L-Glutamate Regulates Npy via the mGluR4-Ca2+-ERK1/2 Signaling Pathway in Mandarin Fish (Siniperca chuatsi).

Metabotropic glutamate receptor 4 (mGluR4) is widely regarded as an umami receptor activated by L-glutamate to exert essential functions. Numerous studies have shown that umami receptors participate in food intake regulation. However, little is known about mGluR4's role in mediating food ingestion and its possible molecular mechanism. Mandarin fish, a typical carnivorous fish, is sensitive to umami substances and is a promising vertebrate model organism for studying the umami receptor. In this study, we identified the mGluR4 gene and conducted evolutionary analyses from diverse fish species with different feeding habits. mGluR4 of mandarin fish was cloned and functionally expressed to investigate the effects of L-glutamate on mGluR4. We further explored whether the signal pathway mGluR4-Ca2+-ERK1/2 participates in the process in mandarin fish brain cells. The results suggest that L-glutamate could regulate Neuropeptide Y (Npy) via the mGluR4-Ca2+-ERK1/2 signaling pathway in mandarin fish. Our findings unveil the role of mGluR4 in feeding decisions and its possible molecular mechanisms in carnivorous fishes.

Detailed radiosynthesis of [18 F]mG4P027 as a positron emission tomography radiotracer for mGluR4.

We report here the detailed radiosynthesis of [18 F]mG4P027, a metabotropic glutamate receptor 4 (mGluR4) PET radiotracer, which showed superior properties to the currently reported mGluR4 radiotracers. The radiosynthesis in the automated system has been challenging, therefore we disclose here the major limiting factors for the synthesis via step-by-step examination. And we hope this thorough study will help its automation for human use in the future.

Mechanisms of umami taste perception: From molecular level to brain imaging.

Due to unique characteristics, umami substances have gained much attention in the food industry during the past decade as potential replacers to sodium or fat to increase food palatability. Umami is not only known to increase appetite, but also to increase satiety, and hence could be used to control food intake. Therefore, it is important to understand the mechanism(s) involved in umami taste perception. This review discusses current knowledge of the mechanism(s) of umami perception from receptor level to human brain imaging. New findings regarding the molecular mechanisms for detecting umami tastes and their pathway(s), and the peripheral and central coding to umami taste are reviewed. The representation of umami in the human brain and the individual variation in detecting umami taste and associations with genotype are discussed. The presence of umami taste receptors in the gastrointestinal tract, and the interactions between the brain and gut are highlighted. The review concludes that more research is required into umami taste perception to include not only oral umami taste perception, but also the wider "whole body" signaling mechanisms, to explore the interaction between the brain and gut in response to umami perception and ingestion.

Activation of metabotropic glutamate receptor 4 regulates proliferation and neural differentiation in neural stem/progenitor cells of the rat subventricular zone and increases phosphatase and tensin homolog protein expression.

Neural stem/progenitor cells (NSPCs) persist in the mammalian subventricular zone throughout life, where they can be activated in response to physiological and pathophysiological stimuli. A recent study indicates metabotropic glutamate receptor 4 (mGluR4) is involved in regulating NSPCs behaviors. Therefore, defining mGluR4 function in NSPCs is necessary for determining novel strategies to enhance the intrinsic potential for brain regeneration after injuries. In this study, mGluR4 was functionally expressed in SVZ-derived NSPCs from male Sprague-Dawley rats, in which the cyclic adenosine monophosphate concentration was reduced after treatment with the mGluR4-specific agonist VU0155041. Additionally, lateral ventricle injection of VU0155041 significantly decreased 5-bromo-2'-deoxyuridine (BrdU)+ and Ki67+ cells, while increased Doublecortin (DCX)/BrdU double-positive cells in SVZ. In cultured NSPCs, mGluR4 activation decreased the ratio of BrdU+ cells, G2/M-phase cells, and inhibited Cyclin D1 expression, whereas it increased neuron-specific class III ß-tubulin (Tuj1) expression and the number of Tuj1, DCX, and PSA-NCAM-positive cells. However, pharmacological blocking mGluR4 with the antagonist MSOP or knockdown of mGluR4 abolished the effects of VU0155041 on NSPCs proliferation and neuronal differentiation. Further investigation demonstrated that VU0155041 treatment down-regulated AKT phosphorylation and up-regulated expression of the phosphatase and tensin homolog protein (PTEN) in NSPCs culture. Moreover VU0155041-induced proliferating inhibition and neuronal differentiating amplification in NSPCs were significantly hampered by VO-OHpic, a PTEN inhibitor. We conclude that activation of mGluR4 in SVZ-derived NSPCs suppresses proliferation and enhances their neuronal differentiation, and regulation of PTEN may be involved as a potential intracellular target of mGluR4 signal. Cover Image for this issue: https://doi.org/10.1111/jnc.15052.

