The NMDA antagonist MK-801 affects nonspatial learning in preweanling rats.

The N-methyl-{d}-aspartate (NMDA) subtype of the excitatory amino acid receptor has been implicated in several kinds of learning and memory, as well as in long-term potentiation (LTP), a putative cellular mechanism for learning and memory. This experiment examined the role of the NMDA receptor in patterned single-alternation (PSA) learning in preweanling rats following intraperitoneal injections of 0.05 mg/kg MK-801, a selective NMDA antagonist. MK-801 significantly inhibited PSA at both 60-sec and 30-sec intervals (ITIs). and attenuated, but did not block Iearning at 8-sec . These results are compared with effects on PSA, a form of nonspatial, memory-based learning, observed; after early postnatal exposure to alcohol, infant hippocampal lesions, and infant exposure to X-irradiation, and they add strongly to these earlier demonstrartions of the role of the hippocampus in learning and memory that is clearly nonspatial and non-cognitive-map-related. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Subchronic MK-801 treatment to juvenile rats attenuates environmental effects on adult spatial learning

Forty eight primary and 20 secondary chondrosarcomas were treated surgically 1975 through 1991. An evaluation of the data of the Bone Tumor Register of the Semmelweis Medical University proved that the incidence of the malignant transformation and development of secondary chondrosarcomas is 3% and 2.6% among solitary osteochondromas. The authors summarize the clinicopathological characteristics of the malignant transformation. A retrospective evaluation of the histological grade of the malignancy proved that 67% of tumors were classified as grade I; 18% as grade II and 15% as grade III. The survival of the patients was mainly determined by the grade of the malignancy. A 95% 5-years survival was found in the grade I group and a 10% survival only in the grade II and III groups. In the cases of highly malignant chondrosarcomas radical surgical intervention i.e. amputation is recommended, considering the most often extra-compartmental location of the tumors. Low malignant and intra-compartmental highly malignant chondrosarcomas should be treated, however, by limb saving surgery. In the cases of large inresecable but low malignant chondrosarcomas debulking surgery is also acceptable.     

Conditioned stimulus familiarity determines effects of MK-801 on fear extinction.

Six experiments studied the role of conditioned stimulus (CS) familiarity in determining the effects of the N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 on fear extinction. Systemic administration of MK-801 (0.1 mg/kg) impaired initial extinction but not reextinction learning. MK-801 impaired reextinction learning when the CS was relatively novel during reextinction training but not initial extinction learning when the CS was relatively familiar during initial extinction training. A context change failed to reinstate the sensitivity of initial fear extinction learning about a relatively familiar CS to MK-801. These experiments show that CS familiarity is an important determinant of effects of MK-801 on fear extinction learning: MK-801 impaired extinction learning about novel stimuli but spared extinction learning about familiar stimuli. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

MK-801 has neuroprotective and antiproliferative effects in retinal laser injury

PURPOSE: Treatment of the retina by laser photocoagulation often is complicated by an immediate side effect of visual impairment, caused by unavoidable, laser-induced destruction of healthy tissue adjacent to the lesion. A neuroprotective therapy that salvages this healthy tissue might enhance the benefit obtained from the treatment. This study was proposed to determine whether glutamate-receptor blockers can provide adjuvant neuroprotection during laser photocoagulation. The effect of MK-801, an NMDA-receptor antagonist, on laser-induced retinal injury was examined, in a rat model. METHODS: Argon laser lesions were created in the retinas of 36 DA rats, and were followed immediately by intraperitoneal injections of MK-801 (2 mg/kg) or saline. The animals were killed after 3, 20, or 60 days and the retinal lesions were evaluated histologically and morphometrically. RESULTS: Photoreceptor-cell loss was significantly less in MK-801-treated rats than in control animals. The proliferative membrane composed of retinal pigment epithelial cells and neovascular blood vessels, which was seen at the base of the lesion in control group retinas, was smaller in the MK-801-treated retinas. In rats treated with a higher dose of MK-801, the lesions showed almost no proliferative reaction. CONCLUSIONS: A potent noncompetitive NMDA-receptor blocker, MK-801 exhibits neuroprotective and antiproliferative properties in the retina. Glutamate-receptor blockers should be investigated further as potential adjuvant therapy in retinal photocoagulation treatments.     

