• Proceedings of the Korean Society of Applied Pharmacology
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• 1996.04a
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• pp.214-214
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• 1996

Intraperitoneal injection of morphine (5 mg/kg) in mice every other day for 8 days produced conditioned place preference (CPP). CPP effects were evaluated by assessing the difference in time spent in the drug-paired compartment and the saline-paired compartment of the place conditioning apparatus. The injection of a non-competitive NMDA antagonist, MK-801 (0.05 and 0.1 mg/kg, i.p.), prior to and during morphine treatment in mice Inhibited morphine-induced CPP. The development of postsynaptic dopamine (DA) receptor supersensitivity in mice displaying a morphine-induced CPP was evidenced by the enhanced response in ambulatory activity to the DA agonist, apomorphine (2 mg/kg). MK-801 inhibited that development of postsynaptic DA receptor supersensitivity MK-801 also inhibited apomorphine-induced climbing behavior, suggesting that MK-801 Inhibits dopaminergic activation mediated via the NMDA receptor.

• The Korean Journal of Physiology and Pharmacology
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• v.2 no.3
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• pp.297-305
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• 1998

This study used in vivo intracellular recording in rat hippocampus to evaluate the effect of lidocaine and MK-801 on the membrane properties and the synaptic responses of individual neurons to electrical stimulation of the commissural pathway. Cells in control group typically fired in a tonic discharge mode with an average firing frequency of $2.4{\pm}0.9$ Hz. Neuron in MK-801 treated group (0.2 mg/kg, i.p.) had an average input resistance of $3.28{\pm}5.7\;M{\Omega}$ and a membrane time constant of $7.4{\pm}1.8$ ms. These neurons exhibited $2.4{\pm}0.2$ ms spike durations, which were similar to the average spike duration recorded in the neurons of the control group. Slightly less than half of these neurons were firing spontaneously with an average discharge rate of $2.4{\pm}1.1$ Hz. The average peak amplitude of the AHP following the spikes in these groups was $7.4{\pm}0.6$ mV with respect to the resting membrane potential. Cells in MK-801 and lidocaine treated group (5 mg/kg, i.c.v.) had an average input resistance of $3.45{\pm}6.0\;M{\Omega}$ and an average time constant of $8.0{\pm}1.4$ ms. The cells were firing spontaneously at an average discharge rate of $0.6{\pm}0.4$ Hz. Upon depolarization of the membrane by 0.8 nA for 400 ms, all of the tested cells exhibited accommodation of spike discharge. The most common synaptic response contained an EPSP followed by early-IPSP and late-IPSP. Analysis of the voltage dependence revealed that the early-IPSP and late-IPSP were putative $Cl^--and\;K^+-dependent$, respectively. Systemic injection of the NMDA receptor blocker, MK-801, did not block synaptic responses to the stimulation of the commissural pathway. No significant modifications of EPSP, early-IPSP, or late-IPSP components were detected in the MK-801 and/or lidocaine treated group. These results suggest that MK-801 and lidocaine manifest their CNS effects through firing pattern of hippocampal pyramidal cells and neural network pattern by changing the synaptic efficacy and cellular membrane properties.

• Journal of Physiology & Pathology in Korean Medicine
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• v.24 no.6
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• pp.983-988
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• 2010

