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Nmda modulation

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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
#1
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/29297151/liver-x-receptor-agonist-gw3965-regulates-synaptic-function-upon-amyloid-beta-exposure-in-hippocampal-neurons
#2
C Báez-Becerra, F Filipello, A Sandoval-Hernández, H Arboleda, G Arboleda
Alzheimer's disease (AD) is a devastating neurodegenerative disease characterized by beta-amyloid (Aβ) accumulation and neurofibrillary tangles formation in the brain which are associated to synaptic deficits and dementia. Liver X receptor (LXR) agonists have been demonstrated to revert of pathologic and cognitive defects in murine models of AD through the regulation of Apolipoprotein E, ATP-Binding Cassette A1 (ABCA1), by dampening neuroinflammation and also by reducing the levels of amyloid-β (Aβ) accumulation in the brain...
January 3, 2018: Neurotoxicity Research
https://www.readbyqxmd.com/read/29295931/somatostatin-and-parvalbumin-inhibitory-synapses-onto-hippocampal-pyramidal-neurons-are-regulated-by-distinct-mechanisms
#3
Meryl E Horn, Roger A Nicoll
Excitation-inhibition balance is critical for optimal brain function, yet the mechanisms underlying the tuning of inhibition from different populations of inhibitory neurons are unclear. Here, we found evidence for two distinct pathways through which excitatory neurons cell-autonomously modulate inhibitory synapses. Synapses from parvalbumin-expressing interneurons onto hippocampal pyramidal neurons are regulated by neuronal firing, signaling through L-type calcium channels. Synapses from somatostatin-expressing interneurons are regulated by NMDA receptors, signaling through R-type calcium channels...
January 16, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29277417/reprint-of-contrasting-effects-of-vortioxetine-and-paroxetine-on-pineal-gland-biochemistry-in-a-tryptophan-depletion-model-of-depression-in-female-rats
#4
M Franklin, N Hlavacova, Y Li, I Bermudez, A Csanova, C Sanchez, D Jezova
We studied the effects of the multi-modal antidepressant, vortioxetine and the SSRI, paroxetine on pineal melatonin and monoamine synthesis in a sub-chronic tryptophan (TRP) depletion model of depression based on a low TRP diet. Female Sprague-Dawley rats were randomised to groups a) control, b) low TRP diet, c) low TRP diet+paroxetine and d) low TRP diet+vortioxetine. Vortioxetine was administered via the diet (0.76mg/kg of food weight) and paroxetine via drinking water (10mg/kg/day) for 14days. Both drugs resulted in SERT occupancies >90%...
December 23, 2017: Progress in Neuro-psychopharmacology & Biological Psychiatry
https://www.readbyqxmd.com/read/29276476/critical-points-and-traveling-wave-in-locomotion-experimental-evidence-and-some-theoretical-considerations
#5
REVIEW
Philippe Saltiel, Andrea d'Avella, Matthew C Tresch, Kuno Wyler, Emilio Bizzi
The central pattern generator (CPG) architecture for rhythm generation remains partly elusive. We compare cat and frog locomotion results, where the component unrelated to pattern formation appears as a temporal grid, and traveling wave respectively. Frog spinal cord microstimulation with N-methyl-D-Aspartate (NMDA), a CPG activator, produced a limited set of force directions, sometimes tonic, but more often alternating between directions similar to the tonic forces. The tonic forces were topographically organized, and sites evoking rhythms with different force subsets were located close to the constituent tonic force regions...
2017: Frontiers in Neural Circuits
https://www.readbyqxmd.com/read/29273965/effects-of-%C3%AE-7-nicotinic-receptor-activation-on-cell-survival-in-rat-organotypic-hippocampal-slice-cultures
#6
Denise F Happ, R Andrew Tasker
Glutamatergic signaling via N-methyl-D-aspartate receptors (NMDARs) is important for physiological functioning, but can also induce cell death via excitotoxic mechanisms in many neuropathological diseases, such as stroke. Altering the cellular response to excitotoxic insults by modulating the downstream effects of NMDAR activation represents a promising therapeutic approach. For example, α7 nicotinic acetylcholine receptors (α7 nAChRs) signaling has been shown to be able to change NMDA-induced neurotoxicity in some models...
