significant neuroprotective effects that reduce midbrain dopaminergic neuronal death. Although the underlying mechanisms of these effects remain to be established, there is evidence that intracellular calcium regulation, anti-inflammatory effects, and glutamatergic network regulation contribute to these properties. These protective effects extend beyond midbrain dopaminergic neurons for some mGluRs. In this review, we discuss recent evidence for mGluR-mediated neuroprotection in PD and highlight the challenges to translate these findings into human trials.

The thalamo-corticothalamic network underpins sensory, motor and cognitive processing. All three of the mGlu receptor groups are represented in these pathways. Of the Group I receptors, it seems clear that mGlu1 receptors are located postsynaptically to corticothalamic terminals on dendrites of thalamic relay cells and may function to modulate relay cell transmission under various conditions. Group III mGlu receptors (mGlu4, mGlu7, mGlu8) may also modulate this synapse via a presynaptic mechanism. GABAergic inhibitory processes can be modulated via activation of either Group II (mGlu2 and mGlu3) receptors or Group III receptors, acting either on GABAergic terminals or on thalamic cell bodies, including those in the thalamic reticular nucleus (TRN). There is also evidence that mGlu receptors can modulate astrocyte function in the thalamus. The heterogeneous expression of mGlu receptors at specific sites within the thalamus makes them potential therapeutic targets for a variety of conditions including pain, epilepsy and cognitive disorders.

The assembly of two covalently linked monomers into dimeric complexes is a prerequisite for metabotropic glutamate receptor 1 (mGluR1) function. The former concept of a strictly homodimeric subunit contribution in metabotropic glutamate receptor complexes has recently been brought into question. Alternative splicing of the GRM1 gene results in expression of variants that vary within their intracellular C-termini. Here we bring evidence that the short mGluR1b variant is found preferentially in a complex with the long mGluR1a variant in the rodent brain. The mGluR1a and mGluR1b variants distribution overlaps in Purkinje cells and the two variants colocalize in their spines. However mGluR1a and mGluR1b show distinct sub-cellular localization when expressed alone in neurons. We discovered that trafficking of mGluR1b to distal dendrites is reliant on its association with mGluR1a and that the long C-terminus of mGluR1a within the mGluR1a/b dimer is necessary for trafficking of the complex.

A number of studies have indicated that antagonists of the N-methyl-d-aspartate subtypes of glutamate receptors can cause schizophrenia-like symptoms in healthy individuals and exacerbate symptoms in individuals with schizophrenia. These findings have led to the glutamate hypothesis of schizophrenia. Here we review the evidence for this hypothesis in postmortem studies of brain tissue from individuals affected by schizophrenia, summarizing studies of glutamate neuron morphology, of expression of glutamate receptors and transporters, and of the synthesizing and metabolizing enzymes for glutamate and its co-agonists. We found consistent evidence of morphological alterations of dendrites of glutamatergic neurons in the cerebral cortex of subjects with schizophrenia and of reduced levels of the axon bouton marker synaptophysin. There were no consistent alterations of mRNA expression of glutamate receptors, although there has been limited study of the corresponding proteins. Studies of the glutamate metabolic pathway have been limited, although there is some evidence that excitatory amino acid transporter-2, glutamine synthetase, and glutaminase have altered expression in schizophrenia. Future studies would benefit from additional direct examination of glutamatergic proteins. Further advances, such as selective testing of synaptic microdomains, cortical layers, and neuronal subtypes, may also be required to elucidate the nature of glutamate signaling impairments in schizophrenia.

The metabotropic glutamate (mGlu) receptors are a group of Class C seven-transmembrane spanning/G protein-coupled receptors (7TMRs/GPCRs). These receptors are activated by glutamate, one of the standard amino acids and the major excitatory neurotransmitter. By activating G protein-dependent and non-G protein-dependent signaling pathways, mGlus modulate glutamatergic transmission both in the periphery and throughout the central nervous system. Since the discovery of the first mGlu receptor, and especially during the last decade, a great deal of progress has been made in understanding the signaling, structure, pharmacological manipulation and therapeutic indications of the 8 mGlu members.