The present study aims to investigate a possible mechanism of electroacupuncture (EA) in the spinal dorsal horn that may underlie N-methyl-D-aspartate (NMDA) receptor-associated extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) signaling pathways. The hot plate latency of the ipsilateral hindpaw of EA-treated rats was significantly decreased compared with complete Freund's adjuvant (CFA)-injected ones. The expressions of NR1 and NR2B subuint mRNA of NMDA receptor in the whole L4-5 segments are decreased by CFA treatment, but NR2B subunit was significantly recovered by EA treatment. When we detected the expression of ERK, there were no significant difference between normal and CFA-treated rats with EA or NMDA receptor antagonist MK801. But phosphorylated ERK expressions were markedly induced by CFA, but these inductions were significantly modulated by EA treatment. Although hosphorylation of ERK was also arrested by MK801, these inductions of CFA-injected rats was markedly inhibited only by co-treatment with EA and MK801. Phosphorylated cAMP response element-binding protein (CREB), ERK-related transcriptional factor, showed a significant increase in CFA-treated rats and this increase was slightly inhibited by EA and MK801 treatments. But immunoreaction for phosphorylated CREB were significantly increased by CFA treatment in the superficial laminae of the dorsal horn and these inductions were significantly arrested by co-treatment of EA and MK801. Consequently, the hyperalgesia induced by CFA are associated NMDA receptor and EA and MK801 may showed anti-hyperalgesia via same mechanism for inhibition of ERK and CREB phosphorylation in the dorsal horn.

• Biomolecules & Therapeutics
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• v.4 no.2
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• pp.196-201
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• 1996

The N-methyl-D-aspartate (NMDA) receptor-ion channel complex is activated by the simultaneous presence of L-glutamate and glycine, allowing the binding of MK-801 to the phencyclidine (PCP) site of the receptor. The $[^3H]$MK-801 binding assay system was established for determination of pharmacological functions of test compounds acting at the glycine site of the receptor. The binding in the presence of 0.1 $\mu$M L-glutamate was increased by an agonist (glycine) in a dose-dependent fashion, while decreased by either partial agonist (R-(+)-HA-966) or antagonist (5,7-dichlorokynurenic acid: 5,7-DCKA). To distinguish partial agonism from antagonism, various concentrations of 7-chlorokynurenic acid (7-CKA) were added in the assay to eliminate the interference of the endogenous glycine present in the membrane preparations. The bindings in the presence of L-glutamate (0.1$\muM$) and 7-CKA (1, 5, or 10$\muM$) were increased by R-(+)-HA-966. Being a weak partial agonist, the extent of potentiation was much less than that by the agonist. These binding profiles were clearly distinguishable from those by the antagonist, 5,7-DCKA, which exhibited no intrinsic activity. The binding assays established in the present study are a useful system to classify ligands acting at the glycine site of the NMDA receptor by their pharmacological functions.

• The Korean Journal of Physiology and Pharmacology
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• v.9 no.3
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• pp.179-186
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• 2005

Whole bee venom (WBV) and its major component, melittin, have been reported to induce long-lasting spontaneous flinchings and hyperalgesia. The current study was designed to elucidate the peripheral and spinal mechanisms of N-methyl-D-aspartate (NMDA) and non-NMDA receptors by which intraplantar (i.pl.) injection of WBV and melittin induced nociceptive responses. Changes in mechanical threshold and flinching behaviors were measured after the injection of WBV (0.04 mg or 0.1 mg/paw) and melittin (0.02 mg or 0.05 mg/paw) into the mid-plantar area of a rat hindpaw. MK-801 and CNQX (6-cyano-7-nitroquinoxaline-2,3-dione disodium) were administered intrathecally (i.t. $10{\mu}g$) or i.pl.($15{\mu}g$) 15 min before or i.t. 60 min after i.pl. WBV and melittin injection. Intrathecal pre- and postadministration of MK-801 and CNQX significantly attenuated the ability of high dose WBV and melittin to reduce paw withdrawal threshold (PWT). In the rat injected with low dose, but not high dose, of WBV and melittin, i.pl. injection of MK-801 effectively suppressed the decrease of PWTs only at the later time-points, but the inhibitory effect of CNQX (i.pl.) was significant at all time-point after the injection of low dose melittin. High dose WBV- and melittin-induced spontaneous flinchings were significantly suppressed by i.t. administration of MK-801 and CNQX, and low dose WBV- and melittin-induced flinchings were significantly reduced only by intraplantarly administered CNQX, but not by MK-801. These experimental flinchings suggest that spinal, and partial peripheral mechanisms of NMDA and non-NMDA receptors are involved in the development and maintenance of WBV- and melittin-induced nociceptive responses.