Activation of type 4 metabotropic glutamate receptor promotes cell apoptosis and inhibits proliferation in bladder cancer.

Bladder cancer, the second most common genitourinary malignancy, severely endangers the human health. Rising evidence suggests that metabotropic glutamate receptors (mGluRs) are involve in tumor progression. In this study, we observed that metabotropic glutamate receptor 4 (mGluR4) was functionally expressed in normal and cancerous bladder cells and its expression was positively correlated with high bladder cancer grading. We further confirmed that the activation of mGluR4 by VU0155041, an mGluR4-specific agonist, decreased cyclic adenosine monophosphate (cAMP) concentration and cell viability, promoted apoptosis and inhibited proliferation in bladder cancer cells, whereas MSOP (group III mGluR antagonist) or mGluR4 knockdown eliminated the effects of mGluR4 activity. Western blotting revealed the decreased cyclin D1 expression, increased procaspase-8/9/3 cleavage, and unbalanced Bcl-2/Bax expression in bladder cancer cell lines after mGluR4 activation, and likewise MSOP and mGluR4 knockdown abrogated the actions of mGluR4 activity. In vivo study showed that mGluR4 activation significantly inhibited tumor growth of bladder cancer via suppressing proliferation and promoting apoptosis. Furthermore, upregulation of phosphatase and tensin homolog (PTEN) and inhibition of Akt phosphorylation were also observed after mGluR4 activation. Similar with VU0155041, the Akt-specific inhibitor markedly promoted apoptosis and inhibited proliferation. Nevertheless, the PTEN-specific inhibitor significantly abolished the mGluR4 activation-induced cell apoptosis and proliferative inhibition in bladder cancer cell lines. These results indicate that mGluR4 can regulate the switch between survival and death via the cAMP/PTEN/AKT signaling pathway in bladder cancer cells. Our findings suggest that mGluR4 has diagnostic and prognostic potential for bladder cancer, and the development of mGluR4 agonist may be a promising strategy for bladder cancer treatment.

Improved Synthesis of the Thiophenol Precursor N-(4-Chloro-3-mercaptophenyl)picolinamide for Making the mGluR4 PET Ligand.

Recently [11C]mG4P012 (previously [11C]KALB012 and presently named as [11C]PXT012253 by Prexton Therapeutics) had been used as a biomarker during the preclinical development of a potential therapeutic drug, PXT0002331 (an mGluR4 PAM), for PD and L-dopa-induced dyskinesia. [11C]mG4P012 was shown to be a promising PET radioligand for mGluR4 in the monkey brain and for further development in human subjects. However, the previously reported multi-step synthesis of the thiophenol precursor suffered from low yields and difficult workup procedures. To support the translational research of [11C]mG4P012 and the other potential applications, we have developed a new route for synthesis of the thiophenol precursor and optimized the reaction conditions. The synthesis of N-(4-chloro-3-mercaptophenyl)picolinamide from 1-chloro-4-nitrobenzene has been greatly improved from 8% to 52% total yield with easy handling and in gram scales.

Roles of Glutamate Receptors in Parkinson's Disease.

