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https://www.readbyqxmd.com/read/29317611/metabotropic-glutamate-receptor-5-binding-in-male-patients-with-alcohol-use-disorder
#1
Funda Akkus, Yoan Mihov, Valerie Treyer, Simon M Ametamey, Anass Johayem, Smeralda Senn, Susanne Rösner, Alfred Buck, Gregor Hasler
Glutamate signaling plays a major role in addiction. Preclinical research strongly suggests an implication of G-protein-coupled metabotropic glutamate receptor subtype 5 (mGluR5) in nicotine addiction and alcohol use disorder. In humans, smoking is related to a global reduction in mGluR5 availability. In the present study, we investigated mGluR5 in vivo in patients with alcohol use disorder without the confounding effects of smoking. A total of 14 male subjects with alcohol use disorder and at least a 25-day abstinence and 14 matched male non-smoking healthy controls were included in the study...
January 10, 2018: Translational Psychiatry
https://www.readbyqxmd.com/read/29315577/bidirectional-variation-in-glutamate-efflux-in-the-medial-prefrontal-cortex-induced-by-selective-positive-and-negative-allosteric-mglur5-modulators
#2
Sarah N Isherwood, Trevor W Robbins, Jeffrey W Dalley, Anton Pekcec
Dysregulation of prefrontal cortical glutamatergic signalling via NMDA receptor hypofunction has been implicated in cognitive dysfunction and impaired inhibitory control in such neuropsychiatric disorders as schizophrenia, attention deficit hyperactivity disorder and drug addiction. Although NMDA receptors functionally interact with metabotropic glutamate receptor 5 (mGluR5), the consequence of this interaction for glutamate release in the prefrontal cortex (PFC) is unknown. We therefore investigated the effects of positive and negative allosteric mGluR5 modulation on changes in extracellular glutamate efflux in the medial PFC (mPFC) induced by systemic administration of the non-competitive NMDA receptor antagonist dizocilpine (or MK801) in rats...
January 6, 2018: Journal of Neurochemistry
https://www.readbyqxmd.com/read/29298905/gliotransmission-beyond-black-and-white
#3
Iaroslav Savtchouk, Andrea Volterra
Astrocytes are highly complex cells with many emerging putative roles in brain function. Of these, gliotransmission (active information transfer from glia to neurons) has probably the widest implications on our understanding of how the brain works: do astrocytes really contribute to information processing within the neural circuitry? "Positive evidence" for this stems from work of multiple laboratories reporting many examples of modulatory chemical signaling from astrocytes to neurons in the timeframe of hundreds of milliseconds to several minutes...
January 3, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29259100/mglur5-antagonism-increases-autophagy-and-prevents-disease-progression-in-the-zq175-mouse-model-of-huntington-s-disease
#4
Khaled S Abd-Elrahman, Alison Hamilton, Shaunessy R Hutchinson, Fang Liu, Ryan C Russell, Stephen S G Ferguson
Huntington's disease (HD) is a neurodegenerative disease caused by an expansion in the huntingtin protein (also called Htt) that induces neuronal cell death with age. We found that the treatment of 12-month-old symptomatic heterozygous and homozygous zQ175 huntingtin knockin mice for 12 weeks with CTEP, a negative allosteric modulator of metabotropic glutamate receptor 5 (mGluR5), reduced the size and number of huntingtin aggregates, attenuated caspase-3 activity, and reduced both neuronal apoptosis and neuronal loss in brain tissue...
December 19, 2017: Science Signaling
https://www.readbyqxmd.com/read/29225043/neurogranin-in-the-nucleus-accumbens-regulates-nmda-receptor-tolerance-and-motivation-for-ethanol-seeking
#5
Ashlie N Reker, Alfredo Oliveros, John M Sullivan, Lailun Nahar, David J Hinton, Taehyun Kim, Robert C Bruner, Doo-Sup Choi, Nicholas E Goeders, Hyung W Nam
Dysfunction of N-methyl-D-aspartate receptor (NMDAR) signaling in the nucleus accumbens (NAc) has been implicated in the pathophysiology of alcohol use disorders (AUD). Neurogranin (Ng), a calmodulin-binding protein, is exclusively expressed in the post-synapse, and mediates NMDAR driven synaptic plasticity by regulating the calcium-calmodulin (Ca2+-CaM) pathway. To study the functional role of Ng in AUD, we administrated behavior tests including Pavlovian instrument transfer (PIT), operant conditioning, and rotarod test using Ng null mice (Ng-/- mice)...