• The Korean Journal of Physiology and Pharmacology
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• v.9 no.1
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• pp.17-22
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• 2005

We examined whether the abnormal EEG state by NMDA receptor blocker MK-801 can be reversed by typical and atypical antipsychotics differentially by comparing their spectral profiles after drug treatment in rats. The spectral profiles produced by typical antipsychotics chlorpromazine (5 mg/kg, i.p.) and haloperidol (0.5 mg/kg, i.p.) were differ from that by atypical antipsychotic clozapine (5 mg/kg, i.p.) in the rats treated with or without MK-801 treatment (0.2 mg/kg, i.p.) which produce behavioral abnormalities like hyperlocomotion and stereotypy. The dissimilarity between the states produced by antipsychotics and the control state was examined with the distance of the location of the canonical variables calculated by stepwise discriminant analysis with the relative band powers as input variables. Although clozapine produced more different state from normal state than typical antipsychotics, clozapine could reverse the abnormal schizophrenic state induced by MK-801 to the state closer to the normal state than the typical antipsychotics. The results suggest that atypical anesthetic can reverse the abnormal schizophrenic state with negative symptom to the normal state better than typical antipsychotic. The results indicate that the multivariate discriminant analysis using the spectral parameters can help differentiate the antipsychotics with different actions.

• International Journal of Oral Biology
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• v.34 no.2
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• pp.97-103
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• 2009

L-trans-pyrrolidine-2,4-dicarboxylate (PDC) is a potent inhibitor of glutamate transporters. In our current study, we investigated whether the neuronal death induced by PDC involves mechanisms other than excitotoxicity in mixed mouse cortical cultures. Cortical cultures at 13-14 days in vitro were used and cell death was assessed by measuring the lactate dehydrogenase efflux into bathing media. Glutamate and PDC both induced neuronal death in a concentration-dependent manner but the neurotoxic effects of glutamate were found to be more potent than those of PDC. Treatment with 10, 100 and 200 ${\mu}$M PDC equally potentiated 50 ${\mu}$M glutamate-induced neuronal death. The neuronal death induced by 75 ${\mu}$M glutamate was almost abolished by treatment with the NMDA antagonists, MK-801 and AP-5, but was unaffected by NBQX (an AMPA antagonist), trolox (antioxidant), BDNF or ZVAD-FMK (a pan-caspase inhibitor). However, the neuronal death induced by 200 ${\mu}$M PDC was partially but significantly attenuated by single treatments with MK-801, AP-5, trolox, BDNF or ZVAD-FMK but not NBQX. Combined treatments with MK-801 plus trolox, MK-801 plus ZVAD-FMK or MK-801 plus BDNF almost abolished neuronal death, whereas combined treatments with trolox plus ZVADFMK, trolox plus BDNF or ZVAD-FMK plus BDNF did not enhance the inhibitory action of any single treatment with these drugs. These results demonstrate that the neuronal death induced by PDC involves not only in the excitotoxicity induced by the accumulation of glutamate but also the oxidative stress induced by free radical generation. This suggests that apoptotic neuronal death plays a role in PDCinduced oxidative neuronal injury.

• The Korea Journal of Herbology
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• v.20 no.2
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• pp.115-125
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• 2005

