Radio-frequency lesions of the thalamus produce delayed-nonmatching-to-sample impairments comparable to pyrithiamine-induced encephalopathy in rats.

Rats were trained and matched on a delayed-nonmatching-to-sample (DNMTS) task and randomly assigned to treatment. In Experiment 1, radio-frequency (RF) lesions were aimed at lateral portions of the internal medullary lamina (L-IML), midline thalamus (MT), mammillary bodies (MB), and the combination of MT and MB. In Experiment 2, RF lesions were aimed at the fornix. After recovery, DNMTS was retrained at retention intervals retention interval of 3.0-18.0 s, the critical retention interval for 75% DNMTS accuracy was determined by a staircase procedure, and spontaneous exploration was observed in an open field. L-IML lesions produced significant deficits on DNMTS and exploratory behavior that were comparable to deficits on the same tasks in rats recovered from pyrithiamine-induced thiamine deficiency. Fornix lesions produced significant DNMTS deficits that were substantially smaller than for the L-IML group. The MT, MB, and MT+MB treatments had no significant effect on DNMTS.     

Interactive effect of MK-801 and pre-training on spatial learning in rats

In experiment 1, the effect of an NMDA receptor antagonist, MK-801, on the formation of the spatial representation was investigated. The administration of 0.1 mg/kg of MK-801 induced learning deficits in rats (n = 10) with the Morris watermaze task. However, when rats (n = 10) were pre-trained in the same task without drug treatment, and then trained in the same task in a different environment under the influence of the same amount of the drug, their performance was not impaired. The result suggests that rats treated with MK-801 can acquire a spatial representation of their environment, and that the impairment shown by the drug-treated rats without pre-training may be due to the impairment in the learning of the problem-solving strategy required for the watermaze place task. Experiment 2 examined this possibility. Rats (n = 10) were pre-trained with a visual cue discrimination task without drug treatment and then trained in the place task with MK-801 (0.1 mg/kg) treatment. They did not show impairment in the place task, indicating that rats treated with MK-801 can learn a new problem-solving strategy. Thus the learning deficits of MK-801-treated rats that have not been pre-trained do not seem to be due to impaired acquisition of the spatial representation or of the learning of strategy required to solve the watermaze place task.     

Analysis of sensitivity to MK-801 treatment in a novel active allothetic place avoidance task and in the working memory version of the Morris water maze reveals differences between Long-Evans and Wistar rats

The aims of the present study were to compare the effect of subchronic administration of MK-801 on performance in the active allothetic place avoidance (AAPA) task and in the working version of Morris water maze (MWM) in Long-Evans and Wistar rats. Animals were trained for four daily sessions either in the AAPA or in the working memory version of the MWM. Wistar rats treated by MK-801 (0.1 mg/kg) showed a cognitive deficit in the AAPA task without a significant hyperlocomotion, whereas they were not impaired in the working memory version of the MWM compared to controls. Long-Evans rats treated by MK-801 (0.1 mg/kg) were not impaired either in the AAPA task or in the MWM task. Higher doses of MK-801 (0.2 and 0.3 mg/kg) produced hyperlocomotion in both strains which corresponded to an inability to solve both spatial tasks. Long-Evans rats were superior in the MWM to the Wistar rats in the groups treated with the low dose of MK-801. In conclusion, intact Wistar rats can efficiently solve both spatial tasks; however, they are more sensitive to MK-801-induced behavioural deficit. This has relevance for modeling of the schizophrenia-related deficits and for screening substances for their therapeutic potential.     

Response latency and accuracy on a pretrained nonmatching-to-sample task in rats recovered from pyrithiamine-induced thiamine deficiency

Rats were trained for 1,345 spatial nonmatching-to-sample (NMTS) trials, matched, assigned to pyrithiamine-induced thiamine deficiency (PTD) or control treatments, recovered, and re-tested for 400 trials of NMTS. The PTD model produced two bilaterally symmetrical lesions: one of medial thalamus that was centered on the internal medullary lamina (IML) and another involving the mammillary bodies. PTD rats with complete IML lesions showed a sharp drop in performance that persisted throughout posttreatment training. PTD rats with IML sparing were impaired immediately after treatment but improved to a level comparable to that of controls. For all animals, NMTS accuracy decreased for longer latency responses. PTD animals differed from controls primarily in the low frequency and inaccuracy of their short-latency (0-2.9 s) responses. The improvement of the PTD rats with IML sparing was marked by an increase in both the number and accuracy of short-latency responses.     