Parkinson's disease is a progressive neurodegenerative disorder resulting from the degeneration of pigmented dopaminergic neurons in the substantia nigra pars compacta. It induces a series of functional modifications in the circuitry of the basal ganglia nuclei and leads to severe motor disturbances. The amino acid glutamate, as an excitatory neurotransmitter, plays a key role in the disruption of normal basal ganglia function regulated through the interaction with its receptor proteins. It has been proven that glutamate receptors participate in the modulation of neuronal excitability, transmitter release, and long-term synaptic plasticity, in addition to being related to the altered neurotransmission in Parkinson's disease. Therefore, they are considered new targets for improving the therapeutic strategies used to treat Parkinson's disease. In this review, we discuss the biological characteristics of these receptors and demonstrate the receptor-mediated neuroprotection in Parkinson's disease. Pharmacological manipulation of these receptors during anti-Parkinsonian processes in both experimental studies and clinical trials are also summarized.

Radiosynthesis and evaluation of 5-methyl-N-(4-[(11)C]methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine ([(11)C]ADX88178) as a novel radioligand for imaging of metabotropic glutamate receptor subtype 4 (mGluR4).

ADX88178 (1) has been recently developed as a potent positive allosteric modulator for metabotropic glutamate receptor 4 (mGluR4). The aim of this study was to develop [(11)C]1 as a novel positron emission tomography ligand and to evaluate its binding ability for mGluR4. Using stannyl precursor 3, [(11)C]1 was efficiently synthesized by introducing an [(11)C]methyl group into a pyrimidine ring via C-(11)C coupling and deprotection reactions, in 16±6% radiochemical yield (n=10). At the end of synthesis, 0.54-1.10GBq of [(11)C]1 was acquired with >98% radiochemical purity and 90-120GBq/µmol of specific activity. In vitro autoradiography and ex vivo biodistribution study in rat brains showed specific binding of [(11)C]1 in the cerebellum, striatum, thalamus, cerebral cortex, and medulla oblongata, which showed dose-dependent decreases by administration with multi-dose of unlabeled 1.

Expressions of multiple umami taste receptors in oral and gastrointestinal tissues, and umami taste synergism in chickens.

Umami taste is one of the five basic taste qualities, along with sweet, bitter, sour, and salty, and is elicited by some l-amino acids and their salts, including monopotassium l-glutamate (MPG). The unique characteristic of umami taste is that it is synergistically enhanced by 5'-ribonucleotides such as inosine 5'-monophosphate (IMP). Unlike the other four basic taste qualities, the presence of umami taste sense in avian species is not fully understood. In this study, we demonstrated the expression of multiple umami taste receptor candidates in oral and gastrointestinal tract tissues in chickens using RT-PCR analysis. We first showed the metabotropic glutamate receptors (mGluRs) expressed in these tissues. Furthermore, we examined the preference for umami taste in chickens, focusing on the synergistic effect of umami taste as determined by the two-feed choice test. We concluded that chickens preferred feed containing both added MPG and added IMP over feeds containing either added MPG or added IMP alone and over the control feed. These results suggest that the umami taste sense and synergism are conserved in chickens.

Fully Automated Radiosynthesis of [18F]mG4P027 for mGluR4 Imaging.

Fluorine-18 labeled N-(4-chloro-3-(((fluoro-18F)methyl-d2)thio)phenyl)picolinamide, [18F]mG4P027, is a potent positron emission tomography (PET) radiotracer for metabotropic glutamate receptor 4 (mGluR4). Our previous in vitro and in vivo evaluations have demonstrated that this tracer is promising for further translational studies. To automate the radiosynthesis of [18F]mG4P027, significant modifications were made to the manual process by carefully examining this process and addressing the root causes of the challenges associated with its automation. We successfully implemented its automated radiosynthesis using the TRACERlab FX2N module and consequently, obtained a high-purity radiolabeled [18F]mG4P027 in high yield, meeting the requirements for future human studies.

