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https://www.readbyqxmd.com/read/28294132/5-ht2c-agonists-modulate-schizophrenia-like-behaviors-in-mice
#1
Vladimir M Pogorelov, Ramona M Rodriguiz, Jianjun Cheng, Mei Huang, Claire M Schmerberg, Herbert Y Meltzer, Bryan L Roth, Alan P Kozikowski, William C Wetsel
All FDA-approved antipsychotic drugs (APDs) target primarily dopamine D2 or serotonin (5-HT2A) receptors, or both; however, these medications are not universally effective, they may produce undesirable side-effects, and provide only partial amelioration of negative and cognitive symptoms. The heterogeneity of pharmacological responses in schizophrenic patients suggests additional drug-targets may be effective in improving aspects of this syndrome. Recent evidence suggests that 5-HT2C receptors may be a promising target for schizophrenia since their activation reduces mesolimbic nigrostriatal dopamine release (which conveys antipsychotic action), they are expressed almost exclusively in CNS, and have weight-loss promoting capabilities...
March 15, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28288901/trigeminal-brainstem-modulation-of-persistent-orbicularis-oculi-muscle-activity-in-a-rat-model-of-dry-eye
#2
Mostafeezur Rahman, Kazunari Shiozaki, Keiichiro Okamoto, Randall Thompson, David A Bereiter
Altered corneal reflex activity is a common feature of dry eye disease (DE). Trigeminal sensory nerves supply the ocular surface and terminate at the trigeminal interpolaris/caudalis (ViVc) transition and spinomedullary (VcC1) regions. Although both regions contribute to corneal reflexes, their role under dry eye conditions is not well defined. This study assessed the influence of local inhibitory and excitatory amino acid neurotransmission at the ViVc transition and VcC1 regions on hypertonic saline (HS) evoked orbicularis oculi muscle activity (OOemg) in urethane-anesthetized male rats after exorbital gland removal (DE)...
March 10, 2017: Neuroscience
https://www.readbyqxmd.com/read/28275719/a-negative-allosteric-modulator-for-%C3%AE-5-subunit-containing-gaba-receptors-exerts-a-rapid-and-persistent-antidepressant-like-action-without-the-side-effects-of-the-nmda-receptor-antagonist-ketamine-in-mice
#3
Panos Zanos, Mackenzie E Nelson, Jaclyn N Highland, Samuel R Krimmel, Polymnia Georgiou, Todd D Gould, Scott M Thompson
New antidepressant pharmacotherapies that provide rapid relief of depressive symptoms are needed. The NMDA receptor antagonist ketamine exerts rapid antidepressant actions in depressed patients but also side effects that complicate its clinical utility. Ketamine promotes excitatory synaptic strength, likely by producing high-frequency correlated activity in mood-relevant regions of the forebrain. Negative allosteric modulators of GABA-A receptors containing α5 subunits (α5 GABA-NAMs) should also promote high-frequency correlated electroencephalogram (EEG) activity and should therefore exert rapid antidepressant responses...
January 2017: ENeuro
https://www.readbyqxmd.com/read/28271508/alterations-in-expression-of-cat-315-epitope-of-perineuronal-nets-during-normal-ageing-and-its-modulation-by-an-open-channel-nmda-receptor-blocker-memantine
#4
Jun Yamada, Tomohiro Ohgomori, Shozo Jinno
The perineuronal net (PNN), a specialized aggregate of the extracellular matrix, is involved in neuroprotection against oxidative stress, which is now recognized as a major contributor to age-related decline in brain functions. In this study, we investigated the age-related molecular changes of PNNs using monoclonal antibody Cat-315, which recognizes human natural killer-1 (HNK-1) glycan on aggrecan-based PNNs. Western blot analysis showed that the expression levels of Cat-315 epitope in the hippocampus were higher in middle-aged (MA, 12-month-old) mice than in young adult (YA, 2-month-old) mice...
