• Toxicological Research
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• v.11 no.1
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• pp.63-68
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• 1995

N-methyl-D-aspartate(NMDA) receptor has been well known as an important mediator of several forms of neural and behavioral plasticity. But different results were reported about the effect of MK-801 or dextromethorphan on opioid dependence. The present studies examined whether NMDA receptor antagonists can alter the opioid dependence and tolerance in rodents. Naloxone precipitated withdrawal symptoms and changes of locomotor activities were observed in MK-801 or dextromethorphan pretreated morphine-dependent rats. Tail-flick assay was used for morphine analgesia and tolerance was found after 4 day's consecutive injections (10 mg/kg, s.c., twice/day) of morphine in mice. Locomotor activity was increased and the withdrawal symptoms were decreased by the pretreatment of MK-801 in morphine-dependent rats. But 0.3 mg/kg i.p. of MK-801 intensified the body weight loss and produced severe ataxia and rotation although some withdrawal signs were attenuated. Morphine induced analgesic tolerance was inhibited by the pretreatment of MK-801 and dextromethorphan. Dextromethorphan was more potent than MK-801 in inhibiting the development of the analgesic tolerance in mice. These results suggest that NMDA system may be involved in opioid withdrawal and analgesic tolerance but appropriate caution should be requested when MK-801 is used in combination with opioid because of untoward neurologic signs.

• Animal cells and systems
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• v.15 no.2
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• pp.115-121
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• 2011

Previous studies have demonstrated that N-methyl-D-aspartate (NMDA) receptors and acetylcholine receptors are related to learning and memory in rat and mice. In this study, we examined the effects of MK-801, a non-competitive NMDA receptor antagonist, on learning and memory in zebrafish using a passive avoidance test. We further tested whether or not nicotine, a nicotinic acetylcholine receptor agonist, and physostigmine, an acetylcholinesterase inhibitor, reverse the effects of MK-801. Crossing time was increased significantly in the training and test sessions for the controls. When 20 ${\mu}M$ MK-801 was administered prior to the training session, the crossing time did not increase in either session. The MK-801-induced learning deficit was rescued by pretreatment with 20 ${\mu}M$ physostigmine, and crossing time was increased in the training and test sessions compared to the MK-801-treated zebrafish. Further, the MK-801-induced learning deficit was prevented by pretreatment with 20 ${\mu}M$ nicotine, and crossing time was increased in the training session but not in the test session. These results show that MK-801 induced a learning deficit in zebrafish that was prevented by pretreatment with nicotine and physostigmine.

• Biomolecules & Therapeutics
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• v.6 no.1
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• pp.25-30
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• 1998

The roles of dopamine(DA) and N-methyl-D-aspartate(NMDA) system in the development and expression of morphine dependence were investigated by monitoring the concentrations of extracellular DA and its metabolites by in vivo microdialysis and simultaneous observation of behavioral changes in morphine dependent rats. Extracellular DA level in caudate putamen of morphine-dependent rat was decreased and the concentrations of its metabolites, dihydroxy phenylacetic acid(DOPAC) and homovanillic acid(HVA), were increased during naloxone-precipitated withdrawal. DA contents were recovered to normal levels by pretreatment of MK-801, a noncompetitive NMDA receptor antagonist, which may explain the mechanism of diminishing effect of MK-801 on withdrawal symptoms in morphine-dependent rats. MK-801(0.3 mg/tg, i.p.) induced the untoward hamful neurological signs such as ataxia and severe rotations, which may be produced by hyperactivation of dopaminergic system. These results suggest that MK-801 may inhibit the expression of mophine dependence by altering the dopamine release.

• Korean Journal of Biological Psychiatry
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• v.4 no.2
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• pp.246-250
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• 1997

Tardive dyskinesia(TD) is a serious side effect of long-term treatment with neuroleptic medications. To investigate if glutamatergic hyperfunction is associated with TD, effect of MK-801 on the prevention and treatment of TD was studied using a rat model, ie, vacuous chewing movements(VCM). When comparing VCM scores of GroupI(haldol decanoate+MK-801) with that of GroupII(haldol decanoate+phosphate buffer saline), late measured VCM scores of former were significantly lower than that of latter, meaning that MK-801 is effective in the prevention of VCM. Furthermore, when MK-801(0.1mg/kg, 0.3mg/kg) is administered to VCM(+) rats(VCM${\geq}$ 7/4min) of GroupII, VCM scores were significantly decreased, meaning that MK-801 is also effective in the treatment of VCM. From the above results, it is suggested that glutamatergic hyperfunction might be involved in the development of TD and MK-801 could be effective in the prevention and treatment of it.