December 22, 2017: Neurotoxicity Research
https://www.readbyqxmd.com/read/29262336/hippocampus-and-entorhinal-cortex-recruit-cholinergic-and-nmda-receptors-separately-to-generate-hippocampal-theta-oscillations
#7
Zhenglin Gu, Georgia M Alexander, Serena M Dudek, Jerrel L Yakel
Although much progress has been made in understanding type II theta rhythm generation under urethane anesthesia, less is known about the mechanisms underlying type I theta generation during active exploration. To better understand the contributions of cholinergic and NMDA receptor activation to type I theta generation, we recorded hippocampal theta oscillations from freely moving mice with local infusion of cholinergic or NMDA receptor antagonists to either the hippocampus or the entorhinal cortex (EC). We found that cholinergic receptors in the hippocampus, but not the EC, and NMDA receptors in the EC, but not the hippocampus, are critical for open-field theta generation and Y-maze performance...
December 19, 2017: Cell Reports
https://www.readbyqxmd.com/read/29258835/the-glun1-glun2b-nmda-receptor-and-metabotropic-glutamate-receptor-1-negative-allosteric-modulator-has-enhanced-neuroprotection-in-a-rat-subarachnoid-hemorrhage-model
#8
Zongyong Zhang, Junke Liu, Cundong Fan, Leilei Mao, Rongxia Xie, Suyun Wang, Mingfeng Yang, Hui Yuan, Xiaoyi Yang, Jingyi Sun, Jian Wang, Jiming Kong, Siluo Huang, Baoliang Sun
Excessive glutamate in cerebrospinal fluid after subarachnoid hemorrhage (SAH) causes excitotoxic damage through calcium overloading and a subsequent apoptotic cascade. GluN1/GluN2B containing N-methyl-Daspartate (NMDA) receptor and metabotropic glutamate receptor 1 (mGluR1) can play a leading role in glutamate-mediated excitotoxicity. Here we report that Ifenprodil (100μM), a negative allosteric modulator (NAM) of GluN1/GluN2B NMDA receptors, and JNJ16259685 (10μM), a NAM of mGluR1, have an additive efficacy against glutamate (100μM)-induced Ca2+ release and cell apoptosis in primary cortical, hippocampal, and cerebellar granule neurons...
December 16, 2017: Experimental Neurology
https://www.readbyqxmd.com/read/29242355/the-bioactive-protein-ligand-conformation-of-glun2c-selective-positive-allosteric-modulators-bound-to-the-nmda-receptor
#9
Thomas Maxwell Kaiser, Steven A Kell, Hirofumi Kusumoto, Gil Shaulsky, Subhrajit Bhattacharya, Matthew P Epplin, Katie L Strong, Eric J Miller, Bryan D Cox, David S Menaldino, Dennis C Liotta, Stephen F Traynelis, Pieter Buys Burger
NMDA receptors are ligand-gated, cation-selective channels that mediate a slow component of excitatory synaptic transmission. Subunit-selective positive allosteric modulators of NMDA receptor function have therapeutically-relevant effects on multiple processes in the brain. A series of pyrrolidinones, such as PYD-106, that selectively potentiate NMDA receptors that contain the GluN2C subunit have structural determinants of activity that reside between the GluN2C amino terminal domain and the GluN2C agonist binding domain, suggesting a unique site of action...
December 14, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/29241709/regulation-of-pleiotrophin-and-fyn-in-the-striatum-of-rats-undergoing-l-dopa-induced-dyskinesia
#10
Gimena Gomez, Mariano D Saborido, María A Bernardi, Oscar S Gershanik, Irene R Taravini, Juan E Ferrario
L-DOPA is the gold standard pharmacological therapy for symptomatic treatment of Parkinson's disease (PD), however, its long-term use is associated with the emergence of L-DOPA-induced dyskinesia (LID). Understanding the underlying molecular mechanisms of LID is crucial for the development of newer and more effective therapeutic approaches. In previous publications, we have shown that Pleiotrophin (PTN), a developmentally regulated trophic factor, is up-regulated by L-DOPA in the striatum of dopamine denervated rats...
