脑缺血再灌流后bFGF基因的表达及MK-801的影响

目的 研究脑缺血再灌流后ｂＦＧＦ基因表达的意义及其机制。方法 采用原位杂交和１免疫组化的方法,观察大鼠脑缺血再灌流后ｂＦＧＦ基因的表达及ＭＫ－８０１对它们的影响。结果 缺血２ｈ再灌流１ｈ可见ｂＦＧＦ表达增高（Ｐ〈０．０５）,ｂＦＧＦ ｍＲＮＡ表达于１２ｈ达高峰,ｂＦＧＦ蛋白于２４ｈ,达高峰;ＭＫ－８０１组与缺血组相比,于再灌流６ｈ～４８ｈ ｂＧＦＧ表达减弱（Ｐ〈０．０５）。结论 局灶性脑缺血再灌流     

Inhibition by MK-801 of cocaine-induced sensitization, conditioned place preference, and dopamine-receptor supersensitivity in mice

Repeated administration of cocaine led to increases in ambulation-accelerating activity (sensitization) and conditioned place preference (CPP). Dopamine (DA)-receptor supersensitivity was also developed in cocaine-induced sensitized and CPP mice. An N-methyl-d-aspartate (NMDA)-receptor antagonist, MK-801, blocked simultaneously developments of cocaine-induced behavioral sensitization, CPP, and DA-receptor supersensitivity. Furthermore, MK-801 inhibited a apomorphine-induced striatal dopaminergic action: climbing behavior. These results suggest that the cocaine-induced dopaminergic behaviors such as sensitization to ambulatory activity and CPP may be produced via activation of the NMDA receptor. The development of postsynaptic DA-receptor supersensitivity may be an underlying common mechanism that mediates cocaine-induced behavioral sensitization and CPP.     

MK-801-induced neuronal damage in rats

The non-competitive N-methyl-

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-aspartate antagonist MK-801 has been frequently used to attenuate neurotoxicity mediated by excessive release of glutamate. However, doses of MK-801, effective to prevent cell loss in some areas have been reported to induce pathological changes in retrosplenial cortex [32]. In the present study, we examined the extent of the MK-801-induced damage. Silver staining techniques were used to label damaged neurons, axon terminals and activated microglia. In addition to the retrosplenial cortex, we observed silver-impregnated neurons in the pyriform, and entorhinal cortices, in amygdala in tenia tecti, and in the temporal two thirds of the dentate gyrus. With the exception of the dentate gyrus, signs of early degeneration appeared in the first 4 days in all observed regions. Activated microglia have been found 1 and 3 weeks after the lesion in the same areas. The time course and dose dependence of the damage was also investigated. The distribution of labeled neurons resembled the pattern observed after certain epileptic states. Our data suggest that irreversible cell damage occurred in the affected regions. These findings confirm and extend previous suggestions that, besides its protective effect, MK-801 may lead to neuronal degeneration. ©1997 Elsevier Science B.V. All rights reserved.     

Antidepressant drugs increase the locomotor hyperactivity induced by MK-801 in rats

Summary MK-801, a non-competitive NMDA receptor antagonist, induced the locomotor hyperactivity in rats. Imipramine (IMI), amitriptyline (AMI), citalopram (CIT) given acutely increased the MK-801-induced locomotor hyperactivity. Mianserin (MIA) showed a similar but weaker effect. Haloperidol completely blocked the hyperactivity induced by the antidepressant drug (AD) + MK-801. Prazosin had an only weak antagonistic effect. Repeated treatment with AD increased the MK-801 locomotor hyperactivity to a greater extent than acute treatment. This effect was completely blocked by haloperidol and only partly by prazosin.The obtained results indicate that the dopamine system may be involved, at least in part, in the potentiating effect of the combined treatment with AD + MK-801.     

MK-801 induced stereotypies in rats are decreased by haloperidol and increased by diazepam

Summary The effects of haloperidol and diazepam were investigated on stereotypies (wall contacts and turn rounds) induced by the non-competitive NMDA antagonist MK-801 in rats. Haloperidol (0.03, 0.10, 0.25 and 0.40mg/kg body weight) caused a dose-dependent antagonism whereas diazepam (3.0 and 5.0 mg/ kg) caused a dose-dependent agonism of the stereotypies induced by 0.30 mg/ kg MK-801 (all drugs given intraperitoneal). Conversely, diazepam (5.0 mg/kg) given alone reduced significantly the number of spontaneous wall contacts and turn rounds. The paradoxial stimulation of MK-801 induced stereotypies by diazepam could be explained by a shift between positive and negative corticostriatothalamic feedback loops envolving GABAergic neurons in favour of the former.     