Objectives : Polygalae Radix (PR) from Polygalae tenuifolia (Polygalaceae) has been clinically used as a sedative, anti-inflammatory, and anti-bacterial agent. To extend pharmacological effects of PR in the central nervous system (CNS) on the basis of its CNS protective effect, the present study was conducted to identify the effect of PR, whether it shows the neuroprotective action against excitatory neurotoxicity. Methods : To identify the protective effect of PR to excitatory neuro-toxic agent, the present study was focused on the PR effect on cell death, that was caused by applying NMDA to nerve cell, elevation of $(Ca^{2+})_i$, releasement of glutamate, and ROS generation. Result : 1. PR methanol extract, at the concentration range of 0.05 to 5 g/ml, significantly inhibited NMDA (1 mM)-induced neuronal cell death as well as MK-801 (non competitive NMDA antagonist). 2. PR methanol extract $(0.5\;{\mu}g/ml)$ inhibited NMDA (1 mM)-induced elevation of cytosolic calcium concentration $[Ca^{2+}]_i$. NMDA application in the presence of MK-801 $(10\;{\mu}M)$ failed to produce the increase of $[Ca^{2+}]_i$ through all the measurement time. 3. PR methanol extract $(0.5\;{\mu}g/ml)$ inhibited the NMDA-induced elevation of glutamate release. Also, MK-801 showed similar protective effects. 4. PR methanol extract $(0.5\;{\mu}g/ml)$ inhibited the NMDA-induced elevation of ROS generation. Also, MK-801 showed similar protective effects. Conclusion : The present study provides the availability of PR to exert its protective effect on the neuronal cell death in various neurodegenerative pathophysiological conditions.

• Biomolecules & Therapeutics
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• v.4 no.2
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• pp.167-173
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• 1996

This study was undertaken to evaluate a behavior-electroencephalogram (EEG) pattern relationship in pilocarpine- and kainic acid-induced convulsions of rats. Also we intended to examine the effect of a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801, and diazepam on the pilocarpine-induced behavioral and electrical seizures in rats. The electrical activities at frontal and hippocampal areas and behavior activities were measured in freely moving rats. At the beginning of the experiments, the rats displayed an exploratory behavior. This awake and moving phase with a low amplitude, irregular, 4-10 Hz wave was followed by a still phase. Pilocarpine (400 mg/kg, i.p.) and kainic acid (0.5 mg/kg, i.c.v.) induced tonic and clonic seizures. The pilocarpine-induced change in electrical activities exhibited a weak correlation with behavioral convulsion at all stages. The amplitude and duration of the electrical response were not linear with the degree of behavioral score. An application of MK-801 (dizocilpine, 7.5 mg/kg) did not affect the amplitudes of the convulsant-induced electrical activities, though the same dose of this drug caused the deformation of the electrical pattern. There was no effect of MK-801 on the behavioral and electrical activities as expected. Diazepam (1 mg/kg) did not affect the amplitude of the electrical activities induced by pilocarpine but changed the pattern of these activities. Our study shows that there is no linear relationship between degree of behavior and amplitude of electrical activities of convulsants. This may indicate that the NMDA receptor stimulation can be processed by the neocortical or hippocampal network in a different way between behavioral and electrical activities.

• The Korean Journal of Physiology and Pharmacology
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• v.1 no.2
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• pp.117-125
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• 1997

The N-methyl-D-aspartate (NMDA) receptor-mediated glutamatergic neurotransmission is involved in synaptic plasticity, developmental processes, learning and memory and many neuropathological disorders including age-related diseases. In the present study, regulation of the NMDA receptor properties by various ligands was investigated using $[^3H]MK-801$ binding studies in the synaptic membranes of young and aged rat forebrains. The binding in the presence of glutamate and glycine increased dramatically with growth between 1 and 6 weeks old, and thereafter declined gradually with aging. Glutamate, glycine or spermine respectively increased the binding with growth. Glutamate maintained the binding during aging, while glycine or spermine significantly decreased the binding in the aged brain. The maximum stimulation by glycine varied depending on the ages of brains. Greater sensitivity to glycine was observed at 1 week and 3 months and the sensitivity was significantly reduced in the aged brain. In contrast, spermine showed similar stimulation patterns in young and aged rats. These results indicated that the functional properties of the NMDA receptor-ion channel complex in young and aged rat forebrains are differentially regulated by agonists, and the reduction of the receptor function with normal aging may be, in some degree, due to the reduction of the receptor sensitivity to glycine.