December 11, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/29239974/additive-and-subadditive-antiallodynic-interactions-between-%C3%AE-opioid-agonists-and-n-methyl-d-aspartate-antagonists-in-male-rhesus-monkeys
#11
Jeremy C Cornelissen, Floyd F Steele, Kenner C Rice, Katherine L Nicholson, Matthew L Banks
μ-Opioid agonists are clinically effective analgesics, but also produce undesirable effects such as sedation and abuse potential that limit their clinical utility. Glutamatergic systems also modulate nociception and N-methyl D-aspartate (NMDA) receptor antagonists have been proposed as one useful adjunct to enhance the therapeutic effects and/or attenuate the undesirable effects of μ-opioid agonists. Whether NMDA antagonists enhance the antiallodynic effects of μ-agonists in preclinical models of thermal hypersensitivity (i...
December 12, 2017: Behavioural Pharmacology
https://www.readbyqxmd.com/read/29224722/nrap-1-is-a-presynaptically-released-nmda-receptor-auxiliary-protein-that-modifies-synaptic-strength
#12
Ning Lei, Jerry E Mellem, Penelope J Brockie, David M Madsen, Andres V Maricq
NMDA receptors (NMDARs) are a subtype of postsynaptic ionotropic glutamate receptors that function as molecular coincidence detectors, have critical roles in models of learning, and are associated with a variety of neurological and psychiatric disorders. To date, no auxiliary proteins that modify NMDARs have been identified. Here, we report the identification of NRAP-1, an auxiliary protein in C. elegans that modulates NMDAR function. NMDAR-mediated currents were eliminated in nrap-1 mutants, as was NMDA-dependent behavior...
December 20, 2017: Neuron
https://www.readbyqxmd.com/read/29223589/breakthroughs-in-neuroactive-steroid-drug-discovery
#13
REVIEW
Maria-Jesus Blanco, Daniel La, Quinn Coughlin, Caitlin A Newman, Andrew M Griffin, Boyd L Harrison, Francesco G Salituro
Endogenous and synthetic neuroactive steroids (NASs) or neurosteroids are effective modulators of multiple signaling pathways including receptors for the γ-aminobutyric acid A (GABAA) and glutamate, in particular N-methyl-d-aspartate (NMDA). These receptors are the major inhibitory and excitatory neurotransmitters in the central nervous system (CNS), and there is growing evidence suggesting that dysregulation of neurosteroid production plays a role in numerous neurological disorders. The significant unmet medical need for treatment of CNS disorders has increased the interest for these types of compounds...
December 2, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29203848/bdnf-release-and-signaling-are-required-for-the-antidepressant-actions-of-glyx-13
#14
T Kato, M V Fogaça, S Deyama, X-Y Li, K Fukumoto, R S Duman
Conventional antidepressant medications, which act on monoaminergic systems, display significant limitations, including a time lag of weeks to months and low rates of therapeutic efficacy. GLYX-13 is a novel glutamatergic compound that acts as an N-methyl-d-aspartate (NMDA) modulator with glycine-like partial agonist properties; like the NMDA receptor antagonist ketamine GLYX-13 produces rapid antidepressant actions in depressed patients and in preclinical rodent models. However, the mechanisms underlying the antidepressant actions of GLYX-13 have not been characterized...
December 5, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/29195907/presynaptic-%C3%AE-2-adrenoceptor-modulates-glutamatergic-synaptic-transmission-in-rat-nucleus-accumbens-in-vitro
#15
Shi-Yu Peng, Bin Li, Kang Xi, Jian-Jun Wang, Jing-Ning Zhu
The nucleus accumbens (NAc), integrating information from the prefrontal cortex and limbic structures, plays a critical role in reward and emotion regulation. Previous studies have reported that the NAc shell receives direct noradrenergic projections, and activation of α2-adrenoceptor (α2-AR) in the NAc shell decreases the fear or anxiety level of rats. However, the underlying mechanism is still little known. Intriguingly, glutamatergic neurotransmission in the NAc shell is closely related to reward and emotion...
November 30, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/29194360/the-modulation-of-nmda-and-ampa-kainate-receptors-by-tocotrienol-rich-fraction-and-%C3%AE-tocopherol-in-glutamate-induced-injury-of-primary-astrocytes
#16
Zahra Abedi, Huzwah Khaza'ai, Sharmili Vidyadaran, Mohd Sokhini Abd Mutalib
Astrocytes are known as structural and supporting cells in the central nervous system (CNS). Glutamate, as a main excitatory amino acid neurotransmitter in the mammalian central nervous system, can be excitotoxic, playing a key role in many chronic neurodegenerative diseases. The aim of the current study was to elucidate the potential of vitamin E in protecting glutamate-injured primary astrocytes. Hence, primary astrocytes were isolated from mixed glial cells of C57BL/6 mice by applying the EasySep® Mouse CD11b Positive Selection Kit, cultured in Dulbecco's modified Eagle medium (DMEM) and supplemented with special nutrients...