Group III metabotropic glutamate receptors as promising targets for neuroprotective therapy: Particular emphasis on the role of mGlu4 and mGlu7 receptors.

There is still no effective treatment for central nervous system (CNS) pathologies, including cerebral ischemia, neurotrauma, and neurodegenerative diseases in which the Glu/GABA balance is disturbed with associated excitotoxicity. It is thus important to search for new efficacious therapeutic strategies. Preclinical studies on the role of metabotropic glutamate receptors (mGluRs) in neuroprotection conducted over the years show that these receptors may have therapeutic potential in these CNS disorders. However, clinical trials, especially for treating Parkinson's disease, have been unsatisfactory. This review focuses on the specific role of group III mGluRs in neuroprotection in experimental in vitro and in vivo models of excitotoxicity/neurotoxicity using neurotoxins as well as ischemia, traumatic brain injury, and neurodegenerative diseases such as Parkinson's disease, Alzheimer's diseases, and multiple sclerosis. The review highlights recent preclinical studies in which group III mGluR ligands (especially those acting at mGluR4 or mGluR7) were administered after damage, thus emphasizing the importance of the therapeutic time window in the treatment of ischemic stroke and traumatic brain injury. From a clinical standpoint, the review also highlights studies using group III mGluR agonists with favorable neuroprotective efficacy (histological and functional) in experimental ischemic stroke, including healthy normotensive and-hypertensive rats. This review also summarizes possible mechanisms underlying the neuroprotective activity of the group III mGluR ligands, which may be helpful in developing more effective and safe therapeutic strategies. Therefore, to fully assess the role of these receptors in neuroprotection, it is necessary to uncover new selective ligands, primarily those stimulating mGlu4 and mGlu7 receptors.

Putative mGluR4 positive allosteric modulators activate Gi-independent anti-inflammatory mechanisms in microglia.

Chronic dysregulated microglial activation may lead to persistent inflammation and progressive neurodegeneration. A previous study reported that ADX88178, a putative metabotropic glutamate receptor 4 (mGluR4) positive allosteric modulator (PAM), exerts anti-inflammatory effects in microglia by activating mGluR4. We employed in vitro models of immortalized microglia cell lines and primary microglia to elucidate the molecular mechanisms responsible for the regulation of inflammatory pathways by ADX88178 and other mGluR4 PAMs. ADX88178 downregulated lipopolysaccharide (LPS)-induced expression of pro-inflammatory mediators, including TNF-α, IL-1ß, CCL-2, IL-6, NOS2, and miR-155, as well as NO levels, in BV2 cells and primary microglia. Other mGluR4 modulators had divergent activities; VU0361737 (PAM) showed anti-inflammatory effects, whereas the orthosteric group III agonist, L-AP4, and VU0155041 (PAM) displayed no anti-inflammatory actions. In contrast to the earlier report, ADX88178 anti-inflammatory effects appeared to be mGluR4-independent as mGluR4 expression in our in vitro models was very low and its actions were not altered by pharmacological or molecular inhibition of mGluR4. Moreover, we showed that ADX88178 activated Gi-independent, alternative signaling pathways as indicated by the absence of pertussis toxin-mediated inhibition and by increased phosphorylation of cAMP-response element binding protein (CREB), an inhibitor of the NFkB pro-inflammatory pathway. ADX88178 also attenuated NFkB activation by reducing the degradation of IkB and the associated translocation of NFkB-p65 to the nucleus. ADX88178 did not exert its anti-inflammatory effects through adenosine receptors, reported as mGluR4 heteromerization partners. Thus, our results indicate that in microglia, putative mGluR4 PAMs activate mGluR4/Gi-independent mechanisms to attenuate pro-inflammatory pathways.

Activation of Type 4 Metabotropic Glutamate Receptor Regulates Proliferation and Neuronal Differentiation in a Cultured Rat Retinal Progenitor Cell Through the Suppression of the cAMP/PTEN/AKT Pathway.