MK-801在脊髓缺血中的神经保护作用

目的地佐环平(MK-801)对脊髓缺血中神经保护作用的研究。方法建立新西兰兔脊髓缺血模型,利用HE染色、原位末端转移酶标记技术(TUNEL)、免疫组化、逆转录反应系统(RT-PCR)等技术检测N-甲基-D-天门冬氨酸受体(N-methyl-D-aspartate receptor,NMDAR)、诱导型一氧化氮合酶(inducible Nitric Oxide Synthase,iNOS)、半胱氨酸天冬氨酸蛋白酶3(Caspase-3)的表达水平,观察不同剂量MK-801在脊髓缺血中的神经保护作用。结果对照组脊髓结构完全消失,低剂量组结构较完整,高剂量组缺血损害程度最轻,假手术组脊髓结构正常。NMDAR、iNOS、Caspase-3等蛋白在神经元中有明确表达。凋亡指数、NMDAR、iNOS、Caspase-3 mRNA表达水平在对照组最高,低剂量组、高剂量组,假手术组则逐渐降低,差别具有统计学意义(P<0.05)。结论 MK-801能抑制神经细胞凋亡,对脊髓缺血具有神经保护作用。     

Electrophysiological effects of MK-801 on rat nigrostriatal and mesoaccumbal dopaminergic neurons

The electrophysiological effects of the non-competitive (NMDA) antagonist (+)-MK801 (MK-801) on nigrostriatal and mesoaccumbal dopaminergic (DA) neurons were evaluated in chloral hydrate-anesthetized rats. MK-801 (0.05–3.2 mg/kg, i.v.) stimulated the firing rates of 14 (74%) of 19 nigrostriatal DA (NSDA) neurons and all 16 mesoaccumbal DA (MADA) neurons tested. Stimulatory effects of the drug were more prominent on MADA neurons. Interspike interval analysis revealed that MK-801 also regularized DA neuronal firing pattern. Acute brain hemitransection between the midbrain and forebrain attenuated the stimulatory effects of MK-801 on firing rate and blocked the effects on firing pattern. Similar to MK-801, hemitransection itself increased NSDA and MADA cell firing rates and regularized firing pattern. Both i.v. and iontophoretic MK-801 blocked the excitatory effects of iontophoretic NMDA but did not effect excitations caused by the non-NMDA glutamatergic receptor agonists quisqualate and kainate. Iontophoretic MK-801 had no effect alone. These results suggest that the excitatory effects of i.v. MK-801 on DA neuronal activity are not due to direct actions on DA neurons. Glutamatergic projections originating anterior to the hemistransection appear to play a role in the effectrs of MK-801 on DA neuronal activity.     

A single pretreatment with MK-801 or cocaine enhances their locomotor stimulant effects in rats

A single dose of MK-801 (1.0 mg/kg, s.c.) induces an enhanced locomotor response to a subsequent lower dose of MK-801 (0.3 mg/kg) administered 4, 7 or 14 days later in young adult rats (>90 days). MK-801 (1.0 mg/kg) administration did not significantly enhance the effects of cocaine (10, 20 mg/kg) administered 7 days later. Cocaine (20 mg/kg) enhanced the effect of a subsequent dose of 10 mg/kg cocaine, but did not significantly alter the response to a higher dose cocaine (20 mg/kg) or of MK-801 (0.1 or 0.3 mg/kg) again given 7 days later. MK-801 (1.0 mg/kg) did not significantly enhance the locomotor response to a second dose of MK-801 (0.3 mg/kg) in 28-day-old rats tested 7 days after the initial dose, but did enhance the effects of a lower (0.1 mg/kg) dose. These findings indicate that even a single dose of a stimulant such as MK-801 and cocaine can induce enduring changes in sensitivity to subsequent doses of the same stimulants in young adult rats. The lack of significant effects seen in cross-sensitization studies suggests that separate mechanisms maybe involved in the sensitization to cocaine and MK-801. The more pronounced enhancement of activity in the older animals is in accord with previous findings that sensitization processes are developmentally regulated.     

Intrahippocampal -cycloserine improves MK-801-induced memory deficits: radial-arm maze performance in rats

In order to investigate whether strychnine-insensitive glycine sites coupled with hippocampal NMDA (N-methyl- -aspartate) receptors are involved in spatial memory in rats, we examined the effects of intrahippocampal treatment of -cycloserine (DCS), a glycine-site agonist, on spatial-memory deficits which were produced by an NMDA antagonist MK-801 (dizocilpine) on the radial-arm maze task. After the acquisition of this task, the radial-maze performance was tested under the combined treatments of intraperitoneal MK-801 or saline (SAL) and intrahippocampal DCS or SAL. The results showed that MK-801 impaired the performance, and that DCS improved the MK-801-induced performance impairment. These results suggest that glycine sites are involved in spatial memory through their modulatory action on hippocampal NMDA receptors.     