The work deals with study of character of localization in the honeybee head ganglion of metabotropic receptor ImGluR5 and its role in memory formation. With aid of pharmacological method (injections of antisense oligonucleotide and of selective receptor agonist and antagonist) and of behavioral criterion (formation and testing of preservation in memory of conditioned alimentary reflex for olfactory stimulus), there has been shown for the first time the participation of the studied receptor in formation of the honeybee long-term memory. By using the immunohistochemical method, there is first revealed the predominant expression of the ImGluRS receptor in the mushroom body Canyon cells responsible for the insect integrative activity. The present study, together with the previous ones, allows concluding about the presence in the honeybee head ganglion of the group I of metabotropic glutamate receptors with two subtypes 1 and 5 (ImGluRl,5) that have similar with mammals pharmacological properties favoring preservation of the individually acquired experience in the long-term memory.

Glutamate, a nonessential amino acid, is a major bioenergetic substrate for proliferating normal and neoplastic cells on one hand and an excitatory neurotransmitter that is actively involved in biosynthetic, bioenergetic, metabolic, and oncogenic signaling pathways on the other. It exerts its action through a family of receptors consisting of metabotropic glutamate receptors (mGluRs) and ionotropic glutamate receptors (iGluRs), both of which have been implicated previously in a broad spectrum of acute and chronic neurodegenerative diseases. In this review, we discuss existing data on the role of glutamate as a growth factor for neoplastic cells, the expression of glutamate receptors in various types of benign and malignant neoplasms, and the potential roles that GluRs play in cancer development and progression along with their clinical significance. We conclude that glutamate-related receptors and their signaling pathways may provide novel therapeutic opportunities for a variety of malignant human diseases.

It is well established that glutamate and GABA signal through both ionotropic and metabotropic receptors. Conversely, it is thought that, with one exception, monoamines (dopamine, serotonin, and norepinephrine) signal via metabotropic receptors. Given their capacity to generate fast-acting currents, I suggest that the monoamine transporters should be considered as ionotropic receptors.

It has been shown that the metabotropic glutamate receptor subtype 5 (mGluR5) is functionally associated with the NMDA subtype of the glutamate receptor family (NMDA receptors). These two receptors colocalize in brain regions associated with schizophrenia. Although the role of the NMDA receptor in cognitive and negative symptoms of schizophrenia is well studied, information about the role of mGluR5 receptors in schizophrenia is sparse. In our work, we show that subchronic administration of ketamine, a well-studied, non-competitive antagonist of NMDA receptors, caused cognitive deficits in rats as shown by testing novel object recognition (NOR). Moreover, we reveal that subchronic administration of ketamine increased the mRNA and protein expression levels of mGluR5 receptors in regions CA1 and CA3 of the dorsal part of the hippocampus, both of which are strongly associated with the formation of visual memory, which is tested via NOR. We postulate that increased expression of mGluR5 receptors in the dorsal part of the hippocampus may reflect compensatory changes to imbalanced glutamate neurotransmission associated with the hypoactivation of NMDA receptors.

Glutamate is a ubiquitous neurotransmitter, mediating information flow between neurons. Defects in the regulation of glutamatergic transmission can result in glutamate toxicity, which is associated with neurodegeneration. Interestingly, glutamate receptors are expressed in glia, but little is known about their function, and the effects of their misregulation, in these non-neuronal cells. Here, we report a glio-protective role for Drosophila mir-263a mediated by its regulation of glutamate receptor levels in glia. mir-263a mutants exhibit a pronounced movement defect due to aberrant overexpression of CG5621/Grik, Nmdar1, and Nmdar2. mir-263a mutants exhibit excitotoxic death of a subset of astrocyte-like and ensheathing glia in the CNS. Glial-specific normalization of glutamate receptor levels restores cell numbers and suppresses the movement defect. Therefore, microRNA-mediated regulation of glutamate receptor levels protects glia from excitotoxicity, ensuring CNS health. Chronic low-level glutamate receptor overexpression due to mutations affecting microRNA (miRNA) regulation might contribute to glial dysfunction and CNS impairment.