NMDA antagonist MK-801 does not interfere with the use of spatial representation in a familiar environment

There is disagreement among researchers concerning whether glutamatergic N-methyl-D-aspartate (NMDA) receptors play a role in constructing spatial representations. Therefore, the authors reexamined the effects of the NMDA antagonist on a spatial discrimination task using rats in a water pool. The authors confirmed that MK-801 impaired acquisition of the spatial discrimination task (Experiment 1). When rats were pretrained before drug treatment, MK-801 induced learning deficits in the novel environment but not in the familiar environment (Experiment 2). Moreover, in a familiar environment, MK-801 did not impair spatial learning, even when the task was completely novel for the rats (Experiment 3). These results suggest that NMDA receptors play an important role in the construction of spatial representations but not in the use of them.     

Delayed-nonmatching-to-sample performance is impaired by extensive, but not by limited, lesions of the thalamus in the rat.

Two experiments were conducted to determine whether lesions affecting limited areas of the thalamus can impair the performance of rats on a spatial delayed-nonmatching-to-sample (DNMTS) task trained before surgery. In Experiment 1, DNMTS was not affected by lesions produced by injecting 5 microliters of 1 mM N-methyl-D-aspartate into either the midline thalamus (n = 16) or bilaterally 1.0 mm from the midline (n = 16). In experiment 2, radio-frequency lesions were made 1.0 mm lateral to the midline at 3 anterior-posterior locations that destroyed the full rostral-caudal extent of the lateral internal medullary lamina (L-IML; n = 8), or at single anterior-posterior locations that destroyed either the anterior (n = 8) or posterior (n = 8) portions of the L-IML site. Although complete L-IML lesions disrupted DNMTS performance to an extent comparable to that of another study (Mair & Lacourse, 1992), lesions that were restricted to either the anterior or posterior portion of the L-IML site had no significant effect on this task.     

The selective 5-HT(1A) receptor agonist repinotan HCl attenuates histopathology and spatial learning deficits following traumatic brain injury in rats

The selective 5-HT(1A) receptor agonist Repinotan HCl (BAY x3702) has been reported to attenuate cortical damage and improve functional performance in experimental models of cerebral ischemia and acute subdural hematoma. Using a clinically relevant contusion model of traumatic brain injury, we tested the hypothesis that a 4-h continuous infusion of Repinotan HCl (10 microg/kg/h i.v.) commencing 5 min post-injury would ameliorate functional outcome and attenuate histopathology. Forty isoflurane-anesthetized male adult rats were randomly assigned to receive either a controlled cortical impact (2.7 mm tissue deformation, 4 m/s) or sham injury (Injury/Vehicle=10, Injury/MK-801=10, Injury/Repinotan HCl=10, Sham/Vehicle=10), then tested for vestibulomotor function on post-operative days 1-5 and for spatial learning on days 14-18. Neither Repinotan HCl nor the non-competitive N-methyl-D-aspartate receptor antagonist MK-801, which served as a positive control, improved vestibulomotor function on beam balance and beam walk tasks relative to the Injury/Vehicle group, but both did significantly attenuate spatial learning and memory deficits on a water maze task. Repinotan HCl also reduced hippocampal CA(1) and CA(3) neuronal loss, as well as cortical tissue damage, compared to the Injury/Vehicle group at 4 weeks post-trauma. No significant difference in histological outcome was revealed between the Repinotan HCl- and MK-801-treated groups.These findings extend the therapeutic efficacy of Repinotan HCl to a contusion model of experimental brain injury and demonstrate for the first time that 5-HT(1A) receptor agonists confer neuroprotection and attenuate spatial learning deficits following controlled cortical impact injury. This treatment strategy may be beneficial in a clinical context where memory impairments are common following human traumatic brain injury.     

