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https://www.readbyqxmd.com/read/27920147/accumbens-nnos-interneurons-regulate-cocaine-relapse
#1
Alexander C W Smith, Michael D Scofield, Jasper A Heinsbroek, Cassandra D Gipson, Daniela Neuhofer, Doug J Roberts-Wolfe, Sade Spencer, Neringa M Stankeviciute, Rachel Smith, Nicholas P Allen, Melissa R Lorang, William C Griffin, Heather A Boger, Peter W Kalivas
: Relapse to drug use can be initiated by drug-associated cues. The intensity of cue-induced relapse is correlated with the induction of transient synaptic potentiation (t-SP) at glutamatergic synapses on medium spiny neurons (MSNs) in the nucleus accumbens core (NAcore), and requires spillover of glutamate from prefrontal cortical afferents. We used a rodent self-administration/reinstatement model of relapse to show that cue-induced t-SP and reinstated cocaine-seeking result from glutamate spillover initiating a metabotropic glutamate receptor 5 (mGluR5)-dependent increase in nitric oxide (NO) production...
December 5, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27886171/transduction-of-group-i-mglur-mediated-synaptic-plasticity-by-%C3%AE-arrestin2-signalling
#2
Andrew G Eng, Daniel A Kelver, Tristan P Hedrick, Geoffrey T Swanson
Conventional signalling by the group I metabotropic glutamate receptors, mGluR1 and mGluR5, occurs through G-protein coupling, but evidence suggests they might also utilize other, non-canonical effector pathways. Here we test whether group I mGluRs require β-arrestin signalling during specific forms of plasticity at hippocampal excitatory synapses. We find that genetic ablation of β-arrestin2, but not β-arrestin1, results in deficits in plasticity mediated by mGlu1 receptors in CA3 pyramidal neurons and by mGlu5 receptors in CA1 pyramidal neurons...
November 25, 2016: Nature Communications
https://www.readbyqxmd.com/read/27881780/negative-allosteric-modulation-of-mglur5-partially-corrects-pathophysiology-in-a-mouse-model-of-rett-syndrome
#3
Jifang Tao, Hao Wu, Amanda A Coronado, Elizabeth de Laittre, Emily K Osterweil, Yi Zhang, Mark F Bear
: Rett syndrome (RTT) is caused by mutations in the gene encoding methyl-CpG binding protein 2 (MECP2), an epigenetic regulator of mRNA transcription. Here, we report a test of the hypothesis of shared pathophysiology of RTT and fragile X, another monogenic cause of autism and intellectual disability. In fragile X, the loss of the mRNA translational repressor FMRP leads to exaggerated protein synthesis downstream of metabotropic glutamate receptor 5 (mGluR5). We found that mGluR5- and protein-synthesis-dependent synaptic plasticity were similarly altered in area CA1 of Mecp2 KO mice...
November 23, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27878759/loss-of-adenylyl-cyclase-type-5-in-the-dorsal-striatum-produces-autistic-like-behaviors
#4
Hannah Kim, Yunjin Lee, Jin-Young Park, Ji-Eun Kim, Tae-Kyung Kim, Juli Choi, Jung-Eun Lee, Eun-Hwa Lee, Daesoo Kim, Kyoung-Shim Kim, Pyung-Lim Han
Autism spectrum disorders (ASDs) are a heterogeneous group of psychiatric illness characterized by common core symptoms including sociability deficits and stereotyped behaviors. ASD is caused by various genetic and non-genetic factors. The genetic effects of autism-related genes are usually global and are presented with multiple symptoms, which hamper understanding of the mechanism through which the diverse causes of ASD produce common symptoms. In the present study, we demonstrate that genetic or molecular disruption of an array of molecular networks centered on adenylyl cyclase type-5 (AC5 or ADCY5) in the dorsal striatum produces autistic-like behaviors...
November 23, 2016: Molecular Neurobiology
https://www.readbyqxmd.com/read/27872582/separate-ionotropic-and-metabotropic-glutamate-receptor-functions-in-depotentiation-vs-ltp-a-distinct-role-for-group1-mglur-subtypes-and-nmdars
#5
Amira Latif-Hernandez, Enrico Faldini, Tariq Ahmed, Detlef Balschun
Depotentiation (DP) is a mechanism by which synapses that have recently undergone long-term potentiation (LTP) can reverse their synaptic strengthening within a short time-window after LTP induction. Group 1 metabotropic glutamate receptors (mGluRs) were shown to be involved in different forms of LTP and long-term depression (LTD), but little is known about their roles in DP. Here, we generated DP by applying low-frequency stimulation (LFS) at 5 Hz after LTP had been induced by a single train of theta-burst-stimulation (TBS)...
