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.     

Contrasting effects of the competitive NMDA antagonist CPP and the non-competitive NMDA antagonist MK 801 on performance of an operant delayed matching to position task in rats

The effects of the competitive NMDA antagonist CPP and the non-competitive NMDA antagonist MK 801 (dizolcipine) on short term working memory in the rat were investigated. The behavioural paradigm used was discrete trial, operant delayed matching to position, as originally described by Dunnett (1985), with delays of 0, 5, 15 and 30 s. These delays generated an orderly forgetting curve in control rats, with matching accuracy decreasing from approximately 100% at 0-s delay to approximately 75% at 30-s delay. Intraperitoneal (IP) administration of CPP (10 mg/kg) produced a markeddelay dependent impairment in performance, suggesting a specific effect on short term working memory. This effect was accompanied by a minor decrease in the speed of responding, and a slight increase in the number of missed trials. Lower doses of CPP had no significant effects on either matching accuracy or sedation. In contrast, IP administration of MK 801 (0.1 and 0.2 mg/kg) caused a markeddelay independent impairment in the accuracy of delayed matching performance, suggesting a non-specific disruption of performance. A lower dose (0.05 mg/kg) of MK 801 had no significant effect on matching accuracy. The two lower doses of MK 801 increased the number of nose pokes made during the delays and tended to increase the speed of responding, suggesting a stimulant-like action. The highest dose of MK 801 had the opposite effects and also decreased the number of trials completed. The results with CPP therefore support the hypothesized role of NMDA receptors in learning and memory, and the contrasting effects of these two NMDA antagonists support previous suggestions of different behavioural effects resulting from administration of competitive and non-competitive NMDA antagonists.     

NMDA Actions on Rat Abducens Motoneurons

Intracellular recordings were made from rat abducens motoneurons in vivo during local extracellular micro-ionophoretic application of N-methyl-d-aspartate (NMDA) and NMDA receptor antagonists. Typical NMDA responses, at a resting potential of -60 mV, consisted of a slow depolarization with an apparent increase in membrane resistance, bursts of action potentials followed by stable repetitive firing. Ionophoretic applications of aminophosphonovalerate (APV), kynurenate or MK801 reduced or blocked the NMDA-induced responses. The NMDA responses were voltage-dependent. NMDA responses induced by short (< 30 s) NMDA application pulses were blocked by hyperpolarizing the neuron. Long duration (> 30 s) NMDA applications induced rhythmic plateau potentials in hyperpolarized abducens motoneurons. The rhythmic depolarizations (15 - 30 mV) were modulated in both frequency and duration by current injection. They were abolished by further hyperpolarization or replaced by stable repetitive firing when hyperpolarization was removed. Our data show that NMDA receptors are present in rat abducens motoneurons and may be involved in the induction of rhythmic activities. The voltage-dependent blockade of somatic NMDA receptor-associated ion channels by cell hyperpolarization may be important for these oscillations. It is suggested that the rhythmic behaviour is due to the activation of dendritic NMDA receptors.     

精神分裂症动物模型学习记忆实验研究

目的研究精神分裂症动物模型大鼠学习记忆能力的变化特点。方法用MK801建立精神分裂症的动物模型。将动物分成正常组和模型组。采用主动回避反应(AAR),一次性被动回避反应(OPAR),空间分辨记忆(SDM)3种模式对学习记忆过程进行系统研究。结果在大鼠AAR实验中,对照组大鼠AAR习得率明显高于模型组,并且消退也慢于模型组;在大鼠OPAR实验中,大鼠电击24h后,模型组大鼠STL较短;在大鼠SDM实验中,模型大鼠操作错误的次数明显多于对照组,训练时不吃的次数亦多于对照组,对照组完成一次训练的总时间需要216s左右,而模型组大鼠需要306s左右。结论精神分裂症的动物模型伴有学习记忆能力下降,并与神经系统的谷氨酸含量密切相关。     

Behavioral interactions caused by combined administration of morphine and MK-801 in rats