Acute interactive effects of MK-801 and morphine on cortical EEG and EEG power spectra in rats

The interaction between MK-801 and morphine-induced effects on cortical electroencephalography (EEG) was investigated. Rats were administered one of five MK-801 doses (IP) prior to morphine (IV). MK-801 dose-dependently increased morphine-induced global spectral power, duration of morphine-induced EEG bursts and latency to sleep onset, and decreased morphine-induced mean frequency, mobility, complexity, and edge frequency. MK-801 pretreatment shifted the relative distribution of total power to the left. Significant interaction effects were found for all spectral parameters except peak frequency. A second group of rats was administered MK-801 prior to an increasing cumulative morphine dose. MK-801 increased maximal morphine effects on all spectral parameters except peak frequency. The results are in agreement with those of recent analgesia and in vitro studies in spinal neurons, and support observations of a synergistic interaction between effects of NMDA antagonism and morphine. These data further suggest that the component of cortical EEG that is produced by mu-opioid- and NMDA-receptor interactive effects may be dominated by an inhibitory effect of morphine on NMDA receptor activity.     

Effects of NMDA antagonist MK-801 on radial maze performance in Zucker rats

We examined the participation of the NMDA receptor in the histaminergic system using radial maze performance in Zucker rats. Although pyrilamine caused a significant effect on spatial memory deficit in lean rats, no significant spatial memory deficit was observed in obese rats. On the other hand, MK-801 caused significant spatial memory deficits in obese rats in comparison with lean rats. These results indicate that the histaminergic neuron is not closely related with the radial maze performance in obese rats. In addition, the potent effect of MK-801 observed in obese rats compared with lean rats may be responsible for the activation of NMDA receptors in obese rats.     

NMDA receptor antagonists, MK-801 and ACEA-1011, prevent the development of tonic pain following subcutaneous formalin

Subcutaneous injection of formalin produces a biphasic pain response: an early, transient phase followed by a late tonic phase. The present study examined the involvement of the acid (NMDA) receptor in the development of the late pain produced following subcutaneous injection of formalin into the hind paw in mice. Blockade of the NMDA receptor by its non-competitive antagonist, MK-801, prior to formalin injection, but not after, reduced pain during the late phase. Similarly, blockade of the NMDA receptor allosteric site by the novel glycine site antagonist, ACEA-1011, also reduced the pain response in the late phase. These results suggest that the development of the late phase of formalin pain is due to NMDA-mediated activity during the early phase.     

Proteome analysis after co-administration of clozapine or haloperidol to MK-801-treated rats

Summary MK-801, a glutamergic, N-methyl-D-aspartate (NMDA)-receptor antagonist that mediates neurotransmission and has psychotomimetic properties, giving schizophrenia-like symptom. The objective of this study was to investigate the effects on the thalamic and cortical proteome of one typical (haloperidol) and one atypical (clozapine) antipsychotic drug in interaction with MK-801 in rats. Rats received subcutaneous injections of MK-801 or vehicle (controls) or MK-801 together with concurrent administration of haloperdol or clozapine for eight days. Protein samples from thalamus and cortex were analyzed with two-dimensional gel electrophoresis in combination with mass spectrometry. MK-801 induced alterations in the levels of three proteins in both cortex and thalamus. Clozapine reversed all the protein changes. Haloperidol reversed two. Both antipsychotics induced new protein changes in both cortex and thalamus not seen after MK-801-treatment by alone. In conclusion, the MK-801 animal model shows potential for investigation of different antipsychotic drugs and biochemical treatment effects in schizophrenia.     

Effects of zotepine,haloperidol and clozapine on MK-801-induced stereotypy and locomotion in rats

Summary In the present study we compared the effects of the atypical neuroleptic zotepine to haloperidol and clozapine on stereotypies and locomotion induced in rats by the N-methyl-D-aspartate (NMDA) antagonist MK-801. Zotepine caused a dose-dependent reduction of MK-801-induced stereotypies and locomotion. Zotepine at a dosis of 2.5 mg/kg body weight showed a similar effect to 0.25 mg/kg haloperidol in reducing sterotypies and locomotion. Clozapine (5.0 mg/kg) reduced significantly locomotion and non-significantly stereotypies. These results add support to the assumption that MK-801-induced behavior provides an adequate animal model to test the potential efficacy of typical and atypical neuroleptics in the treatment of psychoses.     