Nociceptive primary afferents release glutamate, activating postsynaptic glutamate receptors on spinal cord dorsal horn neurons. Glutamate receptors, both ionotropic and metabotropic, are also expressed on presynaptic terminals, where they regulate neurotransmitter release. During the last two decades, a wide number of studies have characterized the properties of presynaptic glutamatergic receptors, particularly those expressed on primary afferent fibers. This review describes the subunit composition, distribution and function of presynaptic glutamate ionotropic (AMPA, NMDA, kainate) and metabotropic receptors expressed in rodent spinal cord dorsal horn. The role of presynaptic receptors in modulating nociceptive information in experimental models of acute and chronic pain will be also discussed.

N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-4-11C-methoxy-N-methylbenzamide (11C-ITMM) is a potential radioligand for mapping metabotropic glutamate receptor type 1 (mGluR1) in the brain by PET. The present study was performed to determine the safety, distribution, radiation dosimetry, and initial brain imaging of 11C-ITMM in healthy human subjects. Methods: The multiorgan biodistribution and radiation dosimetry of 11C-ITMM were assessed in 3 healthy human subjects, who underwent 2-h whole-body PET scans. Radiation dosimetry was estimated from the normalized number of disintegrations of source organs using the OLINDA/EXM program. Five healthy human subjects underwent 90-min dynamic 11C-ITMM scans of brain regions with arterial blood sampling. For anatomic coregistration, T1-weighted MR imaging was performed. Metabolites in plasma and urine samples were analyzed by high-performance liquid chromatography. 11C-ITMM uptake was assessed quantitatively using a 2-tissue-compartment model. Results: There were no serious adverse events in any of the subjects throughout the study period. 11C-ITMM PET demonstrated high uptake in the urinary bladder and gallbladder, indicating both urinary and fecal excretion of radioactivity. The absorbed dose (μGy/MBq) was highest in the urinary bladder wall (13.2 ± 3.5), small intestine (9.8 ± 1.7), and liver (9.1 ± 2.0). The estimated effective dose for 11C-ITMM was 4.6 ± 0.3 μSv/MBq. 11C-ITMM showed a gradual increase of radioactivity in the cerebellar cortex. The total distribution volume in the brain regions ranged from 2.61 ± 0.30 (cerebellar cortex) to 0.52 ± 0.17 (pons), and the rank order of the corresponding total distribution volume of 11C-ITMM was cerebellar cortex > thalamus > frontal cortex > striatum ≈ pons, which was consistent with the known distribution of mGluR1 in the primate brain. The rate of 11C-ITMM metabolism in plasma was moderate: at 60 min after injection, 62.2% ± 8.2% of the radioactivity in plasma was intact parent compound. Conclusion: The initial findings of the present study indicated that 11C-ITMM PET is feasible for imaging of mGluR1 in the brain. The low effective dose will permit serial examinations in the same subjects.

Metabotropic glutamate receptors (mGluRs) are found throughout thalamus and cortex and are clearly important to circuit behavior in both structures, and so considering only participation of ionotropic glutamate receptors (e.g., [R,S]-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA] and N-methyl-d-aspartate receptors [NMDA] receptors) in glutamatergic processing would be an unfortunate oversimplification. These mGluRs are found both postsynaptically, on target cells of glutamatergic afferents, and presynaptically, on various synaptic terminals themselves, and when activated, they produce prolonged effects lasting at least hundreds of msec to several sec and perhaps longer. Two main types exist: activation of group I mGluRs causes postsynaptic depolarization, and group II, hyperpolarization. Both types are implicated in synaptic plasticity, both short term and long term. Their evident importance in functioning of thalamus and cortex makes it critical to develop a better understanding of how these receptors are normally activated, especially because they also seem implicated in a wide range of neurological and cognitive pathologies.

