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Madelyne A Bisby, Kathryn D Baker, Rick Richardson
NMDA receptors (NMDARs) are considered critical for the consolidation of extinction but recent work challenges this assumption. Namely, NMDARs are not required for extinction retention in infant rats as well as when extinction training occurs for a second time (i.e., reextinction) in adult rats. In this study, a possible third instance of NMDAR-independent extinction was tested. Although adolescents typically exhibit impaired extinction retention, rats that are conditioned as juveniles and then given extinction training as adolescents (JuvCond-AdolesExt) have good extinction retention...
April 2018: Learning & Memory
Diego E Pafundo, Takeaki Miyamae, David A Lewis, Guillermo Gonzalez-Burgos
BACKGROUND: Testing hypotheses regarding the role of N-methyl-D-aspartate receptor (NMDAR) hypofunction in schizophrenia requires understanding the mechanisms of NMDAR regulation of prefrontal cortex (PFC) circuit function. NMDAR antagonists are thought to produce pyramidal cell (PC) disinhibition. However, inhibitory parvalbumin-positive basket cells (PVBCs) have modest NMDAR-mediated excitatory drive and thus are unlikely to participate in NMDAR antagonist-mediated disinhibition. Interestingly, recent studies demonstrated that presynaptic NMDARs enhance transmitter release at central synapses...
January 31, 2018: Biological Psychiatry
Jeffrey G Varnes, Hui Xiong, Janet M Forst, Christopher R Holmquist, Glen E Ernst, William Frietze, Bruce Dembofsky, Don W Andisik, William E Palmer, Lindsay Hinkley, Gary B Steelman, Deidre E Wilkins, Gaochao Tian, Gerald Jonak, William M Potts, Xia Wang, Todd A Brugel, Cristóbal Alhambra, Michael W Wood, Chris A Veale, Jeffrey S Albert
A series of isoquinuclidine benzamides as glycine uptake inhibitors for the treatment of schizophrenia are described. Potency, lipophilicity, and intrinsic human microsomal clearance were parameters for optimization. Potency correlated with the nature of the ortho substituents of the benzamide ring, and reductions in lipophilicity could be achieved through heteroatom incorporation in the benzamide and pendant phenyl moieties. Improvements in human CLint were achieved through changes in ring size and the N-alkyl group of the isoquinuclidine itself, with des-alkyl derivatives (40-41, 44) demonstrating the most robust microsomal stability...
February 14, 2018: Bioorganic & Medicinal Chemistry Letters
Nermin Eissa, Nadia Khan, Shreesh K Ojha, Dorota Łazewska, Katarzyna Kieć-Kononowicz, Bassem Sadek
The role of Histamine H3 receptors (H3Rs) in memory, and the prospective of H3R antagonists in pharmacological control of neurodegenerative disorders, e.g., Alzheimer disease (AD) is well-accepted. For that reason, the procognitive effects of the H3R antagonist DL77 on cognitive impairments induced with MK801 were tested in an inhibitory passive avoidance paradigm (PAP) and novel object recognition (NOR) task in adult male rats, using donepezil (DOZ) as a standard drug. Acute systemic pretreatment with DL77 (2...
2018: Frontiers in Neuroscience
Jeong Hwan Oh, Eun-Young Kim, Taek-Jeong Nam
SCOPE: Glutamate-induced excitotoxicity involves in various neurodegenerative disorders. This study aimed to investigate whether a phycoerythrin-derived tryptic peptide of Pyropia yezoensis (PYP) reduces glutamate-induced excitotoxicity and neuronal senescence in primary rat hippocampal neurons. METHODS AND RESULTS: Glutamate exposure (100 μM) decreased cell viability and increased expression of endoplasmic reticulum (ER) stress response protein glucose-regulated protein 78 (GRP78) starting at 60 min following glutamate exposure, which was attenuated by PYP pretreatment (1 μg/mL)...
February 21, 2018: Molecular Nutrition & Food Research
Ya-Nan Wang, Dwight Figueiredo, Xiang-Dong Sun, Zhao-Qi Dong, Wen-Bing Chen, Wan-Peng Cui, Fang Liu, Hong-Sheng Wang, Hai-Wen Li, Heath Robinson, Er-Kang Fei, Bing-Xing Pan, Bao-Ming Li, Wen-Cheng Xiong, Lin Mei
Neuregulin3 (NRG3) is a growth factor of the neuregulin (NRG) family and a risk gene of various severe mental illnesses including schizophrenia, bipolar disorders, and major depression. However, the physiological function of NRG3 remains poorly understood. Here we show that loss of Nrg3 in GFAP-Nrg3 f/f mice increased glutamatergic transmission, but had no effect on GABAergic transmission. These phenotypes were observed in Nex-Nrg3 f/f mice, where Nrg3 was specifically knocked out in pyramidal neurons, indicating that Nrg3 regulates glutamatergic transmission by a cell-autonomous mechanism...