Intrathecal MK-801 inhibits formalin-induced activation of spinal p38-MAPK in rats

BACKGROUND: p38 mitogen-activated protein kinase (MAPK) plays an instrumental role in signal transduction from the cell surface to the nucleus, while subcutaneous injection of formalin can induce increased activation of spinal p38 MAPK. However, the mechanisms underlying the formalin-induced activation of spinal p38 MAPK in rats are unclear. OBJECTIVE: To observe the effects of N-methyl-D-aspartic acid (NMDA) receptor antagonist MK-801 on the formalin-induced activation of spinal p38 MAPK in rats. DESIGN, TIME AND SETTING: This randomized grouping, controlled animal experiment was performed at the Department of Physiology and Neurobiology, Shanxi Medical University between May and November 2007. MATERIALS: Forty eight healthy, adult Wistar rats were randomly divided into two groups: formalin + normal saline (n = 12) and formalin + MK-801 (n = 36). The formalin + MK-801 group was further divided into three subgroups according to the dosage of MK-801 (10, 50, and 100 nmol/L, 12 rats for each subgroup) METHODS: Following anesthesia, polyethylene tubing filled with sterile normal saline was implanted into the subarachnoid cavity. On postoperative days 5-8, rats received a 15 minute perfusion of normal saline or MK-801 (10, 50, and 100 nmol/L) in the formalin + normal saline and formalin + MK-801 groups, respectively, followed by formalin injection for the induction of nociceptive behavior. MAIN OUTCOME MEASURES: Detection of total p38 MAPK and of phosphorylated p38 MAPK by western Blot analysis; observation of nociceptive behaviors in the 1 hour after formalin injection. RESULTS: Western Blot analysis revealed that injection of formalin had no effect on total p38 MAPK expression but resulted in increased phosphorylation of p38 MAPK in the spinal cord. This increase was apparent after 5 minutes, peaked at 20 minutes, and thereafter descended and reached control levels after 45 minutes. Pretreatment with MK-801 (10, 50, 100 nmol/L) resulted in a dose-dependent reduction of p38 MAPK phosphorylation in the spinal cord, 20 minutes after formalin injection. Injection of 50 and 100 nmol/L MK-801 produced a suppression of the first phase of nociceptive behaviors, and all three doses of MK-801 resulted in dose-dependent inhibition of the second phase of nociceptive behaviors. CONCLUSION: The NMDA receptor participates in formalin-induced activation of p38 MAPK in the rat spinal cord.     

Intrathecal MK-801 inhibits formalin-induced activation of spinal p38-MAPK in rats**★

BACKGROUND： p38 mitogen-activated protein kinase （MAPK） plays an instrumental role in signal transduction from the cell surface to the nucleus, while subcutaneous injection of formalin can induce increased activation of spinal p38 MAPK. However, the mechanisms underlying the formalin-induced activation of spinal p38 MAPK in rats are unclear. OBJECTIVE： To observe the effects of N-methyl-D-aspartic acid （NMDA） receptor antagonist MK-801 on the formalin-induced activation of spinal p38 MAPK in rats. DESIGN, TIME AND SETTING： This randomized grouping, controlled animal experiment was performed at the Department of Physiology and Neurobiology, Shanxi Medical University between May and November 2007. MATERIALS： Forty eight healthy, adult Wistar rats were randomly divided into two groups： formalin ＋ normal saline （n = 12） and formalin ＋ MK-801 （n = 36）. The formalin ＋ MK-801 group was further divided into three subgroups according to the dosage of MK-801 （10, 50, and 100 nmol/L, 12 rats for each subgroup） METHODS： Following anesthesia, polyethylene tubing filled with sterile normal saline was implanted into the subarachnoid cavity. On postoperative days 5-8, rats received a 15 minute perfusion of normal saline or MK-801 （10, 50, and 100 nmol/L） in the formalin ＋ normal saline and formalin ＋ MK-801 groups, respectively, followed by formalin injection for the induction of nociceptive behavior. MAIN OUTCOME MEASURES： Detection of total p38 MAPK and of phosphorylated p38 MAPK by western Blot analysis; observation of nociceptive behaviors in the 1 hour after formalin injection. RESULTS： Western Blot analysis revealed that injection of formalin had no effect on total p38 MAPK expression but resulted in increased phosphorylation of p38 MAPK in the spinal cord. This increase was apparent after 5 minutes, peaked at 20 minutes, and thereafter descended and reached control levels after 45 minutes. Pretreatment with MK-801 （10, 50, 100 nmol/L） resulted in a dose-dependent reduc     