Glutamate-mediated excitotoxicity plays a major role in ALS and reduced astrocytic glutamate transport was suggested as a cause. Based on previous work we have proposed that abnormal release may represent another source of excessive glutamate. In this line, here we studied the modulation of glutamate release in ALS by Group I metabotropic glutamate (mGlu) receptors, that comprise mGlu1 and mGlu5 members. Synaptosomes from the lumbar spinal cord of SOD1/G93A mice, a widely used murine model for human ALS, and controls were used in release, confocal or electron microscopy and Western blot experiments. Concentrations of the mGlu1/5 receptor agonist 3,5-DHPG >0.3 μM stimulated the release of [(3)H]d- aspartate, used to label the releasing pools of glutamate, both in control and SOD1/G93A mice. At variance, ≤0.3 μM 3,5-DHPG increased [(3)H]d-aspartate release in SOD1/G93A mice only. Experiments with selective antagonists indicated the involvement of both mGlu1 and mGlu5 receptors, mGlu5 being preferentially involved in the high potency effects of 3,5-DHPG. High 3,5-DHPG concentrations increased IP3 formation in both mouse strains, whereas low 3,5-DHPG did it in SOD1/G93A mice only. Release experiments confirmed that 3,5-DHPG elicited [(3)H]d-aspartate exocytosis involving intra-terminal Ca(2+) release through IP3-sensitive channels. Confocal microscopy indicated the co-existence of both receptors presynaptically in the same glutamatergic nerve terminal in SOD1/G93A mice. To conclude, activation of mGlu1/5 receptors produced abnormal glutamate release in SOD1/G93A mice, suggesting that these receptors are implicated in ALS and that selective antagonists may be predicted for new therapeutic approaches. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.

Metabotropic glutamate receptors (mGlus) are 7 Transmembrane Spanning Receptors (7TMs) that are differentially expressed throughout the brain and modulate synaptic transmission at both excitatory and inhibitory synapses. Recently, mGlus have been implicated as therapeutic targets for many disorders of the central nervous system, including Parkinson's disease (PD). Previous studies have shown that nonselective agonists of group III mGlus have antiparkinsonian effects in several animal models of PD, suggesting that these receptors represent promising targets for treating the motor symptoms of PD. However, the relative contributions of different group III mGlu subtypes to these effects have not been fully elucidated. Here we report that intracerebroventricular (icv) administration of the mGlu(8)-selective agonist (S)-3,4-dicarboxyphenylglycine (DCPG [ 2.5, 10, or 30 nmol]) does not alleviate motor deficits caused by acute (2 h) treatment with haloperidol or reserpine. However, following prolonged pretreatment with haloperidol (three doses evenly spaced over 18-20 h) or reserpine (18-20 h), DCPG robustly reverses haloperidol-induced catalepsy and reserpine-induced akinesia. Furthermore, DCPG (10 nmol, icv) reverses the long-lasting catalepsy induced by 20 h pretreatment with the decanoate salt of haloperidol. Finally, icv administration of DCPG ameliorates forelimb use asymmetry caused by unilateral 6-hydroxydopamine lesion of substantia nigra dopamine neurons. These findings suggest that mGlu(8) may partially mediate the antiparkinsonian effects of group III mGlu agonists in animal models of PD in which dopamine depletion or blockade of D(2)-like dopamine receptors is prolonged and indicate that selective activation of mGlu(8) may represent a novel therapeutic strategy for alleviating the motor symptoms of PD. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.

Neurotransmitters such as glutamate are potential regulators of neurogenesis. Interference with defined glutamate receptor subtypes affects proliferation, migration and differentiation of neural progenitor cells. The cellular targets for the actions of different glutamate receptor ligands are less well known. In this study we have combined calcium imaging, measurement of membrane potential, time-lapse imaging and immunocytochemistry to obtain a spatial overview of migrating mouse embryonic neural progenitor cell-derived cells responding to glutamate receptor agonists and antagonists. Responses via metabotropic glutamate receptor 5 correlated with radial glial cells and dominated in the inner migration zones close to the neurosphere. Block of metabotropic glutamate receptor 5 resulted in shorter radial glial processes, a transient increase in neuron-like cells emerging from the neurosphere and increased motility of neuron-like cells. α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptors are present on the majority of migrating neuronal cells, which with time accumulate at the outer edge of the migration zone. Blocking these receptors leads to an enhanced extension of radial glial processes and a reduced motility of neuron-like cells. Our results indicate that functional glutamate receptors have profound effects on the motility of neural progenitor cells. The main target for metabotropic glutamate receptor 5 appears to be radial glial cells while AMPA/kainate receptors are mainly expressed in newborn neuronal cells and regulate the migratory progress of these cells. The results suggest that both metabotropic glutamate receptor 5 and AMPA/kainate receptors are of importance for the guidance of migrating embryonic progenitor cells.

