NMDA receptor activation mediates glutamate and aspartate release from rat striatum: prevention by MK-801

The present study was designed to identify possible signaling pathways, which may play a role in prevention of neuronal apoptosis in the sexually dimorphic nucleus of the preoptic area (SDN-POA) after physiological activation of the N-methyl-D-aspartate (NMDA) receptor. Gene response to the blockage of the NMDA receptor by an antagonist (dizocilpine hydrogen maleate; MK-801) was screened after suppression subtractive hybridization (SSH). The results showed that dfferential screening after SSH detected the presence of some neurotrophic genes (RNA binding motif protein 3 (RBM3), α-tubulin) as well as apoptosis-related genes (Bcl-2, cytochrome oxidase subunit II, cytochrome oxidase subunit III) in the SDN-POA of male rats, which were down-regulated by blocking the NMDA receptor. The RT-PCR products of the aforementioned genes in MK-801-treated males were significantly less than that in untreated males. In particular, the expression of Bcl-2 mRNA, including Bcl-2 protein, in male rats were significantly suppressed by MK-801 treatment. Moreover, the binding activity of nuclear factor κB (NFκB) was significantly higher in male rats than in females, but significantly diminished by blocking the NMDA receptor with MK-801 in male rats. No significant difference in cAMP response element-binding protein (CREB) binding activity was observed among untreated male, MK-801-treated male, untreated female and MK-801-treated female groups. These results suggest that genes regulated by NMDA receptor activation might participate in neuronal growth and/or anti-apoptosis, and support an important signaling pathway of NFκB activation and its target gene, Bcl-2, in preventing neuronal apoptosis in the SDN-POA of male rats during sexual development.

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Spinal NMDA receptor activation is necessary for de novo, but not the maintenance of, A2a receptor-mediated phrenic motor facilitation

Journal of Applied Physiology ◽

10.1152/japplphysiol.00183.2009 ◽

2009 ◽

Vol 107 (1) ◽

pp. 217-223 ◽

Cited By ~ 1

Author(s):

F. J. Golder

Keyword(s):

Nmda Receptor ◽

Phrenic Nerve ◽

De Novo ◽

Receptor Activation ◽

Nerve Activity ◽

Mk 801 ◽

Phrenic Nerve Activity ◽

Cgs 21680 ◽

A2a Receptor ◽

Nmda Receptor Activation

Adenosine 2a (A2a) receptor agonists elicit persistent increases in phrenic nerve activity by transactivating the neurotrophin receptor, TrkB, near phrenic motoneurons. Our working model proposes that A2a receptor-mediated TrkB receptor activation strengthens glutamatergic synapses onto phrenic motoneurons. Activation of glutamate N-methyl d-aspartate (NMDA) receptors has been implicated in other models of phrenic motor plasticity. Thus we hypothesized that NMDA receptor activation also would contribute to A2a receptor-mediated phrenic motor facilitation. Adult male Sprague-Dawley rats were anesthetized with urethane, mechanically ventilated, neuromuscularly paralyzed, and bilaterally vagotomized. The A2a receptor agonist CGS-21680 and the NMDA receptor-channel blocker MK-801 were administered intrathecally over the C4 spinal segment. Phrenic nerve activity was recorded before, during, and after drug administration. MK-801 (concentration range 0.1, 1.0, 10.0, and 100 μM) was administered 30 min before CGS-21680 (50 μM). MK-801 dose-dependently blocked A2a receptor-mediated phrenic motor facilitation. When administered at 60 min post-CGS-21680, MK-801 prevented further increases in phrenic nerve activity compared with the CGS-21680 alone (CGS-21680 alone at 120 min: 114 ± 19%; CGS-21680 and MK-801 at 60 min post-CGS-21680: 61 ± 11%, above baseline, P < 0.05) but did not return phrenic motor output to baseline values. Our data suggest that NMDA receptor activation is necessary for de novo A2a receptor-mediated phrenic motor facilitation and that the maintenance of preexisting phrenic motor facilitation does not involve NMDA receptor-dependent mechanisms.