• The Korean Journal of Nuclear Medicine
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• v.29 no.3
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• pp.294-306
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• 1995

There has recently been increasing interest in the use of NMDA receptor antagonists as potential neuroprotective agents for the treatment of ischemic stroke. To evaluate the neuroprotective effect of the selective non-competitive NMDA receptor antagonist MK-801 in focal cerebral ischemia, local cerebral glucose utilization (ICGU) was examined in 15 neuroanatomically discrete regions of the conscious rat brain using the 2-deoxy-D[$^{14}C$] glucose quantitative autoradiographic technique 24 hr after left middle cerebral artery occlusion (MCAO). Animals received MK-801 (5 mg/kg i.v.) or saline vehicle before (20-30 min) or after (30 min) MCAO. Both pretreatment and posttreatment of MK-801 increased occluded/non-occluded ICGU ratio in 7 and 5 of the 15 regions measured, respectively (most notably in cortical structures). Following MK-801 pretreatment, there was evidence of widespread increases in ICGU not only in the non-occluded hemisphere (12 of the 15 areas studied) but also in the occluded hemisphere (13 of the 15 areas studied), while MK-801 postreatment did not significantly increase ICGU both in the normal and occluded hemispheres. These data indicate that MK-801 has a neuroprotective effect in focal cerebral ischemia and demonstrate that MK-801 provides widespread alterations of glucose utilization in conscious animals.

• The Korean Journal of Nuclear Medicine
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• v.35 no.4
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• pp.258-267
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• 2001

Purpose/Methods: Repeated administration of methamphetamine (METH) produces high extracellular levels of dopamine (DA) and subsequent striatal DA terminal damage. The effect of MK-801, a noncompetitive N-methyl-D-aspartate receptor antagonist, on METH-induced changes in DA transporter (DAT) and DA release evoked by an acute METH challenge was evaluated in rodent striatum uslng $[^3H]$]WIN 38,428 ex vivo auto-radiography and in vivo microdialysis. Results: Four injections of METH (10 mg/kg, i.p.), each given 2 h apart, produced 71% decrease in DAT levels in mouse striatum 3 d after administration. Pretreatment with MK-801 (2.5 mg/kg, i.p.) 15 min before each of the four METH injections protected completely against striatal DAT depletions. Four injections of MK-801 alone did not significantly change striatal DAT levels. Striatal DA release evoked by an acute METH challenge (4 mg/kg, i.p.) at 3 d after repeated administration of METH in rats was decreased but significant compared with controls, which was attenuated by repeated pretreatment with MK-801. Also, repeated injections of MK-801 alone attenuated acute METH-induced striatal DA release 3 d after administration. Conclusion: These results suggest that repeated administration of MK-801 may exert a preventive effect against METH-induced DA terminal injury through long-term attenuation of DA release induced by METH and other stimuli.

• Korean Journal of Pharmacognosy
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• v.44 no.2
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• pp.97-103
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• 2013

Schizophrenia is a severe psychiatric disorder and characterized by positive symptom (i.e., delusions, hallucinations), negative symptom (i.e., lack of emotion, social withdrawal), and cognitive impairment. Previously, we reported that the ethanolic extract of Prunella vulgaris var. lilacina attenuated the MK-801-induced schizophrenia-like behaviors such as prepulse inhibition (PPI) deficits and cognitive impairment in mice. The aim of the present study was to investigate whether danshensu isolated from P. vulgaris var. lilacina attenuates MK-801-induced sensorimotor gating dysfunction (PPI deficits), hyperlocomotion, and memory impairment in mice. Acute administration of danshensu (1, 3, or 10 mg/kg) significantly ameliorated the MK-801-induced PPI deficits in the acoustic startle response test. We also observed that the impaired recognition memory induced by MK-801 was attenuated by danshensu (1 mg/kg) in the novel object recognition test. However, danshensu failed to reverse the MK-801-induced hyperlocomotion in the open-field test. Collectively, the present results indicate danshensu would be an active agent for treating neuropsychiatric disorders such as schizophrenia.

• Journal of Korean Neurosurgical Society
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• v.29 no.9
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• pp.1153-1160
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• 2000

Objectives : This study was undertaken to investigate the effect of noncompetitive NMDA receptor blocker, MK801 on motor recovery, SSEP and pathology in spinal cord injured rat. Methods : The effects of MK801 on neuronal function protection, SSEP, and pathology were measured on spinal cord injury rats which were divided into 6 groups according to dose, time of drug delivery and magnitude of injury. Spinal cord injury was made with the magnitude of 25gm-cm and 50gm-cm on 42 rats. BBB locomotor function test was performed to evaluate the motor power recovery in hindlimb for 2 weeks after injury. After motor function test was completed, SSEP was measured. Amplitude and latency of the P1, N1 peak was measured and compared between groups. Finally rats were sacrificed, and pathologic findings including measurement of area of necrotic cord were studied and compared between groups. Results : Motor recovery at 2 weeks was better in MK801 group comparing to saline control group. SSEP at 2 weeks showed no difference in N1, P1 latencies, but significantly greater amplitude in MK801 group, compared to saline control group. On light microscope, there was no specific histologic differences between experimental groups. The cystic necrotic area in coronal plane was measured and compared in each group. The necrotic area was significantly smaller in MK801 1mg/kg group(delivered after injury) than vehicle group. The necrotic area in MK801 5mg/kg group and MK801 1mg/kg group(delivered before injury) was smaller than vehicle group even though it was not statistically significant. Conclusion : From the above result, it is speculated that NMDA blocker, MK801 can improve impaired neuronal function in spinal cord injury.

