Thiopental Inhibits Increases in [Ca2+]iInduced by Membrane Depolarization, NMDA Receptor Activation, and Ischemia in Rat Hippocampal and Cortical Slices 

1998 ◽  
Vol 89 (2) ◽  
pp. 456-466 ◽  
Author(s):  
Ren-Zhi Zhan ◽  
Naoshi Fujiwara ◽  
Hiroshi Endoh ◽  
Tomohiro Yamakura ◽  
Kiichiro Taga ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Nmda Receptors ◽  
Hippocampal Slices ◽  
Receptor Activation ◽  
Membrane Depolarization ◽  
In Vitro Ischemia ◽  
High K ◽  
Nmda Receptor Activation ◽  
Cortical Slices

Background This study examined the effects of thiopental on intracellular calcium ([Ca2+]i) changes induced by membrane depolarization, N-methyl-D-aspartate (NMDA) receptor activation, and ischemia. Methods Experiments were performed in brain slices prepared from Wistar rats. [Ca2+]i measurements were taken on the CA1 pyramidal cell layer of the hippocampus or layers II to III of the somatosensory cortex using the fura-2 fluorescence technique. Membrane depolarization and NMDA receptor activation were induced by exposing slices to 60 mM K+ and 100 microM NMDA, respectively. In vitro ischemia was induced by superfusing slices with glucose-free Krebs solution equilibrated with 95% nitrogen and 5% carbon dioxide. Thiopental was applied 5 min before application of high K+ and NMDA, or before in vitro ischemia. Results Ischemia for 15 min produced a characteristic [Ca2+]i increase in both hippocampal and cortical slices. Thiopental prolonged the latency to the appearance of the [Ca2+]i plateau and reduced the magnitudes of increase in [Ca2+]i 8, 10, and 15 min after the onset of ischemia. Thiopental also suppressed the high K+- and NMDA-induced [Ca2+]i increases. The NMDA-induced [Ca2+]i increases were attenuated to a greater extent in cortical slices than were those in hippocampal slices. The inhibition of thiopental on the 200-microM NMDA-mediated [Ca2+]i response was confirmed in cultured cortical neurons. Conclusions The results indicate that thiopental attenuates ischemia-induced [Ca2+]i increases in the hippocampus and cortex in vitro, probably because of its inhibition of both voltage-gated calcium channels and NMDA receptors. The regionally different inhibition of thiopental on NMDA receptors may relate to its region-specific action against ischemia.

Intrathecal Amitriptyline Acts as an N-Methyl-D-Aspartate Receptor Antagonist in the Presence of Inflammatory Hyperalgesia in Rats

1995 ◽  
Vol 83 (5) ◽  
pp. 1046-1054 ◽  
Author(s):  
James C. Eisenach ◽  
G. F. Gebhart
Keyword(s):  
Nmda Receptor ◽  
Tricyclic Antidepressants ◽  
Hippocampal Slices ◽  
Receptor Activation ◽  
Affinity Binding ◽  
Inflammatory Hyperalgesia ◽  
High Affinity ◽  
Aspartate Receptor ◽  
Nmda Receptor Activation

Abstract Background Amitriptyline and other tricyclic antidepressants exhibit high affinity binding to N-methyl-D-aspartate (NMDA) receptors in vitro and inhibit NMDA receptor activation-induced neuroplasticity in hippocampal slices. Because spinal NMDA receptor activation is believed to be central to generation and maintenance of hyperalgesic pain, the purpose of this study was to test whether intrathecal amitriptyline reduced inflammation-induced hyperalgesia in the rat.

The effect of varying stimulus intensity on NMDA-receptor activity in cat visual cortex

1990 ◽  
Vol 64 (5) ◽  
pp. 1413-1428 ◽  
Author(s):  
K. Fox ◽  
H. Sato ◽  
N. Daw
Keyword(s):  
Visual Cortex ◽  
Nmda Receptor ◽  
Nmda Receptors ◽  
Receptor Activation ◽  
Visual Response ◽  
Background Luminance ◽  
Stimulus Contrast ◽  
Cat Visual Cortex ◽  
Low Levels ◽  
Nmda Receptor Activation