Aging and the effects of MK-801 on anoxic damage in rat hippocampal slices

A high-performance liquid chromatography assay for hydroxyurea in human serum was developed based on a commercial colorimetric assay kit for urea (Sigma Diagnostics). Serum (0.5 ml), spiked with methylurea as an internal standard, was treated with 70% perchloric acid. Supernatant (0.2 ml) was combined with 0.7 ml of BUN acid reagent and 0.6 ml of BUN color reagent. The resulting colored reactant (100 microl) was analyzed on a 300 x 3.9 mm Bondclone 10 C18 column coupled with a UV-Vis detector, at 449 nm. The mobile phase was 13% acetonitrile in water. Retention times of colored derivatives of hydroxyurea and methylurea were 6.5 and 12.2 min, respectively. The log-log calibration curve was linear from 0.0065 to 1.31 mM. Average accuracy was 99.9+/-4.0% and the intra- and inter-day error of assay did not exceed 11%.     

The effect of dizocilpine (MK-801) on conditional discrimination learning in the rat

OBJECTIVES: To report the effects of the anti-oestrogen tamoxifen on biochemical and haematological parameters. DESIGN: Randomized, double-blind comparison of tamoxifen 20 mg per day and placebo, over two years. SETTING: A university hospital. SUBJECTS: Forty-six healthy late-postmenopausal women (mean, SD time since menopause; 11, seven years). MAIN OUTCOME MEASURES: Blood specimens were drawn in the fasting state at baseline, six months and two years for measurement of haemoglobin, haematocrit, erythrocyte mean cell volume, mean erythrocyte haemoglobin, leucocyte count, platelet count, urea, electrolytes, creatinine and albumin. RESULTS: There was a significant decline in the haemoglobin concentration in the tamoxifen group (-4.4, 1.2 g/L; mean, SE) and its levels were lower in this group than in those receiving placebo (P = 0.004). Similarly, haematocrit, erythrocyte count and total leucocyte count were lower in those on placebo (P = 0.002, P = 0.01 and P = 0.01, respectively) and platelet count showed a similar trend (P = 0.08). In the tamoxifen group, the level of serum albumin fell significantly (-2.2, 0.4 g/L) and was lower throughout the study than that in the placebo group (P = 0.006). That of serum urea tended to fall (-0.4, 0.2 mmol L) but the between-groups comparison was not significant (P = 0.18). CONCLUSIONS: These data suggest that tamoxifen exerts a haemodilutory effect in normal postmenopausal women. Since a similar effect has been reported in response to postmenopausal oestrogen therapy, it is likely that the observed changes represent another oestrogenic effect of tamoxifen in postmenopausal women. Haemodilution may contribute to the reduced incidence of cardiovascular disease reported in tamoxifen-treated women, and, therefore, its assessment in the new oestrogen agonists/antagonists being developed for cardiovascular disease prevention may be important.     

Parallel recovery of MK-801-induced spatial learning impairment and neuronal injury in male mice

The relationship between spatial learning impairment and reversible neuronal injury in the posterior cingulate/retrosplenial (PC/RS) cortex induced by MK-801 in male mice was studied using a four-corner holeboard task. Mice were dosed with 1 mg/kg MK-801 and tested on acquisition of a new "baited" hole at 5 or 12 h posttreatment. Acquisition in drugged mice was impaired at 5 h, but not at 12 h posttreatment. Their retention performances were unaffected 24 h after either the 5 or 12 h posttreatment acquisition sessions. MK-801 (1 mg/kg) was found to induce locomotor hyperactivity and some sensorimotor impairment at 5 h posttreatment. which could have contributed to the acquisition deficit. However, nonassociative effects of the drug were not prominent because this same dose did not impair holeboard performance at 5 h posttreatment when the task was well learned. Histologic experiments showed that many injured neurons (containing cytoplasmic vacuoles) were present in the PC/RS cortex at 5 h posttreatment but the reaction was essentially reversed at 12 h posttreatment. The results suggest that the acquisition impairment and neuronal injury induced by MK-801 evolve and recover in parallel according to a similar time schedule.     