Retinal progenitor cells (RPCs) remain in the eye throughout life and can be characterized by their ability for self-renewal as well as their specialization into different cell types. A recent study has suggested that metabotropic glutamate receptors (mGluRs) participate in the processes of multiple types of stem cells. Therefore, clarifying the functions of different subtypes of mGluRs in RPCs may provide a novel treatment strategy for regulating the proliferation and differentiation of endogenous RPCs after retinal degeneration. In this study, we observed that mGluR4 was functionally expressed in RPCs, with an effect on cell viability and intracellular cAMP concentration. The activation of mGluR4 by VU0155041 (VU, mGluR4 positive allosteric selective modulator) reduced the number of BrdU+/Pax6+ double-positive cells and Cyclin D1 expression levels while increasing the number of neuron-specific class III beta-tubulin (Tuj1)- and Doublecortin (DCX)-positive cells. The knockdown of mGluR4 by target-specific siRNA abolished the effects of VU on RPC proliferation and neuronal differentiation. Further investigation demonstrated that mGluR4 activation inhibited AKT phosphorylation and up-regulated PTEN protein expression. Moreover, the VU0155041-induced inhibition of proliferation and enhancement of neuronal differentiation in RPCs were significantly hampered by Forskolin (adenylyl cyclase activator) and VO-OHpic trihydrate (PTEN inhibitor). In contrast, the effect of LY294002 (a highly selective Akt inhibitor) on proliferation and differentiation was similar to that of VU. These results indicate that mGluR4 activation can suppress proliferation and promote the neural differentiation of cultured rat RPCs through the cAMP/PTEN/AKT pathway. Our research lays the foundation for further pharmacological work exploring a novel potential therapy for several retinal diseases.

Group III metabotropic glutamate receptors gate long-term potentiation and synaptic tagging/capture in rat hippocampal area CA2.

Metabotropic glutamate receptors (mGluRs) play an important role in synaptic plasticity and memory and are largely classified based on amino acid sequence homology and pharmacological properties. Among group III metabotropic glutamate receptors, mGluR7 and mGluR4 show high relative expression in the rat hippocampal area CA2. Group III metabotropic glutamate receptors are known to down-regulate cAMP-dependent signaling pathways via the activation of Gi/o proteins. Here, we provide evidence that inhibition of group III mGluRs by specific antagonists permits an NMDA receptor- and protein synthesis-dependent long-lasting synaptic potentiation in the apparently long-term potentiation (LTP)-resistant Schaffer collateral (SC)-CA2 synapses. Moreover, long-lasting potentiation of these synapses transforms a transient synaptic potentiation of the entorhinal cortical (EC)-CA2 synapses into a stable long-lasting LTP, in accordance with the synaptic tagging/capture hypothesis (STC). Furthermore, this study also sheds light on the role of ERK/MAPK protein signaling and the downregulation of STEP protein in the group III mGluR inhibition-mediated plasticity in the hippocampal CA2 region, identifying them as critical molecular players. Thus, the regulation of group III mGluRs provides a conducive environment for the SC-CA2 synapses to respond to events that could lead to activity-dependent synaptic plasticity.

A case study of foliglurax, the first clinical mGluR4 PAM for symptomatic treatment of Parkinson's disease: translational gaps or a failing industry innovation model?

INTRODUCTION: Approximately 40% of Parkinson's disease (PD) patients that take mostly dopamine receptor agonists for motor fluctuations, experience the return of symptoms between regular doses. This is a phenomenon known as 'OFF periods.' Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 4 (mGluR4) are a promising non-dopaminergic mechanism with potential to address the unmet need of patients suffering from OFF periods. Foliglurax is the first mGluR4 PAM that has advanced into clinical testing in PD patients. AREAS COVERED: We summarize the chemistry, pharmacokinetics, and preclinical pharmacology of foliglurax. Translational PET imaging studies, clinical efficacy data, and a competitive landscape analysis of available therapies are presented to the readers. In this Perspective article, foliglurax is used as a case study to illustrate the inherent R&D challenges that companies face when developing drugs. These challenges include the delivery of drugs acting through novel mechanisms, long-term scientific investment, and commercial success and shorter-term positive financial returns. EXPERT OPINION: Failure to meet the primary and secondary endpoints in a Phase 2 study led Lundbeck to discontinue the development of foliglurax. Understanding the evidence supporting compound progression into Phase 2 will enable the proper assessment of the therapeutic potential of mGluR4 PAMs.