December 7, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/29217836/drug-development-for-neurodevelopmental-disorders-lessons-learned-from-fragile-x-syndrome
#6
REVIEW
Elizabeth M Berry-Kravis, Lothar Lindemann, Aia E Jønch, George Apostol, Mark F Bear, Randall L Carpenter, Jacqueline N Crawley, Aurore Curie, Vincent Des Portes, Farah Hossain, Fabrizio Gasparini, Baltazar Gomez-Mancilla, David Hessl, Eva Loth, Sebastian H Scharf, Paul P Wang, Florian Von Raison, Randi Hagerman, Will Spooren, Sébastien Jacquemont
Neurodevelopmental disorders such as fragile X syndrome (FXS) result in lifelong cognitive and behavioural deficits and represent a major public health burden. FXS is the most frequent monogenic form of intellectual disability and autism, and the underlying pathophysiology linked to its causal gene, FMR1, has been the focus of intense research. Key alterations in synaptic function thought to underlie this neurodevelopmental disorder have been characterized and rescued in animal models of FXS using genetic and pharmacological approaches...
December 8, 2017: Nature Reviews. Drug Discovery
https://www.readbyqxmd.com/read/29214202/dataset-for-phase-i-randomized-clinical-trial-for-safety-and-tolerability-of-get-73-in-single-and-repeated-ascending-doses-including-preliminary-pharmacokinetic-parameters
#7
Carolina L Haass-Koffler, Kimberly Goodyear, Victoria M Long, Harrison H Tran, Antonella Loche, Roberto Cacciaglia, Robert M Swift, Lorenzo Leggio
The data in this article outline the methods used for the administration of GET 73 in the first time-in-human manuscript entitled "Phase I randomized clinical trial for the safety, tolerability and preliminary pharmacokinetics of the mGluR5 negative allosteric modulator GET 73 following single and repeated doses in healthy male volunteers" (Haass-Koffler et al., 2017) [1]. Data sets are provided in two different manners. The first series of tables provided includes procedural information about the experiments conducted...
December 2017: Data in Brief
https://www.readbyqxmd.com/read/29209553/antidyskinetic-treatment-with-mtep-affects-multiple-molecular-pathways-in-the-parkinsonian-striatum
#8
Jing-Ya Lin, Zhen-Guo Liu, Cheng-Long Xie, Lu Song, Ai-Juan Yan
Parkinson's disease is characterized by dopaminergic neuron loss and dopamine (DA) depletion in the striatum. Standard treatment is still focused on the restoration of dopamine with exogenous L-Dopa, which however causes L-Dopa-induced dyskinesia (LID). Several studies have shown that antagonism of the metabotropic glutamate receptor 5 alleviates LID, but the underlying mechanisms have remained unclear. We set out to determine where this alleviation may depend on restoring the equilibrium between the two main striatofugal pathways...
2017: Parkinson's Disease
https://www.readbyqxmd.com/read/29207276/environmental-enrichment-improves-hippocampal-function-in-aged-rats-by-enhancing-learning-and-memory-ltp-and-mglur5-homer1c-activity
#9
Guiseppe P Cortese, Andrew Olin, Kenneth O'Riordan, Rikki Hullinger, Corinna Burger
Previous studies from our laboratory have shown that environmental enrichment (EE) in young rats results in improved learning ability and enhanced metabotropic glutamate receptor-dependent long-term potentiation (mGluR-dependent LTP) resulting from sustained activation of p70S6 kinase. Here, we investigated whether 1-month EE is sufficient to improve hippocampus-dependent learning and memory and enhance hippocampal LTP in 23-24 month-old Fischer 344 male rats. Aged rats were housed in environmentally enriched, socially enriched, or standard housing conditions...
November 16, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/29206810/mglur5-modulation-of-behavioral-and-epileptic-phenotypes-in-a-mouse-model-of-tuberous-sclerosis-complex
#10
Elyza Kelly, Samantha M Schaeffer, Sameer C Dhamne, Jonathan O Lipton, Lothar Lindemann, Michael Honer, Georg Jaeschke, Chloe E Super, Stephen Ht Lammers, Meera E Modi, Jill L Silverman, John R Dreier, David J Kwiatkowski, Alexander Rotenberg, Mustafa Sahin
Drugs targeting metabotropic glutamate receptor 5 (mGluR5) have therapeutic potential in autism spectrum disorders (ASD), including Tuberous Sclerosis Complex (TSC). The question whether inhibition or potentiation of mGluR5 could be beneficial depends, among other factors, on the specific indication. To facilitate the development of mGluR5 treatment strategies, we tested the therapeutic utility of mGluR5 negative and positive allosteric modulators (an mGluR5 NAM and PAM) for TSC, using a mutant mouse model with neuronal loss of Tsc2 that demonstrates disease-related phenotypes including behavioral symptoms of ASD and epilepsy...