Epileptogenic insult causes a shift in the form of long-term potentiation expression

The relationship between epilepsy, modeled here by pentylenetetrazol kindling, and learning deficits, modeled here by long-term potentiation (LTP), was studied. The field excitatory postsynaptic potentials and population spikes (PS) were recorded from strata radiatum and pyramidale, respectively, in urethane-anesthetized rat dorsal hippocampus CA1 area upon stimulation of Schaffer collaterals. To induce LTP, a 100 Hz primed-burst stimulation protocol was used. Experiments were carried out at approximately 30 days after the last pentylenetetrazol dose. The effects of voltage dependent calcium channel blocker verapamil and N-methyl-D-aspartate receptor antagonist MK-801 on LTP expression were examined. Tetanic stimulation elicited both field excitatory postsynaptic potential LTP and PS LTP in control animals, and LTP-induction of the PS in control animals was attenuated by MK-801, but not by verapamil. By contrast, kindled rats showed LTP of the PS only. MK-801 reduced the extent of potentiation of PS amplitude and verapamil inhibited the PS amplitude potentiation, completely. The results suggest that seizure induction modifies mechanisms underlying LTP induction and causes a shift in the form of LTP expression. The pentylenetetrazol-kindling-induced increase in PS LTP is sensitive to verapamil and not to MK-801 and therefore primarily dependent on activation of voltage dependent calcium channels rather N-methyl-D-aspartate receptors. Kindling may lead to a shift in synaptic plasticity thresholds much like the shift that occurs during aging, and such alterations may contribute to deficits in learning and memory.     

Assessment of sustained attention in ad libitum fed Wistar rats: effects of MK-801

RATIONALE: Rodent models designed to assess cognitive function, such as sustained attention tasks, use food and/or fluid restriction in order to motivate responding. However, evidence indicates that dietary restriction can have profound effects on brain function and on the neurobehavioral effects of drugs. OBJECTIVE: The primary objective of this study was to demonstrate the feasibility of using ad libitum fed rats to assess sustained attention in an operant 2-choice reaction time (2-CRT) task. Because N-methyl-D-aspartate (NMDA) receptor function is critical for sustaining attention in animal models, the effects of the NMDA antagonist MK-801 on 2-CRT performance were also assessed. METHODS: Male Wistar rats (n = 20) rats were trained to perform an operant 2-CRT task. A 10% sucrose solution was used as the reinforcer. After performance levels stabilized, the effects of MK-801 (0.01-0.12 mg/kg, IP) were assessed. RESULTS: Stable levels of performance on the final version of the 2-CRT task was established after 2-3 months of training. Consistent with prior reports, correct trials varied as a function of stimulus light duration (1000 ms: 67 +/- 3%, 500 ms: 59 +/- 3%, 100 ms: 51 +/- 3%, 50 ms: 43 +/- 2%). Administration of 0.06 mg/kg MK-801 significantly increased choice accuracy. Administration of 0.12 mg/kg MK-801 significantly slowed reaction times and resulted in pronounced motor incoordination. CONCLUSIONS: This study demonstrates that ad libitum fed rats can be trained to perform a 2-CRT task. However, the levels of choice accuracy are lower than typically observed under conditions of dietary restriction. The increase in choice accuracy following MK-801 is consistent with the effects of psychomotor stimulants and may suggest sustained attention was slightly enhanced by MK-801.     

Effects of the NMDA receptor antagonist MK-801 on short-interval timing in rats

Effects of MK-801, an N-methyl-D-aspartate antagonist, on short-interval timing were examined using the peak-interval (PI) and PI-gap procedures. Fisher 344 rats were given daily injections of 0.025 mg/kg, 0.05 mg/kg, and 0.2 mg/kg MK-801. The main results were (a) 0.2 mg/kg MK-801 produced an immediate overestimation of the criterion time; (b) MK-801 increased peak rate of responding; (c) 0.2 mg/kg MK-801 produced an increase in variability; (d) during the PI-gap procedure, a reset pattern was observed for all rats (MK-801 and saline). Results suggest that MK-801 has at least 2 effects. First, MK-801 interferes with short-interval timing by producing an overestimation of time and a nonscalar increase in variability. Second, MK-801 increases response rate, suggesting a decrease in response inhibition.     