1. A study was made of the relative contribution of N-methyl-D-aspartate (NMDA) and non-NMDA receptors to the visual responses of cells in different layers of the cat visual cortex at different levels of excitatory drive (which was varied by altering the stimulus contrast). 2. Receptive fields were mapped for 121 cells in area 17 of cat cortex. Cells were characterized to determine the optimal visual stimulus, the brightness of which was then varied relative to background luminance to construct a contrast-response (C-R) curve for each cell. Curves were made during control conditions and during application of agonists (NMDA and quisqualate) and/or antagonists [(D)-2-amino-5-phosphonovaleric acid (D-APV) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX)] to examine the excitatory amino acid components of the visual response. 3. Threshold responses were obtained with stimuli between 1/60 and 1.8 X background luminance. The cell response, measured by firing rate, was linearly related to stimulus contrast over 1-2 decades and saturated at higher contrasts. 4. Application of APV reduced the slope of the linear portion of the C-R curve for cells located in layers II and III (average reduction, 59% of control). APV did not decrease the threshold to stimulation. The "just suprathreshold" responses to stimulation were reduced by the same proportion as the saturation responses for individual cells. The principal effect was therefore to reduce the gain of the C-R curve in these layers. 5. Application of APV reduced the spontaneous activity of cells located in layers IV, V, and VI with little if any effect on the gain of the C-R curve. This suggests a tonic background level of NMDA-receptor activation in these layers, which is not directly related to the visual response. 6. Low levels of NMDA increased the gain of the C-R curve in layers II/III and V/VI. On the other hand, low levels of quisqualate increased the overall level of firing without affecting the gain of the C-R curve. NMDA did not increase the gain of the curve in layer IV. 7. These experiments show that visual stimuli that produce just suprathreshold responses activate NMDA receptors. The degree of activation is proportionally the same for small responses and large responses for an individual cell. Rather than finding a threshold for NMDA-receptor activation, a continuous range of NMDA-receptor influence was observed over the entire response range.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Enhanced NMDA receptor-mediated intracellular calcium signaling in magnocellular neurosecretory neurons in heart failure rats

2013 ◽  
Vol 305 (4) ◽  
pp. R414-R422 ◽  
Author(s):  
Javier E. Stern ◽  
Evgeniy S. Potapenko
Keyword(s):  
Heart Failure ◽  
Nmda Receptor ◽  
Nmda Receptors ◽  
Neuronal Activity ◽  
Receptor Activation ◽  
Membrane Depolarization ◽  
Neurosecretory Cells ◽  
Firing Activity ◽  
Nmda Current ◽  
Intracellular Ca

An enhanced glutamate excitatory function within the hypothalamic supraoptic and paraventricluar nuclei is known to contribute to increased neurosecretory and presympathetic neuronal activity, and hence, neurohumoral activation, during heart failure (HF). Still, the precise mechanisms underlying enhanced glutamate-driven neuronal activity in HF remain to be elucidated. Here, we performed simultaneous electrophysiology and fast confocal Ca2+ imaging to determine whether altered N-methyl-d-aspartate (NMDA) receptor-mediated changes in intracellular Ca2+ levels (NMDA-ΔCa2+) occurred in hypothalamic magnocellular neurosecretory cells (MNCs) in HF rats. We found that activation of NMDA receptors resulted in a larger ΔCa2+ in MNCs from HF when compared with sham rats. The enhanced NMDA-ΔCa2+ was neither dependent on the magnitude of the NMDA-mediated current (voltage clamp) nor on the degree of membrane depolarization or firing activity evoked by NMDA (current clamp). Differently from NMDA receptor activation, firing activity evoked by direct membrane depolarization resulted in similar changes in intracellular Ca2+ in sham and HF rats. Taken together, our results support a relatively selective alteration of intracellular Ca2+ homeostasis and signaling following activation of NMDA receptors in MNCs during HF. The downstream functional consequences of such altered ΔCa2+ signaling during HF are discussed.

scholarly journals NMDA Receptor Activation by Spontaneous Glutamatergic Neurotransmission

2009 ◽  
Vol 101 (5) ◽  
pp. 2290-2296 ◽  
Author(s):  
Felipe Espinosa ◽  
Ege T. Kavalali
Keyword(s):  
Nmda Receptor ◽  
Nmda Receptors ◽  
Ampa Receptor ◽  
Cortical Neurons ◽  
Glutamate Release ◽  
Receptor Activation ◽  
Receptor Activity ◽  
Resting Membrane Potential ◽  
Nmda Current ◽  
Nmda Receptor Activation