March 8, 2017: Journal of Comparative Neurology
https://www.readbyqxmd.com/read/28270746/effects-of-repeated-ethanol-exposures-on-nmda-receptor-expression-and-locomotor-sensitization-in-mice-expressing-ethanol-resistant-nmda-receptors
#5
Carolina R den Hartog, Meghin Gilstrap, Bethany Eaton, Daniel H Lench, Patrick J Mulholland, Gregg E Homanics, John J Woodward
Evidence from a large number of preclinical studies suggests that chronic exposure to drugs of abuse, such as psychostimulants or ethanol induces changes in glutamatergic transmission in key brain areas associated with reward and control of behavior. These changes include alterations in the expression of ionotropic glutamate receptors including N-methyl-D-aspartate receptors (NMDAR) that are important for regulating neuronal activity and synaptic plasticity. NMDA receptors are inhibited by ethanol and reductions in NMDA-mediated signaling are thought to trigger homestatic responses that limit ethanol's effects on glutamatergic transmission...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/28269783/modulating-the-balance-of-synaptic-and-extrasynaptic-nmda-receptors-shows-positive-effects-against-amyloid-%C3%AE-induced-neurotoxicity
#6
Yan Huang, Wei Shen, Jie Su, Bin Cheng, Dong Li, Gang Liu, Wen-Xia Zhou, Yong-Xiang Zhang
Alzheimer's disease (AD) patients suffer a disturbance in the balance between synaptic (GluN2A, mediating the protective pathway) and extrasynaptic NMDA receptors (NMDARs) (GluN2B, mediating the excitotoxic pathway), and, therefore, restoring the balance of GluN2A and GluN2B should be beneficial for AD. In this study, the GluN2B-selective antagonist, ifenprodil, and the non-selective NMDAR agonist, NMDA, had little effect on amyloid-β (Aβ)-induced long-term potentiation deficits. Enhancing the activity of GluN2A had a protective effect against Aβ, and specific activation of GluN2A and inhibition of GluN2B showed a better protective effect...
March 2, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28265898/spinal-ccl2-promotes-central-sensitization-long-term-potentiation-and-inflammatory-pain-via-ccr2-further-insights-into-molecular-synaptic-and-cellular-mechanisms
#7
Rou-Gang Xie, Yong-Jing Gao, Chul-Kyu Park, Ning Lu, Ceng Luo, Wen-Ting Wang, Sheng-Xi Wu, Ru-Rong Ji
Mounting evidence supports an important role of chemokines, produced by spinal cord astrocytes, in promoting central sensitization and chronic pain. In particular, CCL2 (C-C motif chemokine ligand 2) has been shown to enhance N-methyl-D-aspartate (NMDA)-induced currents in spinal outer lamina II (IIo) neurons. However, the exact molecular, synaptic, and cellular mechanisms by which CCL2 modulates central sensitization are still unclear. We found that spinal injection of the CCR2 antagonist RS504393 attenuated CCL2- and inflammation-induced hyperalgesia...
March 6, 2017: Neuroscience Bulletin
https://www.readbyqxmd.com/read/28264448/paeoniflorin-attenuates-cerebral-ischemia-induced-injury-by-regulating-ca-2-camkii-creb-signaling-pathway
#8
Yuqin Zhang, Lifei Qiao, Wen Xu, Xiaoying Wang, Huang Li, Wei Xu, Kedan Chu, Yu Lin
Paeoniflorin (PF) is an active ingredient of Paeoniae Radix which possesses the neuroprotective effect. However, so far, the neuroprotective mechanism of PF has still not been fully uncovered. The Ca(2+)/Ca(2+)/calmodulin-dependent protein kinase II (CaMKII)/cAMP response element-binding (CREB) signaling pathway plays an important role in the intracellular signal transduction pathway involved in cell proliferation, cell survival, inflammation and metabolism. Herein, the neuroprotective roles of PF in the models of middle cerebral artery occlusion (MCAO) followed by reperfusion in rats and N-methyl-d-aspartic acid (NMDA)-induced excitotoxicity in primary hippocampal neurons were investigated...
February 27, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28255683/modulation-of-n-methyl-d-aspartate-receptors-nmdar-bcl-2-and-c-fos-gene-expressions-on-exposure-to-individual-and-mixtures-of-low-concentration-metals-in-zebrafish-danio-rerio
#9
Samuel Jerry Cobbina, Guanghua Mao, Ting Zhao, Hai Xu, Zhen Zhang, Hongyang Liu, Yanmin Zou, Xiangyang Wu, Liuqing Yang
Currently, there is limited information on the toxicity of low concentration of metal mixtures in the environment. Of particular interest is the effect of low levels of metal mixtures on neurodevelopment of aquatic organisms. This study reports the neurological gene expressions after exposing zebrafish embryos to low concentration toxic heavy metals, 120 h post fertilization (hpf). Embryos were exposed to low concentration individual and mixtures of lead (Pb), mercury (Hg), arsenic (As), and cadmium (Cd). Quantitative real-time PCR was used to assess gene expressions...