February 20, 2018: Proceedings of the National Academy of Sciences of the United States of America
Tala Khazen, Kuldeep Shrivastava, Reem Jada, Ossama Abu Hatoum, Mouna Maroun
Metaplasticity is the dynamic regulation of the ability to induce activity-dependent synaptic plasticity and is governed by the prior history of the synapses. Previous reports by others and us have shown that behavioral stress induces a form of emotional metaplasticity that affects the ability to induce LTP in the subiculum-medial prefrontal cortex pathway, which depends on NMDA receptors (NMDAr). However, studies addressing the effects of stress on LTP and metaplasticity have mainly focused on the adult animal...
February 10, 2018: Neurobiology of Learning and Memory
X N Sun, H L Wang, G Qiao, J Tao, C Liu, X H Hao
Objective: To investigate the protection effects of the activation of NMDAR1(NMDA receptor 1)/ERK1/2 signal pathway on visual cortex nerve cells induced by levodopa in amblyopia rats. Methods: SD rats of SPF grade, were randomly divided into for groups of 9, group A. Control, B. MD group, C. L-levodopa(20 mg·kg(-1))+MD group, D. H-levodopa (80 mg·kg(-1))+MD group, E. H-levodopa+MD+MK801 group, F. H-levodopa+MD+PD98059 group, G. MD+MK801 group, H. MD+PD98059 group, I. MD+DMSO group. Amblyopia rats were made by suture of the right eye...
December 11, 2017: [Zhonghua Yan Ke za Zhi] Chinese Journal of Ophthalmology
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
A Ahnaou, H Huysmans, T Van de Casteele, W H I M Drinkenburg
Oscillatory activity in the gamma frequency range is a critical mechanism, which integrates neural networks within and across brain structures during cognitive processes. In schizophrenia, abnormalities in high gamma oscillations are ubiquitous and most likely reflect dysfunction in neuronal networks. In conscious rats, disturbed network oscillations associated with positive symptoms and cognitive deficits were modeled in different cortical areas by the dopaminergic agonist (amphetamine) and the N-methyl-D-aspartate (NMDA) receptor antagonists (PCP and MK801)...
December 18, 2017: Translational Psychiatry
Ching-Huang Lin, Jun-Yen Pan, Jung-Jui Chang, Hsin-Hung Chen, Pei-Wen Cheng, Ching-Jiunn Tseng
The growth factor midkine has been implicated in various biologic and pathologic events. It has been shown that the peripheral influence of midkine on cardiovascular regulation is due to an influence on the renin-angiotensin system. The nucleus tractus solitarii (NTS) is the primary integrative center for cardiovascular control and other autonomic functions in the central nervous system. However, the signaling mechanisms involved in midkine-mediated cardiovascular effects in the NTS remain unclear. In this study, we investigated whether the renin-angiotensin system and/ or N-methyl-D-aspartate (NMDA) receptor-calmodulin-eNOS signaling pathways were both involved in midkine-mediated blood pressure (BP) regulation in the NTS of Wistar-Kyoto rats...
December 15, 2017: Chinese Journal of Physiology
Sang Eon Park, Yuan-Zhe Jin, Byung Rim Park
Orthostatic hypotension (OH) is associated with symptoms including headache, dizziness, and syncope. The incidence of OH increases with age. Attenuation of the vestibulosympathetic reflex (VSR) is also associated with an increased incidence of OH. In order to understand the pathophysiology of OH, we investigated the physiological characteristics of the VSR in the disorder. We applied sodium nitroprusside (SNP) to conscious rats with sinoaortic denervation in order to induce hypotension. Expression of pERK in the intermediolateral cell column (IMC) of the T4~7 thoracic spinal regions, blood epinephrine levels, and blood pressure were evaluated following the administration of glutamate and/or SNP...
November 2017: Korean Journal of Physiology & Pharmacology
Ivan Domith, Renato Socodato, Camila C Portugal, Andressa F Munis, Aline T Duarte-Silva, Roberto Paes-de-Carvalho
Vitamin C (in the reduced form ascorbate or in the oxidized form dehydroascorbate) is implicated in signaling events throughout the central nervous system (CNS). In the retina, a high-affinity transport system for ascorbate has been described and glutamatergic signaling has been reported to control ascorbate release. Here, we investigated the modulatory role played by vitamin C upon glutamate uptake and N-methyl-d-aspartate (NMDA) receptor activation in cultured retinal cells or in intact retinal tissue using biochemical and imaging techniques...
November 21, 2017: Journal of Neurochemistry
Dan Ning, Wei Kevin Zhang, Han Tian, Xiao-Jun Li, Min Liu, Yu-Sang Li, He-Bin Tang
NMDA, a molecule that is capable of producing the loss of retinal ganglia cells (RGCs), has been widely studied; however, the detailed mechanism is not yet clarified. Previously, Wnt/β-catenin signaling has been suggested to be involved in the NMDA-induced retinopathy. In addition, previous investigations in our group demonstrated the presence of a Wnt/β-catenin/COX-2 axis in dorsal root ganglions (DRGs). Therefore, here in this paper, we tested whether there is an association of such axis with NMDA-induced RGC loss...