Rationale: The NMDA antagonist MK-801 reportedly blocks experience-dependent changes in sensitivity to morphine, including tolerance to its analgesic actions and sensitization to its locomotor-stimulating effects. However, evidence in the existing literature suggests that some of MK-801’s effects are additive (or synergistic) with those of morphine. Objectives: Experiments were conducted to characterize the effects of acute and repeated administration of the combination of MK-801 and morphine on analgesia, locomotor activity, and drug discrimination in rats. Methods: In each experiment, rats were first tested repeatedly after treatment with the combination of MK-801 and morphine, and then after treatment with either drug alone. Results: The analgesic effects of MK-801 combined with morphine were greater than those of morphine alone, but tolerance to the combination of drugs developed at a similar rate as to morphine alone. The locomotor-stimulating effects of MK-801 combined with morphine were also greater than those of either drug alone, and locomotor sensitization developed to the combination of drugs but not to either drug alone at the low doses used. Rats learned to discriminate a combination of MK-801 and morphine from vehicle as quickly as they learned to discriminate morphine alone from vehicle, but those trained with the combination of MK-801 and morphine responded primarily at the vehicle-appropriate lever when given either drug alone. Conclusions: Since behavioral adaptations readily occur in the presence of MK-801, it appears that NMDA antagonists fail to invariably block the cellular plasticity that underlies such adaptations. Rather, the expression of adaptations in drug sensitivity appears related, at least in part, to the continued presence of the discriminative stimulus cues that are present during conditioning. Although NMDA receptors are important for some forms of cellular plasticity, the present studies illustrate the difficulty in interpreting behavioral studies in which MK-801 is given with morphine. Received: 24 November 1999 / Accepted: 25 March 2000     

Comparison of dopamine receptor antagonists on hyperlocomotion induced by cocaine, amphetamine, MK-801 and the dopamine D1 agonist C-APB in mice

Rationale: Direct or indirect stimulation of dopamine receptors increases locomotor activity in mice. Determining the role played by D₁ and D₂ dopamine receptors in the mediation of this activity can be difficult due to the wide variety of experimental paradigms used to investigate these phenomena. Objectives: This study set out to compare the role of selective antagonism of dopamine D₁ and D₂ receptors on the hyperactivity induced by a range of stimulants. Methods: Mice were habituated to perspex locomotor activity boxes (30×30× 30 cm) and activity was measured via photobeam interrupts. Results: Haloperidol and clozapine both reduced the hyperactivity induced by MK-801. Haloperidol did so only at a dose that also decreased spontaneous activity (0.1 mg/kg), whereas clozapine reduced MK-801-induced hyperactivity at a dose that had no effect on spontaneous activity (1.25 mg/kg). The D₁ antagonist SCH23390 (0.01 mg/kg) reduced hyperlocomotion induced by amphetamine (2.5 mg/kg), cocaine (10 mg/kg) and C-APB (1.0 mg/kg) at doses that did not consistently alter spontaneous activity, whereas the selective D₂ antagonist raclopride only attenuated the hyperlocomotion induced by amphetamine, cocaine and C-APB at doses in excess of the minimum dose required to attenuate spontaneous locomotor activity significantly. The latency to peak levels of hyperlocomotion induced by MK-801 (0.3 mg/kg) was delayed by SCH23390 (0.1 mg/kg) but peak levels of activity were not reduced. Conclusions: The results of the present study suggest that selective blockade of D₁ receptors suppresses amphetamine and cocaine-induced hyperactivity in mice but not MK-801-induced locomotor activity. Received: 1 January 1998 / Final version: 4 March 1999     