Impaired allocentric spatial working memory and intact retrograde memory after thalamic damage caused by thiamine deficiency in rats

Rats were tested on an allocentric-spatial working-memory task--delayed matching-to-place (DMTP) in a water maze--before and after either pyrithiamine-induced thiamine deficiency (PTD) or electrolytic lesions of the lateral internal medullary laminae (IML), an area damaged by PTD. DMTP trials consisted of paired swims, with the escape platform in a new location on each trial. PTD rats were impaired at retention delays of 300 s, but not at delays of 4 or 60 s. Rats with IML lesions performed normally at all delays. Both groups displayed normal retention of object-discrimination problems that they had learned at different intervals before treatment (5 weeks, 3 weeks, and 1 week). The results suggest that PTD causes delay-dependent deficits of allocentric spatial working memory and that damage outside the IML is probably responsible. Neither PTD-induced diencephalic damage nor restricted IML lesions appear to produce a global retrograde amnesia.     

Neuroprotective effect of lamotrigine and MK-801 on rat brain lesions induced by 3-nitropropionic acid: evaluation by magnetic resonance imaging and in vivo proton magnetic resonance spectroscopy

Magnetic resonance imaging and in vivo proton magnetic resonance spectroscopy were used to evaluate the therapeutic effect of lamotrigine and MK-801 on rat brain lesions induced by 3-nitropropionic acid. Systemic administration of 3-nitropropionic acid (15 mg/kg per day) to two-month-old Sprague-Dawley rats (n = 10 for each group) for five consecutive days induced selective striatal and hippocampal lesions and specific behavioral change. Pretreatment with lamotrigine (10 mg/kg or 20 mg/kg per day) or MK-801 (2 mg/kg per day) attenuated the lesions and behavioral change. There were no significant differences in T2 values of the striatum and hippocampus among rats pretreated with MK-801, lamotrigine (20 mg/kg) and sham controls. Significant elevations of succinate/creatine and lactate/creatine ratios and decreases of N-acetylaspartate/creatine and choline/creatine ratios were observed after 3-nitropropionic acid injections (P < 0.001). The changes were nearly prevented after pretreatment with lamotrigine (20 mg/kg). However, the N-acetylaspartate/creatine in rats pretreated with lamotrigine (10 mg/kg) (P < 0.01) and MK-801 (P < 0.05) still showed significant reduction as compared with sham controls. Thus we conclude that both lamotrigine and MK-801 are effective in attenuation of brain lesions induced by 3-nitropropionic acid. A higher dose of lamotrigine provides a better neuroprotective effect than MK-801. With a better therapeutic effect and fewer side effects, lamotrigine is more promising for potential clinical application.     

Kainate-induced functional deficits are not blocked by MK-801

Male, Fischer-344 rats were pretreated with MK-801 (0.1, 1.0 or 10.0 mg/kg, i.p.) prior to bilateral injection of kainate (0.33 micrograms/site) into the dorsal and ventral hippocampus. Kainate impaired the acquisition of a water maze acquisition task 4 weeks after surgery, an effect not attenuated by pretreatment with MK-801. However, higher doses (1.0 and 10.0 mg/kg) of MK-801 reduced the amount of kainate-induced granule cell and to some extent CA1 pyramidal cell damage in the hippocampus. Kainate-induced CA3/CA4 damage was not affected by MK-801 pretreatment. MK-801 (10 mg/kg) also reduced the amount of thalamic damage produced by kainate. These data support the conclusion that intrahippocampal kainate-induced destruction of CA3/CA4 pyramidal cells is mediated by non-N-methyl-D-aspartate (non-NMDA) receptors and that kainate-induced loss of these cells is associated with the neurobehavioral effects of intrahippocampally administered kainate.     