Under physiological conditions N-methyl-d-aspartate (NMDA) receptor activation requires coincidence of presynaptic glutamate release and postsynaptic depolarization due to the voltage-dependent block of these receptors by extracellular Mg2+. Therefore spontaneous neurotransmission in the absence of action potential firing is not expected to lead to significant NMDA receptor activation. Here we tested this assumption in layer IV neurons in neocortex at their resting membrane potential (approximately −67 mV). In long-duration stable recordings, we averaged a large number of miniature excitatory postsynaptic currents (mEPSCs, >100) before or after application of dl-2 amino 5-phosphonovaleric acid, a specific blocker of NMDA receptors. The difference between the two mEPSC waveforms showed that the NMDA current component comprises ∼20% of the charge transfer during an average mEPSC detected at rest. Importantly, the contribution of the NMDA component was markedly enhanced at membrane potentials expected for the depolarized up states (approximately −50 mV) that cortical neurons show during slow oscillations in vivo. In addition, partial block of the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor component of the mEPSCs did not cause a significant reduction in the NMDA component, indicating that potential AMPA receptor-driven local depolarizations did not drive NMDA receptor activity at rest. Collectively these results indicate that NMDA receptors significantly contribute to signaling at rest in the absence of dendritic depolarizations or concomitant AMPA receptor activity.

scholarly journals NMDA Reduces Tau Phosphorylation in Rat Hippocampal Slices by Targeting NR2A Receptors, GSK3β, and PKC Activities

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Audrée De Montigny ◽  
Ismaël Elhiri ◽  
Julie Allyson ◽  
Michel Cyr ◽  
Guy Massicotte
Keyword(s):  
Nmda Receptor ◽  
Molecular Mechanisms ◽  
Glycogen Synthase ◽  
Hippocampal Slices ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Receptor Activation ◽  
Tau Phosphorylation ◽  
Cell Death Mechanisms ◽  
Nmda Receptor Activation

The molecular mechanisms that regulate Tau phosphorylation are complex and currently incompletely understood. In the present study, pharmacological inhibitors were deployed to investigate potential processes by which the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors modulates Tau phosphorylation in rat hippocampal slices. Our results demonstrated that Tau phosphorylation at Ser199-202 residues was decreased in NMDA-treated hippocampal slices, an effect that was not reproduced at Ser262 and Ser404 epitopes. NMDA-induced reduction of Tau phosphorylation at Ser199-202 was further promoted when NR2A-containing receptors were pharmacologically isolated and were completely abrogated by the NR2A receptor antagonist NVP-AAM077. Compared with nontreated slices, we observed that NMDA receptor activation was reflected in high Ser9 and low Tyr216 phosphorylation of glycogen synthase kinase-3 beta (GSK3β), suggesting that NMDA receptor activation might diminish Tau phosphorylation via a pathway involving GSK3βinhibition. Accordingly, we found that GSK3βinactivation by a protein kinase C- (PKC-) dependent mechanism is involved in the NMDA-induced reduction of Tau phosphorylation at Ser199-202 epitopes. Taken together, these data indicate that NR2A receptor activation may be important in limiting Tau phosphorylation by a PKC/GSK3βpathway and strengthen the idea that these receptors might act as an important molecular device counteracting neuronal cell death mechanisms in various pathological conditions.

Pharmacological properties of excitatory amino acid induced changes in extracellular calcium concentration in rat hippocampal slices

1992 ◽  
Vol 70 (S1) ◽  
pp. S194-S205 ◽  
Author(s):  
J. Arens ◽  
J. Stabel ◽  
U. Heinemann
Keyword(s):  
Nmda Receptor ◽  
Extracellular Space ◽  
Excitatory Amino Acid ◽  
Hippocampal Slices ◽  
Receptor Activation ◽  
Similar Action ◽  
Homocysteic Acid ◽  
Glutamate Receptor Agonists ◽  
Kinetics Of ◽  
Nmda Receptor Activation