2017: Journal of Ophthalmology
Su Liu, Yue-Peng Liu, You Lv, Jun-Li Yao, Dong-Mei Yue, Mao-Yin Zhang, Dun-Yi Qi, Gong-Jian Liu
BACKGROUND: Glia cells hyperactivity has been proposed to be responsible for chronic pain, however, the mechanisms remain unclear. IL-18, released from glial cells, has been reported to be involved in neuropathic pain. Here, we investigated the role of IL-18 in bone cancer pain. METHODS: Bone cancer pain was mimicked by injecting Walker-256 mammary gland carcinoma cells into the intramedullary space of the tibia in rats. Expression and location of IL-18 and IL-18 receptor were tested...
October 24, 2017: Journal of Pain: Official Journal of the American Pain Society
Shinobu Yasuo, Ayaka Iwamoto, Sang-Il Lee, Shotaro Ochiai, Rina Hitachi, Satomi Shibata, Nobuo Uotsu, Chie Tarumizu, Sayuri Matsuoka, Mitsuhiro Furuse, Shigekazu Higuchi
Background: The circadian clock is modulated by the timing of ingestion or food composition, but the effects of specific nutrients are poorly understood. Objective: We aimed to identify the amino acids that modulate the circadian clock and reset the light-induced circadian phase in mice and humans. Methods: Male CBA/N mice were orally administered 1 of 20 l-amino acids, and the circadian and light-induced phase shifts of wheel-running activity were analyzed. Antagonists of several neurotransmitter pathways were injected before l-serine administration, and light-induced phase shifts were analyzed...
December 2017: Journal of Nutrition
Barbara Lykke Lind, Sanne Barsballe Jessen, Micael Lønstrup, Charlène Joséphine, Gilles Bonvento, Martin Lauritzen
Cerebral blood flow (CBF) is regulated by the activity of neurons and astrocytes. Understanding how these cells control activity-dependent increases in CBF is crucial to interpreting functional neuroimaging signals. The relative importance of neurons and astrocytes is debated, as are the functional implications of fast Ca(2+) changes in astrocytes versus neurons. Here, we used two-photon microscopy to assess Ca(2+) changes in neuropil, astrocyte processes, and astrocyte end-feet in response to whisker pad stimulation in mice...
October 23, 2017: Glia
Matthias Schoenberger, Frederick A Schroeder, Michael S Placzek, Randall L Carter, Bruce R Rosen, Jacob M Hooker, Christin Y Sander
As one of the major excitatory ion channels in the brain, NMDA receptors have been a leading research target for neuroscientists, physicians, medicinal chemists, and pharmaceutical companies for decades. Molecular imaging of NMDA receptors by means of positron emission tomography (PET) with [(18)F]GE-179 quickly progressed to clinical PET studies, but a thorough understanding of its binding specificity has been missing and has thus limited signal interpretation. Here a preclinical study with [(18)F]GE-179 in rodents and nonhuman primates (NHPs) is presented in an attempt to characterize [(18)F]GE-179 signal specificity...
November 14, 2017: ACS Chemical Neuroscience
Fen Xue, Yun-Chun Chen, Cui-Hong Zhou, Ying Wang, Min Cai, Wen-Jun Yan, Rui Wu, Hua-Ning Wang, Zheng-Wu Peng
Antipsychotic agents have been reported to promote hippocampal neurogenesis and improve cognitive deficits; yet, the molecular mechanisms underlying these actions remain unclear. In the present study, we used a murine model of schizophrenia induced by 5-day intraperitoneal injection with the non-competitive N-methyl-d-aspartate receptor antagonist MK801 (0.3mg/kg/day) to assess cognitive behavioral deficits, changes in Notch signaling, and cellular proliferation in the hippocampus of adult male C57BL/6 mice after 2-week administration of risperidone (Rip, 0...
October 14, 2017: Pharmacology, Biochemistry, and Behavior
Qichao Wu, Yanjun Zhao, Xiangyuan Chen, Minmin Zhu, Changhong Miao
Activated microglia, involved in the occurrence and improvement of sepsis-associated encephalopathy, can induce the expression of pro-inflammatory cytokines and pro-inflammatory enzymes, resulting in inflammation-mediated neuronal cell death. It was reported that propofol could inhibit lipopolysaccharide (LPS)-induced pro-inflammatory cytokines and pro-inflammatory enzymes expression in BV2 and primary microglial cells. However, the underlying mechanism is not well known. In the present study, we investigated whether and how propofol inhibited LPS-induced the expression of pro-inflammatory cytokines and pro-inflammatory enzymes in BV2 cells...
August 17, 2017: Canadian Journal of Physiology and Pharmacology
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