March 2, 2017: Archives of Environmental Contamination and Toxicology
https://www.readbyqxmd.com/read/28248535/bis-3-tacrine-inhibits-the-sustained-potassium-current-in-cultured-rat-hippocampal-neurons
#10
D Huang, R-J Wen, Y Zhang, Y-W Liu
Bis(3)-tacrine is a dimeric AChE inhibitor derived from tacrine with a potential to treat Alzheimer's disease. It was recently been reported to act as a fast off-rate antagonist of NMDA receptors with moderate affinity. In the present study, we aimed to explore whether bis(3)-tacrine could modulate the function of native sustained potassium current in cultured rat hippocampal neurons using whole-cell patch-clamp technique. We found that bis(3)-tacrine inhibited the amplitude of sustained potassium current in a reversible and concentration-dependent manner, with a potency two orders of magnitude higher than that of tacrine...
February 28, 2017: Physiological Research
https://www.readbyqxmd.com/read/28242877/epilepsy-associated-grin2a-mutations-reduce-nmda-receptor-trafficking-and-agonist-potency-molecular-profiling-and-functional-rescue
#11
L Addis, J K Virdee, L R Vidler, D A Collier, D K Pal, D Ursu
Mutations in the N-methyl-D-aspartate receptor (NMDAR) gene GRIN2A cause epilepsy-aphasia syndrome (EAS), a spectrum of epileptic, cognitive and language disorders. Using bioinformatic and patient data we shortlisted 10 diverse missense mutations for characterisation. We used high-throughput calcium-flux assays and patch clamp recordings of transiently transfected HEK-293 cells for electrophysiological characterization, and Western blotting and confocal imaging to assay expression and surface trafficking. Mutations P79R, C231Y, G483R and M705V caused a significant reduction in glutamate and glycine agonist potency, whilst D731N was non-responsive...
December 2017: Scientific Reports
https://www.readbyqxmd.com/read/28241130/nardostachys-jatamansi-targets-bdnf-trkb-to-alleviate-ketamine-induced-schizophrenia-like-symptoms-in-rats
#12
Anjali Janardhanan, Anjana Sadanand, Arambakkam Janardhanam Vanisree
OBJECTIVE: Schizophrenia, a common neurological disorder appearing in the late teens or early adulthood, is characterized by disorganized thinking, behaviour, and perception of emotions. Aberrant N-methyl-D-aspartate (NMDA) receptor-mediated synaptic plasticity is a major pathological event here due to dysfunction of dopamine and glutamate transmission at NMDA receptors. De-regulated brain-derived neurotrophic factor (BDNF), i.e., its signalling through the tropomyosin receptor kinase B (TrkB) receptor, is a major feature of schizophrenia...
February 28, 2017: Neuropsychobiology
https://www.readbyqxmd.com/read/28228087/beyond-ketamine-new-approaches-to-the-development-of-safer-antidepressants
#13
Shigeyuki Chaki
Ketamine has been reported to exert rapid and sustained antidepressant effects in patients with depression, including patients with treatment-resistant depression. However, ketamine has several drawbacks such as psychotomimetic/dissociative symptoms, abuse potential and neurotoxicity, all of which prevent its routine use in daily clinical practice. Therefore, development of novel agents with fewer safety and usage concerns for the treatment of depression has been actively investigated. From this standpoint, searching for active substances (stereoisomers and metabolites) and agents acting on the N-methyl-D-aspartate (NMDA) receptor have recently gained much attention...
February 20, 2017: Current Neuropharmacology
https://www.readbyqxmd.com/read/28222314/systematic-variation-of-the-benzenesulfonamide-part-of-the-glun2a-selective-nmda-receptor-antagonist-tcn-201
#14
Sebastian L Müller, Julian A Schreiber, Dirk Schepmann, Nathalie Strutz-Seebohm, Guiscard Seebohm, Bernhard Wünsch
GluN2A subunit containing N-methyl-d-aspartate receptors (NMDARs) are highly involved in various physiological processes in the central nervous system, but also in some diseases, such as anxiety, depression and schizophrenia. However, the role of GluN2A subunit containing NMDARs in pathological processes is not exactly elucidated. In order to obtain potent and selective inhibitors of GluN2A subunit containing NMDARs, the selective negative allosteric modulator 2 was systematically modified at the benzenesulfonamide part...
March 31, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28218243/nmda-receptor-dependent-plasticity-in-the-bed-nucleus-of-the-stria-terminalis-triggers-long-term-anxiolysis
#15
Christelle Glangetas, Léma Massi, Giulia R Fois, Marion Jalabert, Delphine Girard, Marco Diana, Keisuke Yonehara, Botond Roska, Chun Xu, Andreas Lüthi, Stéphanie Caille, François Georges
Anxiety is controlled by multiple neuronal circuits that share robust and reciprocal connections with the bed nucleus of the stria terminalis (BNST), a key structure controlling negative emotional states. However, it remains unknown how the BNST integrates diverse inputs to modulate anxiety. In this study, we evaluated the contribution of infralimbic cortex (ILCx) and ventral subiculum/CA1 (vSUB/CA1) inputs in regulating BNST activity at the single-cell level. Using trans-synaptic tracing from single-electroporated neurons and in vivo recordings, we show that vSUB/CA1 stimulation promotes opposite forms of in vivo plasticity at the single-cell level in the anteromedial part of the BNST (amBNST)...