2016: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/27856084/difluorocyclobutylacetylenes-as-positive-allosteric-modulators-of-mglur5-with-reduced-bioactivation-potential
#6
Andrew P Degnan, Darrell Maxwell, Anand Balakrishnan, Jeffrey M Brown, Amy Easton, Michael Gulianello, Umesh Hanumegowda, Melissa Hill-Drzewi, Regina Miller, Kenneth S Santone, Arun Senapati, Eric E Shields, Digavalli V Sivarao, Ryan Westphal, Valerie J Whiterock, Xiaoliang Zhuo, Joanne J Bronson, John E Macor
Schizophrenia is a serious illness that affects millions of patients and has been associated with N-methyl-d-aspartate receptor (NMDAR) hypofunction. It has been demonstrated that activation of metabotropic glutamate receptor 5 (mGluR5) enhances NMDA receptor function, suggesting the potential utility of mGluR5 positive allosteric modulators (PAMs) in the treatment of schizophrenia. Herein we describe the optimization of an mGluR5 PAM by replacement of a phenyl with aliphatic heterocycles and carbocycles as a strategy to reduce bioactivation in a biaryl acetylene chemotype...
December 15, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27847973/metabotropic-glutamate-receptor-5-as-a-potential-target-for-smoking-cessation
#7
REVIEW
Cristiano Chiamulera, Claudio Marcello Marzo, David J K Balfour
RATIONALE: Most habitual smokers find it difficult to quit smoking because they are dependent upon the nicotine present in tobacco smoke. Tobacco dependence is commonly treated pharmacologically using nicotine replacement therapy or drugs, such as varenicline, that target the nicotinic receptor. Relapse rates, however, remain high, and there remains a need to develop novel non-nicotinic pharmacotherapies for the dependence that are more effective than existing treatments. OBJECTIVE: The purpose of this paper is to review the evidence from preclinical and clinical studies that drugs that antagonise the metabotropic glutamate receptor 5 (mGluR5) in the brain are likely to be efficacious as treatments for tobacco dependence...
November 16, 2016: Psychopharmacology
https://www.readbyqxmd.com/read/27847228/metabotropic-glutamate-receptor-5-neuroimaging-in-schizophrenia
#8
Funda Akkus, Valerie Treyer, Simon M Ametamey, Anass Johayem, Alfred Buck, Gregor Hasler
The metabotropic glutamate receptor 5 (mGluR5) is a promising drug target for the treatment of schizophrenia. In this study, we compared mGluR5 distribution volume ration (DVR) in subjects with schizophrenia and healthy controls. Given our previous findings, we matched samples for gender, age, and smoking status. Binding to mGluR5 was determined using positron emission tomography and [(11)C]ABP688, which binds to an allosteric site with high selectivity. DVR in the 15 individuals with schizophrenia did not differ from that of the 15 controls...
November 12, 2016: Schizophrenia Research
https://www.readbyqxmd.com/read/27822496/estradiol-facilitation-of-cocaine-self-administration-in-female-rats-requires-activation-of-mglur5
#9
Luis A Martinez, Kellie S Gross, Brett T Himmler, Nicole L Emmitt, Brittni M Peterson, Natalie E Zlebnik, M Foster Olive, Marilyn E Carroll, Robert L Meisel, Paul G Mermelstein
In comparison to men, women initiate drug use at earlier ages and progress from initial use to addiction more rapidly. This heightened intake and vulnerability to drugs of abuse is regulated in part by estradiol, although the signaling mechanisms by which this occurs are not well understood. Recent findings indicate that within the nucleus accumbens core, estradiol induces structural plasticity via membrane-localized estrogen receptor α, functionally coupled to metabotropic glutamate receptor subtype 5 (mGluR5)...
September 2016: ENeuro
https://www.readbyqxmd.com/read/27796754/ketamine-self-administration-reduces-the-homeostasis-of-the-glutamate-synapse-in-the-rat-brain
#10
Lucia Caffino, Alessandro Piva, Giuseppe Giannotti, Marzia Di Chio, Francesca Mottarlini, Marco Venniro, David T Yew, Cristiano Chiamulera, Fabio Fumagalli
Ketamine is a non-competitive antagonist of the NMDA glutamate receptor with psychotomimetic and reinforcing properties, although recent work has pointed out its antidepressant action following acute exposure. Our aim was to investigate the expression of crucial components of the glutamate synapse following chronic ketamine self-administration (S/A), focusing our attention on medial prefrontal cortex (mPFC) and hippocampus (Hip), two brain regions involved in compulsive drug-seeking and drug-related cognitive disorders...