MK-801诱发精神分裂症对大鼠探索能力、疼痛反应及海马神经细胞增殖的影响

目的:观察大鼠精神分裂症后探索能力、痛觉及海马齿状回颗粒细胞层神经细胞增殖的改变。方法:MK-801腹腔注射制备精神分裂症动物模型,分别监测给药后第1、5、10、14 d大鼠的探洞次数和甩尾时间。Brdu标记后取材,应用免疫荧光染色和激光共聚焦显微技术观察海马齿状回神经细胞的增殖情况。结果:①洞板试验:实验组大鼠的探洞次数较对照组显著下降(P<0.01),且随着MK-801给药时间的增加而减少(P<0.01);②甩尾试验:实验组大鼠对疼痛刺激的反应时间较对照组缩短(P<0.01),且随着MK-801给药时间的延长痛觉敏感度不断增加(P<0.01);③神经细胞的增殖:停药后第1 d,实验组海马齿状回颗粒层神经细胞增殖数较对照组减少(P<0.05),第16 d两组间无显著差异(P>0.05)。结纶:MK-801诱发精神分裂症后可致大鼠的探索能力减退、痛觉敏感,同时可降低海马齿状回颗粒细胞层神经细胞的增殖。     

Rescue of motoneurones by MK-801 innervating partially denervated rat muscles

Partial denervation of the extensor digitorum longus muscle by cutting the L4 spinal nerve in 3-day-old rats causes some of the remaining uninjured motoneurones to die. A previous study has shown that of the 12 motor units usually present in the remaining uninjured L5 spinal nerve, a significantly smaller number of motor units to extensor digitorum longus muscle is found in animals operated on at 3 days. This reduction can be caused by a greater sensitivity of neonatal motoneurones with axons in a partially denervated muscle, to excitotoxic effects of glutamate. Therefore an N-methyl-D-aspartic acid (NMDA) receptor antagonist, MK-801, was injected daily for 12 days after partial denervation at 3 days. Two months after the operation contractile properties, motor unit numbers and sizes were studied. Following MK-801 treatment, the reduction in muscle weight and force output of the partially denervated muscle was less than that in the untreated group. Moreover there were more motor units in MK-801 treated animals. After partial denervation only, 15% of the total number of motor units was present whereas when the same operation was followed by treatment with MK-801, 29% remained. The mean motor unit size in the untreated group was 69% while after treatment with MK-801 it was 152% of the control. Thus treatment with MK-801 after partial denervation of neonatal animals rescued some of the motoneurones destined to die, and allowed expansion of motor unit territory of most of the surviving motoneurones. Electronic Publication     

NMDA receptor antagonist disrupts acute and chronic effects of methylphenidate

Methylphenidate (MPD) is a drug widely used for treating attention-deficit/hyperactivity disorder in children. Because of its extensive consumption and because it has pharmacological stimulant properties similar to amphetamine and cocaine, MPD has the potential of abuse. N-methyl-D-aspartate (NMDA) receptors are suggested to be involved in CNS effects of stimulants, and antagonists of the NMDA receptor can potentially alter the stimulants' effects. Dizocilpine (MK-801), a non-competitive antagonist of the NMDA receptor, has been reported to prevent sensitization elicited by repeated administration of amphetamine and cocaine. The objective of the present study was to use the tail-flick latency assay, rectal temperature, and body weight gain to assess effects of repetitive treatment of MPD and whether MK-801 treatment would alter these effects in Sprague-Dawley rats. It was found that: (Ia) Acute administration of MPD or MK-801 did not alter the tail-flick latency, (Ib) Repeated administration of MPD decreased tail-flick latency, while repeated administration of MK-801 had no significant effect on tail-flick latency, (Ic) MK-801 given prior to or with MPD reversed the chronic effect on tail-flick latency produced by MPD; (IIa) When both drugs were independently given, MPD elicited a decrease in rectal temperature, while MK-801 alone produced an increase in temperature, (IIb) When given together, MK-801 had a transient effect in blocking the sensitization to MPD but failed to reverse the sensitization of MPD once it had developed; and (III) Both MK-801 and MPD caused an unstable pattern of body weight gain. Hence, the results of this study in rats suggest that MK-801 can modulate non-motor effects of MPD.     

Irreversible Amnesia in Rats and Edible Snails under Conditions of Associative Memory Reconsolidation Disturbance Caused by NMDA-Glutamate Receptor Antagonist

The effect of MK-801, an antagonist to NMDA-glutamate receptors, on reconsolidation of olfactory discrimination task in rats and taste discrimination in edible snails was examined. Twenty-four hours after conditioning, the animals received a single systemic injection of MK-801 followed by a reminding conditional stimulus. Disturbances in retrieval of the acquired task were observed 10 days after injection followed by a reminding procedure. Repeated conditioning of these animals did not restore the task. Injection of MK-801 without reminding stimulation had no effect on task retention. Thus, disturbances of NMDA-dependent reconsolidation of the associative memory in animals of different taxonomic groups irreversibly eliminated long-term memory.     