December 5, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/29205377/adenosine-a2a-receptors-are-required-for-glutamate-mglur5-and-dopamine-d1-receptor-evoked-erk1-2-phosphorylation-in-rat-hippocampus-involvement-of-nmda-receptor
#11
Paraskevi Krania, Eleni Dimou, Maria Bantouna, Stylianos Kouvaros, Eirini Tsiamaki, Costas Papatheodoropoulos, Konstantinos Sarantis, Fevronia Angelatou
Interaction between mGluR5 and NMDA receptors (NMDAR) is vital for synaptic plasticity and cognition. We recently demonstrated that stimulation of mGluR5 enhances NMDAR-responses in hippocampus by phosphorylating NR2B(Tyr1472) subunit, and this reaction was enabled by adenosine A2A receptors(A2A R) (Sarantis et al.2015). In this study, by using in vitro phosphorylation and western blot analysis in hippocampal slices of male Wistar rats, we show, that mGluR5 stimulation or mGluR5/NMDARs co-stimulation, synergistically activate ERK1/2 signaling leading to c-Fos expression...
December 5, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/29191654/differential-mglur5-expression-in-response-to-the-same-stress-causes-individually-adapted-hippocampal-network-activity
#12
Yeong Shin Yim, Woongsu Han, Jeho Seo, Chul Hoon Kim, Dong Goo Kim
Individual differences in stress vulnerability and resilience have been observed even within a single cohort of inbred rats or mice. Stress phenotypes are typically quantified as changes in the behavior of experimental animals, which is the outcome of altered electrical activity of the brain network. Although mGluR5 is associated with individual vulnerability to stress and can act as a sensitive biomarker of stress adaptation, our understanding of mGluR5-dependent modifications to neural network activities in vivo remains limited...
November 27, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29187078/maternal-fluoride-exposure-during-gestation-and-lactation-decreased-learning-and-memory-ability-and-glutamate-receptor-mrna-expressions-of-mouse-pups
#13
Z Sun, Y Zhang, X Xue, R Niu, J Wang
Previous investigations demonstrated that high fluoride (F) exposure may adversely affect the neurodevelopment and learning and memory ability. However, whether maternal F exposure during gestation and lactation can influence the learning, memory ability, and glutamate receptor expressions of offspring has not yet been elucidated. Hence, in the present study, maternal mice were exposed to F (25, 50, or 100 mg/L sodium fluoride (NaF) in drinking water) during gestation and lactation. Results showed that exposure to 100 mg/L NaF significantly enhanced the number of total arm entries and working memory errors of offspring in the radial arm maze test compared to the control group...
January 2018: Human & Experimental Toxicology
https://www.readbyqxmd.com/read/29176838/inhibition-of-group-i-metabotropic-glutamate-receptors-protects-against-prion-toxicity
#14
Despoina Goniotaki, Asvin K K Lakkaraju, Amulya N Shrivastava, Pamela Bakirci, Silvia Sorce, Assunta Senatore, Rajlakshmi Marpakwar, Simone Hornemann, Fabrizio Gasparini, Antoine Triller, Adriano Aguzzi
Prion infections cause inexorable, progressive neurological dysfunction and neurodegeneration. Expression of the cellular prion protein PrPC is required for toxicity, suggesting the existence of deleterious PrPC-dependent signaling cascades. Because group-I metabotropic glutamate receptors (mGluR1 and mGluR5) can form complexes with the cellular prion protein (PrPC), we investigated the impact of mGluR1 and mGluR5 inhibition on prion toxicity ex vivo and in vivo. We found that pharmacological inhibition of mGluR1 and mGluR5 antagonized dose-dependently the neurotoxicity triggered by prion infection and by prion-mimetic anti-PrPC antibodies in organotypic brain slices...
November 27, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/29176430/the-role-of-n-methyl-d-aspartate-receptors-and-metabotropic-glutamate-receptor-5-in-the-prepulse-inhibition-paradigms-for-studying-schizophrenia-pharmacology-neurodevelopment-and-genetics
#15
Zhemeng Wu, Zhigang Yang, Mengjiao Zhang, Xiaohan Bao, Fang Han, Liang Li
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...