February 20, 2017: Nature Communications
https://www.readbyqxmd.com/read/28204809/ketamine-suppresses-the-substance-p-induced-production-of-il-6-and-il-8-by-human-u373mg-glioblastoma-astrocytoma-cells
#16
Keisuke Yamaguchi, Seiichiro Kumakura, Taisuke Murakami, Akimasa Someya, Eiichi Inada, Isao Nagaoka
The neuropeptide substance P (SP) is an important mediator of neurogenic inflammation within the central and peripheral nervous systems. SP has been shown to induce the expression of pro-inflammatory cytokines implicated in the pathogenesis of several disorders of the human brain via the neurokinin-1 receptor (NK-1R). Ketamine, an intravenous anesthetic agent, functions as a competitive antagonist of the excitatory neurotransmission N-methyl-D‑aspartate (NMDA) receptor, and also antagonizes the NK-1R by interfering with the binding of SP...
March 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28203201/modulation-of-synaptic-plasticity-in-the-cortex-needs-to-understand-all-the-players
#17
REVIEW
Claire N J Meunier, Pascal Chameau, Philippe M Fossier
The prefrontal cortex (PFC) is involved in cognitive tasks such as working memory, decision making, risk assessment and regulation of attention. These functions performed by the PFC are supposed to rely on rhythmic electrical activity generated by neuronal network oscillations determined by a precise balance between excitation and inhibition balance (E/I balance) resulting from the coordinated activities of recurrent excitation and feedback and feedforward inhibition. Functional alterations in PFC functions have been associated with cognitive deficits in several pathologies such as major depression, anxiety and schizophrenia...
2017: Frontiers in Synaptic Neuroscience
https://www.readbyqxmd.com/read/28202572/differential-regulation-of-nmda-receptors-by-d-serine-and-glycine-in-mammalian-spinal-locomotor-networks
#18
David Acton, Gareth Brian Miles
Activation of N-methyl-D-aspartate receptors (NMDARs) requires the binding of a co-agonist, either D-serine or glycine, in addition to glutamate. Changes in occupancy of the co-agonist binding site are proposed to modulate neural networks including those controlling swimming in frog tadpoles. Here, we characterize regulation of the NMDAR co-agonist binding site in mammalian spinal locomotor networks. Blockade of NMDARs by D(-)-2-amino-5-phosphonopentanoic acid (D-APV) or 5,7-dichlorokynurenic acid reduced the frequency and amplitude of pharmacologically induced locomotor-related activity recorded from the ventral roots of spinal-cord preparations from neonatal mice...
February 15, 2017: Journal of Neurophysiology
https://www.readbyqxmd.com/read/28202437/oscillation-patterns-are-enhanced-and-firing-threshold-is-lowered-in-medullary-respiratory-neuron-discharges-by-threshold-doses-of-a-%C3%AE-opioid-receptor-agonist
#19
Peter M Lalley, Steve W Mifflin
μ-Opioid receptors are distributed widely in the brainstem respiratory network, and opioids with selectivity for μ-type receptors slow in-vivo respiratory rhythm in lowest effective doses. Several studies have reported μ-opioid receptor effects on the three-phase rhythm of respiratory neurons, but there are until now no reports of opioid effects on oscillatory activity within respiratory discharges. In this study, effects of the μ-opioid receptor agonist fentanyl on spike train discharge properties of several different types of rhythm-modulating medullary respiratory neuron discharges were analyzed...
February 15, 2017: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
https://www.readbyqxmd.com/read/28198441/pdi-regulates-seizure-activity-via-nmda-receptor-redox-in-rats
#20
Ji Yang Kim, Ah-Rhem Ko, Hye-Won Hyun, Su-Ji Min, Ji-Eun Kim
Redox modulation of cysteine residues is one of the post-translational modifications of N-methyl-D-aspartate receptor (NMDAR). Protein disulfide isomerases (PDI), an endoplasmic reticulum (ER) chaperone, plays a crucial role in catalyzing disulfide bond formation, reduction, and isomerization. In the present study, we found that PDI bound to NMDAR in the normal hippocampus, and that this binding was increased in chronic epileptic rats. In vitro thiol reductase assay revealed that PDI increased the amount of thiols on full-length recombinant NR1 protein...
February 15, 2017: Scientific Reports
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