L-glutamate is produced by a great variety of peripheral tissues in both health and disease. Like other components of the glutamatergic system, metabotropic glutamate (mGlu) receptors also have a widespread distribution outside the central nervous system (CNS). In particular, group III mGlu receptors have been recently found in human stomach and colon revealing an extraordinary potential for these receptors in the treatment of peripheral disorders, including gastrointestinal dysfunction. The significance of these findings is that pharmacological tools originally designed for mGlu receptors in the CNS may also be directed towards new disease targets in the periphery. Targeting mGlu receptors can also be beneficial in the treatment of disorders involving central components together with gastrointestinal dysfunction, such as irritable bowel syndrome, which can be co-morbid with anxiety and depression. Conversely, the development of more specific therapeutic approaches for mGlu ligands both centrally as in the gut will depend on the elucidation of tissue-specific elements in mGlu receptor signalling.

Glutamate is the most important excitatory neurotransmitter of the mammalian central nervous system (CNS), playing an important role in memory, synaptic plasticity and neuronal development. However, glutamate overstimulation is also implicated in neuronal cell death. There are two major types of glutamate receptors: ionotropic and metabotropic. Thus far, eight metabotropic glutamate receptors (mGluRs) subtypes have been characterized and are divided into three subgroups based on sequence homology and cell signaling activation. mGluRs activate a wide variety of cell signaling pathways by G protein-coupled pathways or via G protein-independent cell signaling activation. Moreover, these receptors exhibit widespread distribution in the CNS and are implicated in several neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). This review aims to discuss the latest updates concerning mGluRs and their role in neurodegenerative diseases. mGluRs agonists and antagonists as well as positive and negative allosteric modulators have been tested in several animal models of neurodegenerative diseases. Furthermore, mGluR knockout mouse models have been crossed to mouse models of AD and HD, providing important data about mGluRs role in neurodegenerative disease progression. Thus, mGluRs constitute potential therapeutic targets for the development of therapies to treat neurodegenerative diseases.

SummaryA drug acting at metabotropic glutamate receptors has recently been reported to be an effective antipsychotic, breaking the rule that only dopamine receptor-blocking drugs have this property. The finding complements accumulating evidence that glutamatergic abnormalities are important in the pathophysiology of schizophrenia.

Group II metabotropic glutamate receptors (mGluRs) comprise mGluR2 (mGlu2; encoded by GRM2) and mGluR3 (mGlu3; encoded by GRM3) and modulate glutamate neurotransmission and synaptic plasticity. Here we review the expression and function of mGluR3 and its involvement in schizophrenia. mGluR3 is expressed by glia and neurons in many brain regions and has a predominantly presynaptic distribution, consistent with its role as an inhibitory autoreceptor and heteroceptor. mGluR3 splice variants exist in human brain but are of unknown function. Differentiation of mGluR3 from mGluR2 has been problematic because of the lack of selective ligands and antibodies; the available data suggest particular roles for mGluR3 in long-term depression, in glial function and in neuroprotection. Some but not all studies find genetic association of GRM3 polymorphisms with psychosis, with the risk alleles also being associated with schizophrenia-related endophenotypes such as impaired cognition, cortical activation and glutamate markers. The dimeric form of mGluR3 may be reduced in the brain in schizophrenia. Finally, preclinical findings have made mGluR3 a putative therapeutic target, and now direct evidence for antipsychotic efficacy of a group II mGluR agonist has emerged from a randomised clinical trial in schizophrenia. Together these data implicate mGluR3 in aetiological, pathophysiological and pharmacotherapeutic aspects of the disorder.