November 24, 2017: Behavioural Pharmacology
https://www.readbyqxmd.com/read/29163043/combination-therapy-in-fragile-x-syndrome-possibilities-and-pitfalls-illustrated-by-targeting-the-mglur5-and-gaba-pathway-simultaneously
#16
Shimriet Zeidler, Helen de Boer, Renate K Hukema, Rob Willemsen
Fragile X syndrome (FXS) is the most common monogenetic cause of intellectual disability and autism. The disorder is characterized by altered synaptic plasticity in the brain. Synaptic plasticity is tightly regulated by a complex balance of different synaptic pathways. In FXS, various synaptic pathways are disrupted, including the excitatory metabotropic glutamate receptor 5 (mGluR5) and the inhibitory γ-aminobutyric acid (GABA) pathways. Targeting each of these pathways individually, has demonstrated beneficial effects in animal models, but not in patients with FXS...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/29143330/short-term-high-fat-diet-primes-excitatory-synapses-for-long-term-depression-in-orexin-neurons
#17
Victoria Linehan, Lisa Z Fang, Michiru Hirasawa
KEY POINTS: High-fat diet consumption is a major cause of obesity. Orexin neurons are known to be activated by a high-fat diet and in turn promote further consumption of a high-fat diet. Our study shows that excitatory synapses to orexin neurons become amenable to long-term depression (LTD) after 1 week of high-fat diet feeding. However, this effect reverses after 4 weeks of a high-fat diet. This LTD may be a homeostatic response to a high-fat diet to curb the activity of orexin neurons and hence caloric consumption...
November 15, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/29100629/metabotropic-glutamatergic-receptor-5-and-stress-disorders-knowledge-gained-from-receptor-imaging-studies
#18
REVIEW
Irina Esterlis, Sophie E Holmes, Priya Sharma, John H Krystal, Christine DeLorenzo
The metabotropic glutamatergic receptor subtype 5 (mGluR5) may represent a promising therapeutic target for stress-related psychiatric disorders. Here, we describe mGluR5 findings in stress disorders, particularly major depressive disorder (MDD), highlighting insights from positron emission tomography studies. Positron emission tomography studies report either no differences or lower mGluR5 in MDD, potentially reflecting MDD heterogeneity. Unlike the rapidly acting glutamatergic agent ketamine, mGluR5-specific modulation has not yet shown antidepressant efficacy in MDD and bipolar disorder...
September 19, 2017: Biological Psychiatry
https://www.readbyqxmd.com/read/29074619/presynaptic-mglur5-receptor-controls-glutamatergic-input-through-protein-kinase-c-nmda-receptors-in-paclitaxel-induced-neuropathic-pain
#19
Jing-Dun Xie, Shao-Rui Chen, Hui-Lin Pan
Chemotherapeutic drugs such as paclitaxel cause painful peripheral neuropathy in many cancer patients and survivors. Although NMDA receptors (NMDARs) at primary afferent terminals are known to be critically involved in chemotherapy-induced chronic pain, the upstream signaling mechanism that leads to presynaptic NMDAR activation is unclear. Group I metabotropic glutamate receptors (mGluRs) play a role in synaptic plasticity and NMDAR regulation. Here we report that the Group I mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG) significantly increased the frequency of miniature excitatory postsynaptic currents (EPSCs) and the amplitude of monosynaptic EPSCs evoked from the dorsal root...
December 15, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29070854/altered-norbin-expression-in-patients-with-epilepsy-and-a-rat-model
#20
Yali Xu, Zengyou Li, Li Yao, Xingping Zhang, Dan Gan, Manchun Jiang, Na Wang, Guojun Chen, Xuefeng Wang
Norbin is widely distributed in neuronal tissues, is a regulator of Ca2(+)/calmodulin-dependent protein kinase II (CaMKII) phosphorylation. Norbin is also an important endogenous modulator of metabotropic glutamate receptor 5 (mGluR5) signaling, and nervous system-specific homozygous gene disruptions, result in epileptic seizures. In this study, we aimed to investigate norbin expression patterns in epilepsy and to elucidate the relationships between norbin and mGluR5 and p-CaMKII in epilepsy. Double-immunolabeling, immunohistochemistry and immunoblotting studies showed that norbin was downregulated in the temporal neocortex of patients with temporal lobe epilepsy (TLE) compared with control subjects...
October 25, 2017: Scientific Reports
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