Bivalent effects of MK-801 on ethanol-induced sensitization do not parallel its effects on ethanol-induced tolerance.

The relationship between the effects of the N-methyl-D-aspartate (NMDA) antagonist MK-801 on acute responses to ethanol and its ability to block ethanol sensitization and tolerance was examined in DBA/2J mice. Cross-sensitization between these drugs was also studied. Repeated administration of 0.1 mg/kg MK-801 with ethanol potentiated, whereas 0.25 mg/kg attenuated, sensitization to ethanol's locomotor stimulant effects; rearing was similarly affected. There was evidence for cross-sensitization between ethanol and 0.25 mg/kg MK-801. MK-801 potentiated ethanol's ataxic effects in the grid test, but had no effect on tolerance to this effect. MK-801's effects on ethanol sensitization appeared to be related to its own behavioral effects, rather than NMDA receptor blockade per se. Further, these studies demonstrate dissociation between ethanol sensitization and tolerance. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Modeling the effects of the NMDA receptor antagonist MK-801 on timing in rats.

The NMDA receptor antagonist MK-801 produces different effects on timing tasks. In particular, MK-801 produces an underestimation of duration when animals are tested with the differential reinforcement of low rate of responding (DRL) schedule and an overestimation of duration when animals are tested with the peak-interval (PI) procedure. The goal of this study was to develop a model-based explanation for this discrepancy. Two computer simulations were conducted via an implementation of scalar expectancy theory (SET). In Simulation 1, SET was used to provide a quantitative account of PI timing data. Simulation 2 used parameter estimates from Simulation 1 to predict effects of MK-801 on the DRL task. DRL predictions provided a close match to previous empirical data. Results of the simulations suggest that differences in the literature are likely due to inherent differences between PI and DRL tasks, rather than fundamental differences in timing. Overall, the role of NMDA receptors in timing appears to be multifaceted, impacting perception, memory, and decision processes. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Spatial and nonspatial learning in mice: effects of S100 beta overexpression and age

S100 beta, a Ca2+ binding astrocytic brain protein implicated in brain development and neurophysiology, has elevated levels in progressive neurodegenerative diseases, Down's Syndrome, and Alzheimer Disease. Transgenic mice carrying multiple S100 beta gene copies exhibited abnormal exploratory behaviors and synaptic processes suggesting hippocampal dysfunction. Here we analyze learning in a hippocampal-dependent (spatial) as well as a non-hippocampal-dependent (nonspatial) version of the Morris water maze and compare CD1 control and CD1-derived S100 beta transgenic mice. We also investigate possible progressive age-dependent effects of S100 beta overexpression by comparing two age groups of the above mice: 3- and 16-month-old. We show that 3-month-old S100 beta transgenic mice have a spatial task-specific impairment confirming a hippocampal dysfunction. However, we found the 16-month-old transgenic mice statistically indistinguishable from their normal counterparts, a result that does not confirm progressive S100 beta transgene effects. We also show that age, independently of the transgene, impairs spatial learning, spares nonspatial learning and reference memory, but leads to behavioral rigidity.     

The influence of nimodipine and MK-801 on the brain free arachidonic acid level and the learning ability in hypoxia-exposed rats

1. The influence of voltage dependent calcium channel blocker (VDCC), nimodipine and N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801 on the brain free arachidonic acid (FAA) level and on the learning ability in hypoxia-exposed rats was examined. 2. Some animals were decapitated after cerebral hypoxia had been obtained and the brain FAA level was determined by gas chromatography. The other animals were trained in a passive avoidance procedure and were exposed to hypoxic conditions immediately after the learning trial response had been acquired. A passive avoidance retention test was performed 24 hours later. 3. Various doses of nimodipine (0.03; 0.1; 0.3 and 1.0 mg/kg) and MK-801 (0.03; 0.1 and 0.3 mg/kg) had been injected 30 minutes before biochemical or behavioral procedures started. 4. It was found that hypoxia strongly increased the brain FAA level and impaired the retention of the passive avoidance response. 5. Pretreatment with 0.3 mg/kg and 1.0 mg/kg of nimodipine prevented the brain FAA accumulation. It has also been shown that all tested doses of nimodipine significantly improved the retention deficit in the animals exposed to hypoxia. 6. Neither the one of tested doses of MK-801 influenced significantly the increase of the brain FAA level and/or passive avoidance behavior in hypoxic animals. 7. These results confirm the hypothesis that the brain FAA accumulation and cognitive impairment, caused by hypoxia, are maybe associated with disturbances in calcium homeostasis and that nimodipine may be useful in ameliorating the hypoxia-induced brain tissue damage. Blocade of NMDA receptor-channel complex by MK-801 was not sufficient to prevent hypoxia-induced neuronal damage.     