October 29, 2016: Molecular Neurobiology
https://www.readbyqxmd.com/read/27775719/astrocytes-mediate-neurovascular-signaling-to-capillary-pericytes-but-not-to-arterioles
#11
Anusha Mishra, James P Reynolds, Yang Chen, Alexander V Gourine, Dmitri A Rusakov, David Attwell
Active neurons increase their energy supply by dilating nearby arterioles and capillaries. This neurovascular coupling underlies blood oxygen level-dependent functional imaging signals, but its mechanism is controversial. Canonically, neurons release glutamate to activate metabotropic glutamate receptor 5 (mGluR5) on astrocytes, evoking Ca(2+) release from internal stores, activating phospholipase A2 and generating vasodilatory arachidonic acid derivatives. However, adult astrocytes lack mGluR5, and knockout of the inositol 1,4,5-trisphosphate receptors that release Ca(2+) from stores does not affect neurovascular coupling...
December 2016: Nature Neuroscience
https://www.readbyqxmd.com/read/27763640/methamphetamine-potentiates-hiv-1-gp120-mediated-autophagy-via-beclin-1-and-atg5-7-as-a-pro-survival-response-in-astrocytes
#12
Lu Cao, Mingui Fu, Santosh Kumar, Anil Kumar
Methamphetamine (METH), a commonly used controlled substance, is known to exacerbate neuropathological dysfunction in HIV-infected individuals. The neuropathological manifestation results from cell death or dysfunction in the central nervous system (CNS) wherein autophagy is expected to have an important role. Autophagy is generally considered protective during deprivation/stress. However, excessive autophagy can be destructive, leading to autophagic cell death. This study was designed to investigate if METH and HIV-1 gp120 interact to induce autophagy in SVGA astrocytes, and whether autophagy is epiphenomenal or it has a role in METH- and gp120-induced cytotoxicity...
October 20, 2016: Cell Death & Disease
https://www.readbyqxmd.com/read/27756833/the-frontal-cortex-as-a-network-hub-controlling-mood-and-cognition-probing-its-neurochemical-substrates-for-improved-therapy-of-psychiatric-and-neurological-disorders
#13
Mark J Millan, Jean-Michel Rivet, Alain Gobert
The highly-interconnected and neurochemically-rich frontal cortex plays a crucial role in the regulation of mood and cognition, domains disrupted in depression and other central nervous system disorders, and it is an important site of action for their therapeutic control. For improving our understanding of the function and dysfunction of the frontal cortex, and for identifying improved treatments, quantification of extracellular pools of neuromodulators by microdialysis in freely-moving rodents has proven indispensable...
October 17, 2016: Journal of Psychopharmacology
https://www.readbyqxmd.com/read/27749604/sirt1-attenuates-neuropathic-pain-by-epigenetic-regulation-of-mglur1-5-expressions-in-type-2-diabetic-rats
#14
Cheng-Hua Zhou, Ming-Xing Zhang, Sha-Sha Zhou, Huan Li, Jian Gao, Lei Du, Xiao-Xing Yin
Accumulating evidence has demonstrated that epigenetic modification-mediated changes in pain-related gene expressions play an important role in the development and maintenance of neuropathic pain. Sirtuin 1 (SIRT1), anicotinamide adenosine dinucleotide (NAD)-dependent deacetylase, is involved in the development of chronic pain. Moreover, SIRT1 may be a novel therapeutic target for the prevention of type 2 diabetes mellitus (T2DM). But the role of SIRT1 in T2DM-induced neuropathic pain remains unknown. In this study, we found that spinal SIRT1 expression and activity were down-regulated significantly in high-fat-fed/low-dose STZ-induced neuropathic pain rats...
September 29, 2016: Pain
https://www.readbyqxmd.com/read/27744406/long-lasting-impairment-of-mglur5-activated-intracellular-pathways-in-the-striatum-after-withdrawal-of-cocaine-self-administration
#15
Hanne Mette Hoffmann, Nadine Crouzin, Estefanía Moreno, Noora Raivio, Silvia Fuentes, Peter J McCormick, Jordi Ortiz, Michel Vignes
BACKGROUND: Cocaine addiction continues to be a major heath concern, and despite public health intervention there is a lack of efficient pharmacological treatment options. A newly identified potential target are the group I metabotropic glutamate receptors (mGluR1/5), with allosteric modulators showing particular promise. METHODS: We evaluated the capacity of mGluR1/5 receptors to induce functional responses in ex vivo striatal slices from rats with 1) acute cocaine self-administration (CSA), 2) chronic CSA and 3) 60 days CSA withdrawal by westernblot and extracellular recordings of synaptic transmission...