Behavioral tests predicting striatal dopamine level in a rat hemi-Parkinson's disease model.

Parkinson's disease (PD) is a frequent neurodegenerative disease causing bradykinesia, tremor, muscle rigidity and postural instability. Although its main pathology is progressive dopaminergic (DArgic) neuron loss in the substantia nigra, motor deficits are thought not to become apparent until most DArgic neurons are lost, probably due to compensatory mechanisms that overcome the decline of DA level in the striatum. Even in animal PD models, it is difficult to detect motor deficits when most DArgic neurons are functional. In this study, we performed various behavioral tests (apomorphine-induced rotation, cylinder, forepaw adjustment steps (FAS), beam walking, rota-rod, and open-field), using 6-hydroxydopamine (OHDA) and lipopolysaccharide (LPS)-induced hemi-PD model rats with various striatal DA levels, to find the best way to predict the DA level from earlier disease stages. Different from the 6-OHDA-induced model, reduction in the striatal DA levels in the LPS-model was less significant. Among the behavioral tests, data from cylinder and FAS tests, which evaluate forelimb movements, best correlated with decline of the DA level. They also correlated well with decreased body weight gain. The beam and apomorphine tests showed less significant correlation than the cylinder and FAS tests. Open-field and rota-rod tests were not useful. Expressional levels of mRNA encoding tyrosine hydroxylase (TH), a marker of DArgic neurons, correlated well with the DA level. Metabotropic glutamate receptor 4 mRNA expression correlated with the striatal DA level and may be related to compensatory mechanisms. These results suggest that motor impairments of PD should be evaluated by forelimb movements, or hands and forearms in clinical settings, rather than movement of the body or large joints. The combination of cylinder and FAS tests may be the best to evaluate the rat PD models, in which many DArgic neurons survive.

Short-term perception of and conditioned taste aversion to umami taste, and oral expression patterns of umami taste receptors in chickens.

Umami taste is one of the five basic tastes (sweet, umami, bitter, sour, and salty), and is elicited by l-glutamate salts and 5'-ribonucleotides. In chickens, the elucidation of the umami taste sense is an important step in the production of new feedstuff for the animal industry. Although previous studies found that chickens show a preference for umami compounds in long-term behavioral tests, there are limitations to our understanding of the role of the umami taste sense in chicken oral tissues because the long-term tests partly reflected post-ingestive effects. Here, we performed a short-term test and observed agonists of chicken umami taste receptor, l-alanine and l-serine, affected the solution intakes of chickens. Using this method, we found that chickens could respond to umami solutions containing monosodium l-glutamate (MSG) + inosine 5'-monophosphate (IMP) within 5 min. We also demonstrated that chickens were successfully conditioned to avoid umami solution by the conditioned taste aversion test. It is noted that conditioning to umami solution was generalized to salty and sweet solutions. Thus, chickens may perceive umami taste as a salty- and sweet-like taste. In addition, we found that umami taste receptor candidates were differentially expressed in different regions of the chicken oral tissues. Taken together, the present results strongly suggest that chickens have a sense of umami taste and have umami taste receptors in their oral tissue.

Amino acid sensing in hypothalamic tanycytes via umami taste receptors.