Chronic treatment with MK-801 decreases D2 dopamine receptor function in rat striatum

Present results show that a single treatment with dizocilpine (MK-801, 0.25 mg/kg IP) failed to modify the specific binding to D1 or D2 DA receptors. In contrast, repeated administrations for 3 weeks resulted in a statistically significant decrease of [3H]Spiroperidol binding to cortical or striatal membranes but did not change the number or the apparent affinity of [3H]MK-801 binding in well-washed cortical membranes. Consistent reduction in specific D2 receptor mediated behavior was obtained. The data suggest that the changes in DAergic function following repeated administrations with MK-801 could be suggestive of potential therapeutic uses of negative allosteric drugs in some DA related dysfunctions.     

Clonidine potentiates the neuropathic pain-relieving action of MK-801 while preventing its neurotoxic and hyperactivity side effects

Antagonists of NMDA glutamate receptors have been shown to alleviate neuropathic pain in rats and humans. However, NMDA antagonists can cause significant side effects ranging from behavioral disturbances to injury of neurons in the posterior cingulate/retrosplenial (PC/RS) cortex. We have found that alpha-2 adrenergic agonists prevent the PC/RS neurotoxic side effects of NMDA antagonists. In the present study of adult female rats subjected to sciatic nerve ligation (Bennett neuropathic pain model) and tested for paw withdrawal latency (PWL) following a thermal stimulus, we evaluated the ability of the NMDA antagonist, MK-801, to alleviate neuropathic pain either by itself or when administered together with the alpha-2 adrenergic agonist, clonidine. We found that MK-801, at a dose (0.05 mg/kg s.c.) that is known to cause mild hyperactivity but is subthreshold for producing PC/RS neurotoxic changes, relieved the neuropathic pain state associated with sciatic nerve ligation. However, the relief at this dose was very transient, and no neuropathic pain-relieving effect was observed at a lower dose (0. 025 mg/kg s.c.) of MK-801. Clonidine, at a dose (0.05 mg/kg s.c.) that prevents the cerebrocortical neurotoxic effects of MK-801, decreased sensitivity to the thermal stimulus equally under all conditions (ligated, sham ligated, unoperated), but did not specifically relieve neuropathic pain in the ligated limb. Combining this dose of clonidine with an ineffective dose (0.025 mg/kg s.c.) of MK-801 provided specific, complete and long lasting (up to 4 h) relief from neuropathic pain. Rats receiving this drug combination did not display hyperactivity or any other behavioral disturbance typically associated with MK-801 treatment, nor show neurotoxic changes in cerebrocortical neurons. In separate experiments on normal unoperated rats, we found that clonidine (0.05 mg/kg s.c.) counteracted the hyperactivity induced by MK-801 (0.05 mg/kg s.c.) and returned activity levels to a normal range. These findings signify that clonidine, which does not specifically relieve neuropathic pain, can potentiate the neuropathic pain-relieving action of MK-801, while also protecting against neurotoxicity and hyperactivity side effects of MK-801. The potentiation is of a sufficient magnitude that it permits cutting the MK-801 dose requirement in half, thereby achieving prolonged neuropathic pain relief while doubling the margin of safety against any type of side effect that might be mediated by blockade of NMDA receptors.     