Effect of cannabidiol in a MK-801-rodent model of aspects of schizophrenia

Cannabidiol is a non-psychoactive phytocannabinoid which, based on several previous preclinical and clinical reports, is purported to have antipsychotic potential. The purpose of this investigation was to further investigate if these effects would be seen using an MK-801-induced rat model of aspects of schizophrenia. MK-801 is an NMDA receptor-antagonist known to produce hyperactivity, deficits in prepulse inhibition and social withdrawal, behaviours which correlate well with some of the positive, cognitive and negative symptoms of schizophrenia. Following a 4-day acclimatisation to the holding room, rats were acclimatised to startle chambers on day 5 and their prepulse inhibition (PPI) determined on day 6 following treatment with cannabidiol or vehicle and MK-801 or vehicle. On day 9, rats were acclimatised to the social interaction testing arena and on day 10, were tested for social interaction and locomotor activity following the same treatments. Cannabidiol treatment alone disrupted PPI and produced hyperactivity but had no effect on social behaviour. Cannabidiol had no effect on MK-801-induced disruption of PPI or hyperactivity but showed potential towards inhibiting MK-801-induced social withdrawal. As a comparator, we also tested the effect of the atypical antipsychotic clozapine which only partially reversed MK-801-induced disruption of PPI but was able to reverse MK-801-induced hyperactivity and social withdrawal. In conclusion, cannabidiol showed both propsychotic activity and partial antipsychotic activity in an MK-801-induced model of aspects of schizophrenia. Further behavioural studies would be required using a range of species, strains, animal models and testing paradigms to conclusively establish the antipsychotic potential of cannabidiol.     

NMDA receptor antagonist MK-801 infused into the insular cortex prevents the attenuation of gustatory neophobia in rats

Gustatory neophobia dissipates with repeated exposures to an initially novel taste solution. The aim of the present study was to determine whether NMDA receptors in the insular cortex are involved in this experience-dependent process. Results showed that acute microinfusion of MK-801 into the insular cortex prevented the attenuation of gustatory neophobia indicating that this process is an NMDA receptor-dependent phenomenon.     

CGS-19755 and MK-801 selectively prevent rat striatal cholinergic and gabaergic neuronal degeneration induced by N-methyl-D-aspartate and ibotenate in vivo

Summary The in vivo efficacies and potencies of various excitatory amino acid agonists in inducing cholinergic neuronal degeneration were compared following unilateral injections into the rat striatum. Kainic acid (KA), -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), ibotenic acid (IBO), and N-methyl-D-aspartic acid (NMDA) all produced dose-related decreases in choline acetyltransferase (ChAT) activity. The relative order of potency was KA>AMPA>IBO>NMDA. Quisqualic acid (QUIS) was about as potent as NMDA, but the maximal decrease in ChAT activity was less (36%). N-acetylaspartyl-L-glutamate (NAAG) did not significantly decrease ChAT activity when up to 1,000 nmoles was injected. Approximate equitoxic doses of agonists were then used to examine the ability of i.p. administered CGS-19755 and MK-801 to prevent in vivo excitatory amino acid-induced cholinergic and GABAergic neuronal degeneration. NMDA-induced decreases in ChAT and glutamic acid decarboxylase (GAD) activities were prevented by CGS-19755 (10–40 mg/kg) and MK-801 (1–10 mg/kg). CGS-19755 (40 mg/kg) and MK-801 (10 mg/kg) did not prevent loss of ChAT or GAD induced by KA or AMPA, but did prevent the degenerative effects of IBO. This study shows that CGS-19755 and MK-801, two NMDA receptor antagonists that act by different mechanisms, are completely selective following systemic administration. Moreover, the in vivo excitotoxic effects of IBO are mediated at NMDA receptor sites that are blocked by these compounds.     

Low dose MK-801 protects against iron-induced oxidative changes in a rat model of focal epilepsy

We have used chemiluminescence measurements to examine the relationship between free radical formation and excitotoxicity in a post-traumatic epilepsy model. For this purpose, seven days after injecting iron in rat brain cortices, we measured luminol- and lucigenin-enhanced chemiluminescence in different brain regions (ipsilateral cortex, contralateral cortex, hypothalamus and hippocampus). In all brain regions (except contralateral cortices) both luminol- and lucigenin-enhanced chemiluminescence were increased in iron-injected group compared to saline-injected control group. These increases returned to control values in iron-injected rats pretreated with MK-801. Our results suggest that both free radicals and excitatory amino acids play important roles in the development of post-traumatic epilepsy and that MK-801 has protective effects against iron-induced chemiluminescence formation.