百日咳菌液对大鼠培养脑切片兴奋性氨基酸释放的影响

目的:了解百日咳菌液对培养的大鼠脑切片兴奋性氨基酸(EAAs) 释放的影响及11 双氢5H二苯(a ,d)环庚烯亚胺( MK801) 对脑切片有无保护作用。方法:SD 大鼠随机分成正常脑切片培养组(NC组) ,10 % 百日咳菌液脑切片培养组(PBC 组) 和MK801 预处理后10 % 百日咳菌液脑切片培养组( MPBC组) 。用高效液相色谱法测脑切片培养上清液中的EAAs 释放量。结果:PBC 组的谷氨酸(Glu) 、门冬氨酸(Asp) 及乳酸脱氢酶(LDH) 的释放量明显高于MPBC 组及NC 组。结论:百日咳菌液可使培养的脑切片组织EAAs 和LDH 的释放量增多;MK801 预处理可降低脑切片组织EAAs 及LDH 的释放量。提示MK801 对离体脑组织有保护作用     

MK801-a neuroprotectant in rat hypertensive eyes

Excitatory synaptic transmission in the mammalian CNS and retina is mainly mediated through

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-glutamate. The effect of MK-801, a non-competitive antagonist of the NMDA subtype of glutamate receptor was studied on rat retinal ganglion cells in hypertensive eyes. MK-801 was administered intraperitoneally to the first group, 1 day before the increase, and in the second group, 2 days after the intraocular pressure (IOP) elevation. Phosphate-buffered saline was administered to the control group. Animals were sacrificed 2 and 4 weeks post-IOP increase. The retinal ganglion cells were counted and compared between control (right) and experimental (left) eyes. The data presented here suggests that MK-801 has neuroprotective properties.     

N‐methyl d‐aspartate receptors are involved in the induction,but not expression stage of amphetamine sensitization in schedule‐induced polydipsia in rats

1. The aim of the present study was to examine the role of dopaminergic and glutamatergic receptors on different stages of the amphetamine (AMPH) sensitized effect in schedule‐induced polydipsia (SIP) in rats. 2. Three experiments were designed to evaluate the roles of DAD2 receptor antagonist haloperidol (HAL) and glutamatergic N‐methyl d‐aspartate receptor antagonist MK‐801 on both the induction and the expression stage of AMPH sensitization in SIP rats. First, the induction of AMPH sensitization in the SIP model was tested again to confirm previous findings. Second, HAL or MK‐801 was co‐administered with AMPH on five consecutive days and their effect on induction was examined 14 days after withdrawal. Finally, HAL or MK‐801 was co‐administered with AMPH on the final day of testing in SIP rats in which AMPH sensitization had been established previously. 3. The present results shoed that HAL and MK‐801 affected the effect of AMPH differently during the process of sensitization. Whereas HAL influenced the sensitization during both the induction and the expression phases, MK‐801 affected only the induction phase; thus, once the sensitization had been established, MK‐801 had no further influence. 4. These results suggest that the SIP model could be considered useful for the study of sensitization. In addition, the induction and expression of AMPH sensitization is influenced differently by the dopaminergic and glutamatergic systems.     

Systemic administration of GMP induces anxiolytic-like behavior in rats

The glutamatergic system has received considerable attention over the last few years as potential target to develop anxiolytic drugs. Guanine based purines (GBPs) play an important neurmodulatory effect in the glutamatergic system. Several studies have shown the ability of the GBPs to reduce glutamatergic activity. In the present study, we investigated the anxiolytic effect of GBPs — by Guanosina Monophosphate (GMP) administration — in rodents. Adult male Wistar rats were pretreated with GMP (10, 25, 50, 100 and 150 mg/kg: i.p.); or saline (NaCl 0.9%; i.p.) (control); or, diazepam (2 mg/kg: i.p.) (positive control). One hour after the injection, the anxiety-related behaviors for each animal was evaluated in the light/dark, elevated plus-maze, and open field tasks. Additionally, purines concentration in the cerebrospinal fluid (CSF) was verified. The administration of 25 and 50 mg/kg GMP was able to promote anxiolytic-like behavior, in the light/dark and elevated plus-maze task, similar to diazepam effect. However, no changes in the open field task, or CSF purines concentration were found for either GMP or diazepam treated animals, when compared with saline group. Thus, this study suggests that acute administration of GMP was able to decrease the levels of anxiety in classical behavioral tasks.