OBJECTIVE: Hypothalamic tanycytes are glial cells that line the wall of the third ventricle and contact the cerebrospinal fluid (CSF). While they are known to detect glucose in the CSF we now show that tanycytes also detect amino acids, important nutrients that signal satiety. METHODS: Ca2+ imaging and ATP biosensing were used to detect tanycyte responses to l-amino acids. The downstream pathway of the responses was determined using ATP receptor antagonists and channel blockers. The receptors were characterized using mice lacking the Tas1r1 gene, as well as an mGluR4 receptor antagonist. RESULTS: Amino acids such as Arg, Lys, and Ala evoke Ca2+ signals in tanycytes and evoke the release of ATP via pannexin 1 and CalHM1, which amplifies the signal via a P2 receptor dependent mechanism. Tanycytes from mice lacking the Tas1r1 gene had diminished responses to lysine and arginine but not alanine. Antagonists of mGluR4 greatly reduced the responses to alanine and lysine. CONCLUSION: Two receptors previously implicated in taste cells, the Tas1r1/Tas1r3 heterodimer and mGluR4, contribute to the detection of a range of amino acids by tanycytes in CSF.

Selective and interactive effects of D2 receptor antagonism and positive allosteric mGluR4 modulation on waiting impulsivity.

BACKGROUND: Metabotropic glutamate receptor 4 (mGluR4) and dopamine D2 receptors are specifically expressed within the indirect pathway neurons of the striato-pallidal-subthalamic pathway. This unique expression profile suggests that mGluR4 and D2 receptors may play a cooperative role in the regulation and inhibitory control of behaviour. We investigated this possibility by testing the effects of a functionally-characterised positive allosteric mGluR4 modulator, 4-((E)-styryl)-pyrimidin-2-ylamine (Cpd11), both alone and in combination with the D2 receptor antagonist eticlopride, on two distinct forms of impulsivity. METHODS: Rats were trained on the five-choice serial reaction time task (5-CSRTT) of sustained visual attention and segregated according to low, mid, and high levels of motor impulsivity (LI, MI and HI, respectively), with unscreened rats used as an additional control group. A separate group of rats was trained on a delay discounting task (DDT) to assess choice impulsivity. RESULTS: Systemic administration of Cpd11 dose-dependently increased motor impulsivity and impaired attentional accuracy on the 5-CSRTT in all groups tested. Eticlopride selectively attenuated the increase in impulsivity induced by Cpd11, but not the accompanying attentional impairment, at doses that had no significant effect on behavioural performance when administered alone. Cpd11 also decreased choice impulsivity on the DDT (i.e. increased preference for the large, delayed reward) and decreased locomotor activity. CONCLUSIONS: These findings demonstrate that mGluR4s, in conjunction with D2 receptors, affect motor- and choice-based measures of impulsivity, and therefore may be novel targets to modulate impulsive behaviour associated with a number of neuropsychiatric syndromes.

The Metabotropic Glutamate Receptor 4 Positive Allosteric Modulator ADX88178 Inhibits Inflammatory Responses in Primary Microglia.

While the specific trigger of Parkinson Disease (PD) in most patients is unknown, considerable evidence suggests that the neuroinflammatory response makes an essential contribution to the neurodegenerative process. Drugs targeting metabotropic glutamate receptors (mGlu receptors), 7 Transmembrane (7TM) spanning/G protein coupled receptors that bind glutamate, are emerging as therapeutic targets for PD and may have anti-inflammatory properties. ADX88178 is novel potent, selective, and brain-penetrant positive allosteric modulator of the mGlu4 which is under evaluation for treatment of PD and other neurological disorders. We used microglia cultured from mouse brain to determine if ADX88178 had direct effects on the inflammatory responses of these cells. We studied both microglia from wild type and Grm4 knock out mice. We found that activation of mGlu4 with ADX88178 attenuated LPS-induced inflammation in primary microglia, leading to a decrease in the expression of TNFα, MHCII, and iNOS, markers of pro-inflammatory responses. These effects were absent in microglia from mice lacking mGlu4. These results demonstrate a cell-autonomous anti-inflammatory effect of ADX88178 mediated mGlu4 activation on microglia, and suggest that this drug or similar activators or potentiators of mGlu4 may have disease-modifying as well as symptomatic effects in PD and other brain disorders with an inflammatory component.