December 1, 2017: Biomedicines
https://www.readbyqxmd.com/read/29191857/evaluation-of-11c-me-nb1-as-a-potential-pet-radioligand-for-measuring-glun2b-containing-nmda-receptors-drug-occupancy-and-receptor-crosstalk
#17
Stefanie D Krämer, Thomas Betzel, Linjing Mu, Ahmed Haider, Adrienne Herde Müller, Anna K Boninsegni, Claudia Keller, Marina Szermerski, Roger Schibli, Bernhard Wünsch, Simon M Ametamey
Clinical and preclinical research with modulators binding to the NMDA receptor GluN2B N-terminal domain (NTD) aim for the treatment of various neurological diseases. However, the interpretation of the results is hampered by the lack of a suitable NMDA PET tracer for assessing the receptor occupancy of candidate drugs. We have developed [11C]Me-NB1 as a PET tracer for imaging GluN1/GluN2B-containing NMDA receptors and used it to investigate in rats the dose-dependent receptor occupancy of eliprodil, a GluN2B NTD modulator...
November 30, 2017: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
https://www.readbyqxmd.com/read/29185346/novel-sigma-1-receptor-antagonists-from-opioids-to-small-molecules-what-is-new
#18
Emanuela Arena, Maria Dichiara, Giuseppe Floresta, Carmela Parenti, Agostino Marrazzo, Valeria Pittalà, Emanuele Amata, Orazio Prezzavento
Sigma-1 (σ1) receptor has been identified as a chaperone protein that interacts with other proteins, such as N-methyl-D-aspartate (NMDA) and opioid receptors, modulating their activity. σ1 receptor antagonists have been developed to obtain useful compounds for the treatment of psychoses, pain, drug abuse and cancer. Some interesting compounds such as E-5842 (5) and MS-377 (24), haloperidol and piperazine derivatives, respectively, were endowed with high affinity for σ1 receptors (Ki σ1 = 4 and 73 nM; Ki σ2 = 220 and 6900, respectively)...
November 29, 2017: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/29176858/sepsis-induced-selective-loss-of-nmda-receptors-modulates-hippocampal-neuropathology-in-surviving-septic-mice
#19
Shuibing Zhang, Xueqin Wang, Sha Ai, Wen Ouyang, Yuan Le, Jianbin Tong
BACKGROUND: Sepsis-induced neuroinflammation plays an important role in sepsis-related brain dysfunction. However, the molecules that are targeted during neuroinflammation resulting from sepsis-induced brain dysfunction remain unclear. Herein, we tried to investigate the expression and roles of NMDA receptor subunits during sepsis-related brain dysfunction. METHODS: Sepsis was induced by cecal ligation and perforation (CLP) or by a single intraperitoneal injection of lipopolysaccharide (LPS, 8 mg/kg) in C57BL/6J mice...
2017: PloS One
https://www.readbyqxmd.com/read/29171155/interactions-of-2s-6s-2r-6r-hydroxynorketamine-a-secondary-metabolite-of-r-s-ketamine-with-morphine
#20
Tuomas O Lilius, Hanna Viisanen, Viljami Jokinen, Mikko Niemi, Eija A Kalso, Pekka V Rauhala
Ketamine and its primary metabolite norketamine attenuate morphine tolerance by antagonising N-methyl-D-aspartate (NMDA) receptors. Ketamine is extensively metabolised to several other metabolites. The major secondary metabolite (2S,6S;2R,6R)-hydroxynorketamine (6-hydroxynorketamine) is not an NMDA antagonist. However, it may modulate nociception through negative allosteric modulation of α7 nicotinic acetylcholine receptors. We studied whether 6-hydroxynorketamine could affect nociception or the effects of morphine in acute or chronic administration settings...
November 24, 2017: Basic & Clinical Pharmacology & Toxicology
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