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Neuroprotective effects of MK-801 in vivo: selectivity and evidence for delayed degeneration mediated by NMDA receptor activation

Journal of Neuroscience ◽

10.1523/jneurosci.08-12-04745.1988 ◽

1988 ◽

Vol 8 (12) ◽

pp. 4745-4754 ◽

Cited By ~ 184

Author(s):

AC Foster ◽

R Gill ◽

GN Woodruff

Keyword(s):

Nmda Receptor ◽

Receptor Activation ◽

Neuroprotective Effects ◽

Mk 801 ◽

Nmda Receptor Activation

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123Iodo-MK-801: A spect agent for imaging the pattern and extent of glutamate (NMDA) receptor activation in Alzheimer's disease

Journal of Psychiatric Research ◽

10.1016/s0022-3956(97)00031-9 ◽

1997 ◽

Vol 31 (6) ◽

pp. 605-619 ◽

Cited By ~ 25

Author(s):

Derek R.P. Brown ◽

David J. Wyper ◽

Jonathan Owens ◽

James Patterson ◽

R. Ciara Kelly ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Nmda Receptor ◽

Receptor Activation ◽

Mk 801 ◽

Nmda Receptor Activation

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NF-κB induction during in vivo hypoxia in dorsocaudal brain stem of rat: effect of MK-801 andl-NAME

Journal of Applied Physiology ◽

10.1152/jappl.1998.85.1.372 ◽

1998 ◽

Vol 85 (1) ◽

pp. 372-376 ◽

Cited By ~ 18

Author(s):

Evelyne Gozal ◽

Narong Simakajornboon ◽

David Gozal

Keyword(s):

Nmda Receptor ◽

Brain Stem ◽

Receptor Activation ◽

Hypoxic Ventilatory Response ◽

Mk 801 ◽

Oxide Synthase ◽

Nmda Receptor Channel ◽

Nmda Receptor Activation ◽

Receptor Channel

In the nucleus of the solitary tract, NMDA receptors are critical for the hypoxic ventilatory response while neuronal nitric oxide synthase (NOS) modulates the late component of this response. Nuclear factor (NF)-κB is a ubiquitous transcription factor that increases the expression of multiple stress-activated genes. We sought to examine temporal changes in expression of NF-κB within the dorsocaudal brain stem of conscious rats after exposures to 10% O2. Time-dependent increases in NF-κB occurred with hypoxia and peaked at 60 min. Pretreatment with the N-methyl-d-aspartate (NMDA)-receptor channel antagonist dizocilpine maleate (MK-801) markedly attenuated NF-κB complexes during hypoxia. In contrast, after NOS inhibition with N G-nitro-l-arginine methyl ester (l-NAME), although NF-κB was diminished in normoxia, increased NF-κB expression still occurred with hypoxia. Increased phosphorylation of the NF-κB regulatory unit [inhibitory (I)κB] was detected by immunoblotting and also peaked at 60 min. Phosphorylation of Iκ-B during hypoxia was attenuated by MK-801 but not byl-NAME. Thus NMDA-receptor activation in the dorsocaudal brain stem during hypoxia elicits in NF-κB activity marked enhancements that are unaffected after NOS blockade.

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Phrenic and sympathetic nerve responses to glutamergic blockade during normoxia and hypoxia

Journal of Applied Physiology ◽

10.1152/jappl.1993.74.4.1954 ◽

1993 ◽

Vol 74 (4) ◽

pp. 1954-1963 ◽

Cited By ~ 11

Author(s):

L. O. Chae ◽

J. E. Melton ◽

J. A. Neubauer ◽

N. H. Edelman

Keyword(s):

Nmda Receptor ◽

Sympathetic Nerve ◽

Sympathetic Activity ◽

Receptor Activation ◽

Severe Hypoxia ◽

Extracellular Glutamate ◽

Mk 801 ◽

Before And After ◽

Cervical Sympathetic ◽

Nmda Receptor Activation

Because hypoxia increases brain extracellular glutamate levels, we hypothesized that gasping and increased sympathetic activity during severe hypoxia result from glutamergic excitation. To test this hypothesis, we exposed anesthetized paralyzed vagotomized glomectomized cats to hypoxia before and after N-methyl-D-aspartate (NMDA) glutamergic blockade (MK-801, 1 mg/kg iv) or non-NMDA blockade (NBQX, 3 mg/kg iv) while monitoring phrenic neurogram (PN) and inspiratory-synchronous (ISSN) and tonic (TSN) activity in cervical sympathetic neurogram (SN). Before hypoxia, MK-801 caused apneusis and reduced PN and ISSN amplitude by 38 and 84%, respectively, but TSN activity was unaffected. During hypoxia, MK-801 had no effect on PN gasping or TSN activity but reduced ISSN amplitude during gasping. Before hypoxia, NBQX reduced PN and ISSN amplitude by 54 and 60%, respectively but did not affect inspiratory timing or TSN activity. Gasping activity in PN and ISSN and TSN activity during hypoxia were unaffected by NBQX. We conclude that 1) ionotropic glutamergic receptor activation is important for eupneic phrenic patterning but is not involved in genesis of gasping, 2) NMDA receptor activation is involved in integration of respiratory and sympathetic activity, and 3) changes in TSN activity are independent of ionotropic glutamergic receptor activation.

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