Differential effects of posterior septal lesions on dispositional and representational memory

A distinction between two classes of memory has been made in terms of the sensory availability of cues at the time of making discriminations which are influenced by past experience. Three tasks objectively defining this distinction were learned in a T-maze by three groups of rats: a delayed nonmatching-to-sample (DNMTS) which depends on representational memory; a simple sensory discrimination (SD) which depends on dispositional memory; and a more difficult discrimination, which also depends on dispositional memory, called the simultaneous conditional discrimination (SCD). The DNMTS and SD tasks were acquired quickly; the SCD task took many more trials. Posterior septal lesions impaired DNMTS performance but had no effect on retention of either the conditional discrimination (SCD) or the simple sensory discrimination (SD) tasks which depend on dispositional memory. The present study provides further evidence that dispositional and representational memory systems have at least partially distinct anatomical substrates in the brain and that it is the representational and not the conditional aspects of the DNMTS task that are impaired by the septal lesions.     

Substantia nigra lesion suppresses the antagonistic effects of N-methyl-d-aspartate receptor antagonist (MK-801) on the autotomy in the rat

Rats received right dorsal root ganglionectomy (DRGn) to induce autotomy, and were treated with MK-801 and/or left stantia nigra (SN) lesion after DRGn. The behavior was quantified using an autotomy grading scale. All the rats in the control groups manifested autotomy from 4 to 19 days after DRGn and attained the highest autotomy score. The group treated with MK-801 immediately after DRGn showed suppression of the development of autotomy. The groups receiving left SN lesion with 6-hydroxydopamine immediately, 2, or 4 days after DRGn showed similar patterns of autotomy as the control groups. However, when combined with the administration of MK-801 immediately after DRGn, SN lesion done immediately or 2 days after DRGn suppressed the antagonistic effect of MK-801 (P<0.01). When the SN lesion was delayed by 4 days, the suppression effect disappeared. These data suggest that the action of the NMDA receptor antagonist on the autotomy within 4 days after DRGn depend on the integrity of the dopaminergic system.     

离子型谷氨酸受体拮抗剂MK-801浓度与全脑缺血再灌注大鼠海马内源性神经干细胞的增殖**

背景：脑缺血再灌注后,过度释放的兴奋性氨基酸可通过N-甲基-D-天冬氨酸(NMDA)受体激活内源性神经干细胞,促使其增殖、分化,修复神经细胞,但同时也导致细胞内钙离子超载,引起神经细胞的损伤。 目的：观察NMDA受体拮抗剂MK-801浓度对脑缺血再灌注大鼠海马内源性神经干细胞增殖的影响。 方法：SD大鼠随机分为正常对照组、手术对照组及MK-801 0.2,0.4,0.6,0.8,1.0,1.2 mg/kg组。除正常对照组外,大鼠首先进行侧脑室插管,3 d后进行4条血管阻断方法制备大鼠全脑缺血再灌注模型。在模型制作前30 min按照不同浓度侧脑室注射MK-801。正常对照组和手术对照组侧脑室注射同剂量的生理盐水。免疫组织化学、RT-PCR技术检测各组脑海马nestin阳性细胞及其mRNA表达。 结果与结论：MK-801浓度在0.8 mg/kg以下时,用药组大鼠脑海马nestin mRNA及蛋白的表达与手术对照组差异无显著性意义(P > 0.05),呈现高表达;当MK-801浓度达到0.8 mg/kg时,与手术对照组相比,用药组大鼠脑海马nestin基因及蛋白的表达明显下降(P < 0.05),并随浓度的增高呈递减趋势。提示MK-801在浓度为0.6 mg/kg时,即可抑制钙超载保护神经元,又有良好的刺激神经干细胞增殖作用。 关键词：离子型谷氨酸受体拮抗剂;脑缺血;再灌注;神经干细胞;MK-801 doi:10.3969/j.issn.1673-8225.2012.06.012