October 15, 2016: International Journal of Neuropsychopharmacology
https://www.readbyqxmd.com/read/27743932/brain-mglur5-in-mice-with-amyloid-beta-pathology-studied-with-in%C3%A2-vivo-11-c-abp688-pet-imaging-and-ex%C3%A2-vivo-immunoblotting
#16
Xiaotian T Fang, Jonas Eriksson, Gunnar Antoni, Ulrika Yngve, Linda Cato, Lars Lannfelt, Dag Sehlin, Stina Syvänen
Alzheimer's disease (AD) is characterized by aggregation of amyloid beta (Aβ) into insoluble plaques. Intermediates, Aβ oligomers (Aβo), appear to be the mechanistic cause of disease. The de facto PET AD ligand, [(11)C]PIB, binds and visualizes Aβ plaque load, which does not correlate well with disease severity. Therefore, finding a dynamic target that changes with pathology progression in AD is of great interest. Aβo alter synaptic plasticity, inhibit long-term potentiation, and facilitate long-term depression; key mechanisms involved in memory and learning...
February 2017: Neuropharmacology
https://www.readbyqxmd.com/read/27742888/in%C3%A2-vivo-variation-in-same-day-estimates-of-metabotropic-glutamate-receptor-subtype-5-binding-using-11c-abp688-and-18f-fpeb
#17
Christine DeLorenzo, Jean-Dominique Gallezot, John Gardus, Jie Yang, Beata Planeta, Nabeel Nabulsi, R Todd Ogden, David C Labaree, Yiyun H Huang, J John Mann, Fabrizio Gasparini, Xin Lin, Jonathan A Javitch, Ramin V Parsey, Richard E Carson, Irina Esterlis
Positron emission tomography tracers [(11)C]ABP688 and [(18)F]FPEB target the metabotropic glutamate receptor subtype 5 providing quantification of the brain glutamatergic system in vivo. Previous [(11)C]ABP688 positron emission tomography human test-retest studies indicate that, when performed on the same day, significant binding increases are observed; however, little deviation is reported when scans are >7 days apart. Due to the small cohorts examined previously (eight and five males, respectively), we aimed to replicate the same-day test-retest studies in a larger cohort including both males and females...
October 14, 2016: Journal of Cerebral Blood Flow and Metabolism
https://www.readbyqxmd.com/read/27721389/neurodevelopmental-expression-profile-of-dimeric-and-monomeric-group-1-mglurs-relevance-to-schizophrenia-pathogenesis-and-treatment
#18
Jeremy S Lum, Francesca Fernandez, Natalie Matosin, Jessica L Andrews, Xu-Feng Huang, Lezanne Ooi, Kelly A Newell
Group 1 metabotropic glutamate receptors (mGluR1/mGluR5) play an integral role in neurodevelopment and are implicated in psychiatric disorders, such as schizophrenia. mGluR1 and mGluR5 are expressed as homodimers, which is important for their functionality and pharmacology. We examined the protein expression of dimeric and monomeric mGluR1α and mGluR5 in the prefrontal cortex (PFC) and hippocampus throughout development (juvenile/adolescence/adulthood) and in the perinatal phencyclidine (PCP) model of schizophrenia...
October 10, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27720859/involvement-of-p2x7-receptors-in-retinal-ganglion-cell-apoptosis-induced-by-activated-m%C3%A3-ller-cells
#19
Bo Xue, Yuting Xie, Ying Xue, Nan Hu, Guowei Zhang, Huaijin Guan, Min Ji
Müller cell reactivation (gliosis) is an early response in glaucomatous retina. Previous studies have demonstrated that activation of P2X7 receptors results in retinal ganglion cell (RGC) apoptosis. Here, the issues of whether and how activated Müller cells may contribute to RGC apoptosis through P2X7 receptors were investigated. Either intravitreal injection of (S)-3,5-dihydroxyphenylglycine (DHPG), a group I metabotropic glutamate receptor (mGluR I) agonist, in normal rat retinas, or DHPG treatment of purified cultured rat retinal Müller cells induced an increase in glial fibrillary acidic protein (GFAP) expression, indicative of Müller cell gliosis...
October 6, 2016: Experimental Eye Research
https://www.readbyqxmd.com/read/27650481/theta-burst-stimulation-induced-ltp-differences-and-similarities-between-the-dorsal-and-ventral-ca1-hippocampal-synapses
#20
Stylianos Kouvaros, Costas Papatheodoropoulos
The hippocampal synapses display a conspicuous ability for long-term plasticity, which is thought to contribute to learning and memory. Previous research has shown that long-term potentiation (LTP) greatly differs between the dorsal (DH) and ventral (VH) CA1 hippocampal synapses when induced by high-frequency stimulation. In this study, using rat hippocampal slices and more physiologically relevant activity patterns based on the frequency of the theta rhythm (i.e., theta-burst stimulation, TBS) we found that the DH compared with the VH displayed a higher ability for induction and stability of NMDA receptor-dependent LTP of the field excitatory postsynaptic potential...
December 2016: Hippocampus
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