We have studied extracellular ionic changes induced by iontophoretic application of excitatory amino acids in rat hippocampal slices. In contrast to kinetics of changes in [Ca2+]o, kinetics of changes in [K+]o, [Na+]o, [Cl−]o as well as in extracellular space size were comparable for different glutamate receptor agonists. Thus, α-amino-3-hydroxy-5-methylisoxazolepropionic acid (AMPA), quisqualate (quis), and kainate caused reductions in [Ca2+]o followed by an increase of [Ca2+]o above baseline, whereas glutamate, aspartate, N-methyl-D-aspartate (NMDA), and DL-homocysteic acid caused only reductions in [Ca2+]o. After blocking the NMDA receptors with ketamine and 2-amino-5-phosphonovaleric acid (2-APV), glutamate-induced decreases in [Ca2+]o were followed by an overshoot. Reductions of the transmembrane Na+gradient by lowering [Na+]o, blocking of the Na+–K+ ATPase by lowering [K+]o, and application of ouabain blocked the overshoots after quis application, whereas vanadate, a blocker of the Ca2+–Mg2+ ATPase, had no effects. Lithium enhanced the reductions in [Ca2+]o and blocked the overshoots. Amiloride also reduced the overshoots. All organic Ca2+ entry blockers diminished reductions of [Ca2+]o but increased the overshoots. Inorganic Ca2+ antagonists had variable effects. Ni2+ had similar effects as the organic Ca2+ entry blockers while Cd2+ reduced both the [Ca2+]o decreases as well as the subsequent overshoots. Co2+ had initially a similar action as Ni2+. With prolonged application, [Ca2+]o decreases became augmented and, during wash, overshoots could no longer be elicited. We suggest that the overshoots in [Ca2+]o are due to a combined effect of extracellular space shrinkage and activation of the Na+/Ca2+ exchanger. This would imply that NMDA receptor activation blocks extrusion of Ca2+ from the cells. We tested the hypothesis that quis-induced intracellular Ca2+ release and extrusion of Ca2+ from the cells contributed to the overshoots. Dantrolene was without effect on the quis-induced signals, while ryanodine reduced the overshoots. Caffeine on the other hand diminished the [Ca2+]o decreases with no effects on the overshoots. To test for possible second messenger routes by which NMDA receptor activation might slow Ca2+ extrusion from cells, we investigated the effects of arachidonic acid and N-monomethyl-D-arginine on the quis-induced signals. While these agents reduced decreases in [Ca2+]o, they had no clear effects on the overshoots. Thus a possible route by which NMDA receptor activation may affect Ca2+ extrusion from cells has still to be elucidated.Key words: glutamate, quisqualate, N-methyl-D-aspartate, Ca2+ concentration, hippocampus, rat.

Retinogeniculate EPSPs recorded intracellularly in the ferret lateral geniculate nucleus in vitro: Role of NMDA receptors

1992 ◽  
Vol 8 (6) ◽  
pp. 545-555 ◽  
Author(s):  
Manuel Esguerra ◽  
Young H. Kwon ◽  
Mriganka Sur
Keyword(s):  
Membrane Potential ◽  
Nmda Receptor ◽  
Nmda Receptors ◽  
Lateral Geniculate Nucleus ◽  
Excitatory Amino Acid ◽  
Optic Tract ◽  
Receptor Activation ◽  
Lateral Geniculate

AbstractWe used an in vitro preparation of the ferret lateral geniculate nucleus (LGN) to examine the role of the NMDA class of excitatory amino acid (EAA) receptors in retinogeniculate transmission. Intracellular recordings revealed that blockade of NMDA receptors both shortened the time course and reduced the amplitude of fast and slow components of excitatory postsynaptic potentials (EPSPs) evoked by optic tract stimulation. The amplitude and width of the EPSPs mediated by NMDA receptors increased as membrane potential was depolarized towards spike threshold. Individual LGN cells were influenced to varying extents by blockade of NMDA receptors; NMDA and non-NMDA receptor blockade together attenuated severely the entire retinogeniculate EPSP. The dependence of all components of retinogeniculate EPSPs (and action potentials) on NMDA receptor activation supports the hypothesis that the NMDA receptor participates in fast (<10 ms) synaptic events underlying conventional retinogeniculate transmission. The voltage dependence of the NMDA receptor-gated conductance suggests strongly that the transmission of retinal information through the LGN is subject to modulation by extraretinal inputs that affect the membrane potential of LGN neurons.

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