• Molecular & Cellular Toxicology
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• v.3 no.4
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• pp.282-291
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• 2007

Although the etiology of schizophrenia is known to be linked with the disturbance of glutamatergic and dopaminergic neurotransmission, little is known about the relationship between gene expression and the disease process. To identify genes related to abnormalities in glutamatergic and dopaminergic function, we investigated the effects of olanzapine in the changes of mRNA levels in the animal model of schizophrenia, using a high-density DNA microarray. Olanzapine (3.0 mg/kg, i.p.) significantly reduced hyperlocomotive activities, which was induced by MK-801 (1.0 mg/kg, i.p.). We identified that the expression of 719 genes were significantly altered more than two folds in the prefrontal cortex of the rats treated with MK-801. We selected 15 genes out of them by the changes of the expression pattern in the treatment of Olanzapine and/or MK801 for the further confirmation in RT-PCR. The administration of MK-801 increased the expression of 7 genes (NOS3, Hspb1, Hspa1a, CRH, Serpine1, Igfbp6, Snf1lk) and decreased the expression of 1 gene (Aldh1a2), which was attenuated by olanzapine. One gene (Prss12) was up-regulated after olanzapine treatment although it did not show the significant changes after MK-801 treatment. These results showed that antipsychotic drug, such as olanzapine, may alter the gene expression patterns, which were accompanied by MK-801-induced psychosis. Our results also provide us high-density DNA microarray technology could be potential approaches to find the candidate molecules for the therapeutics and also for the early diagnosis of psychiatric diseases.

• The Korean Journal of Pharmacology
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• v.30 no.3
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• pp.273-289
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• 1994

Reversible brain ischemia was produced by occluding both common carotid arteries for 5 min, and the effects of aminoguanidine (AG), $DL-{\alpha}-difluoromethylornithine$ (DFMO), MK-801, and nimodipine (NM) on the ischemia induced changes of the polyamine, glutamate and acetylcholine levels in the hippocampus CA1 subfield and the specific $[^3H]\;MK-801$ binding to the hippocampus synaptosomal membranes were studied with a histological reference of the cresyl violet stained hippocampus. The basal putrescine level $(PT:\;74.4{\pm}8.8\;nM)$ showed a rapid increase (up to 1.7 fold) for 5 min of ischemia, remained significantly increased for 6 h, and then resumed the further increase to amount gradually up to about 3 fold 96 h after recirculation. However, the level of spermidine was little changed, and the spermine level showed a transient increase during ischemia followed by a sustained decrease to about 40% of the preischemic level after recirculation. The increase of PT level induced by brain ischemia was enhanced with AG or MK-801, but it was reduced by DFMO or NM. The basal glutamate level $(GT:\;0.90{\pm}0.l4\;{\mu}M)$ rapidly increased to a peak level of $8.19{\pm}1.14\;{\mu}M$ within 5 min after onset of the ischemia and then decreased to the preischemic level in about 25 min after recirculation. And NM reduced the ischemia induced increase of GT level by about 25%, but AG, DFMO and MK-801 did not affect the GT increase. The basal acetylcholine level $(ACh:\;118.0{\pm}10.5\;{\mu}M)$ did little change during/after brain ischemia and was little affected by AG or NM. But DFMO and MK-801, respectively, produced the moderate decrease of ACh level. The specific $[^3H]\;MK-801$ binding to the hippocampus synaptosomal membrane was little affected by brain ischemia for 5 min. The control value (78.9 fmole/mg protein) was moderately decreased by AG and MK-801, respectively but was little changed by DFMO or NM. The microscopic findings of the brains extirpated on day 7 after ischemia showed severe neuronal damage of the hippocampus, particularly CA1 subfield. NM and AG moderately attenuated the delayed neuronal damage, and DFMO, on the contrary, aggravated the ischemia induced damage. However, MK-801 did not protect the hippocampus from ischemic damage. These results suggest that unlike to the mode of anti-ischemic action of NM, AG might protect the hippocampus from ischemic injury as being negatively regulatory on the N-methyl-D-aspartate (NMDA) receptor function in the hippocampus.