Neuropeptide Y and the calcitonin gene-related peptide attenuate learning impairments induced by MK-801 via a sigma receptor-related mechanism

It has been shown recently that low doses of sigma (sigma) receptor ligands like 1,3-di-(2-tolyl)guanidine (DTG), (+)N-allylnormetazocine [(+)SKF 10,047] and (+)pentazocine can antagonize learning impairments induced by dizocilpine (MK-801), a non-competitive antagonist at the NMDA receptor channel. This antagonism has been proposed to involve sigma receptor sites since it is blocked by the administration of purported sigma antagonists such as NE-100 and BMY-14802. It has also been demonstrated that peptides of the neuropeptide Y (NPY) and calcitonin gene-related peptide (CGRP) families modulate, in vivo, sigma labelling and electrophysiological effects in the hippocampal formation. Accordingly, we investigated if NPY- and CGRP-related peptides modulate cognitive processes by interacting with sigma sites in mice. In order to test this hypothesis, a step-down passive avoidance task was used. Interestingly, similarly to various sigma agonists, NPY, peptide YY (PYY) and the Y1 agonist [Leu31Pro34]NPY (but not NPY[13-36], a purported Y2 agonist), as well as hCGRPalpha and the purported CGRP2 agonist [Cys(ACM)2-7]hCGRPalpha (but not CGRP[8-37], a CGRP1 receptor antagonist), significantly attenuated learning impairments induced by MK-801. Furthermore, the effects of NPY, [Leu31Pro34]NPY, hCGRPalpha and [Cys(ACM)2-7]hCGRPalpha were blocked by the administration of the sigma antagonist, BMY-14802. The present data suggest that NPY- and CGRP-related peptides can indirectly interact in vivo with sigma receptors to modulate cognitive processes associated with NMDA receptor function.     

Effects of MK-801 on spatial memory in homing and nonhoming pigeon breeds.

Homing pigeon breeds, the product of artificial selection on the basis of navigational and spatial ability, differ from nonhoming breeds in hippocampal size and distribution of N-methyl-{d}-aspartate (NMDA) dependent receptors. The effects of MK-801 (0.1 mg/kg administered intraperitoneally [ip]), a noncompetitive NMDA antagonist, on spatial reference memory (RM) were compared between the 2 breeds in a radial arm maze task. MK-801 disrupted the acquisition of RM in the nonhoming group but not the homing group, which was equivalent to the 2 saline-only control groups. As in previous findings with mammals, working memory was not affected by MK-801. This behavioral dissociation, coupled with differences in NMDA-dependent long-term potentiation between breeds, suggests an exceptional opportunity to investigate the role and function of the dorsomedial telencephalon region in spatial RM, through anatomical, neurochemical, and behavioral comparisons between homing and nonhoming pigeon breeds. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Dissociating the long-term effects of fetal/neonatal iron deficiency on three types of learning in the rat.

Iron deficiency (ID) is a common nutrient deficiency worldwide. This condition is linked to changes in myelin formation, dopaminergic function, and energy metabolism. Early ID results in persistent long-term cognitive and behavioral disturbances in children, despite a return to normal iron status. The present study assesses formerly ID adult rats on maze learning tasks that depend on specific brain regions related to learning, specifically the hippocampus, striatum, and amygdala. Rat dams were fed ID chow starting on gestational Day 2 through postnatal Day 7, and behavioral testing began at postnatal Day 65--following a return to normal iron status. Formerly ID rats exhibited delayed acquisition of the hippocampus-dependant task and no differences from controls on the striatum- and amygdala-dependent tasks. These findings likely reflect long-term reduction in but not abolition of hippocampus-dependent learning and preserved function in other brain structures (e.g., striatum and amygdala). (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Spatial and nonspatial learning across the rat estrous cycle.

Recent evidence has demonstrated that there are fluctuations in both the anatomy and physiology of the hippocampus across the estrous cycle of the female rat. In the present study we examined the behavioral implications of these changes by testing females on either a hippocampal or nonhippocampal version of the Morris water maze during the various phases of the estrous cycle. Males were also tested on these tasks. Although there was little variance on the nonhippocampal cue task, females in proestrus performed significantly better than those in estrus. Optimal female performance on the spatial version of the task occurred during the phase of estrus, whereas the least efficient performance occurred during proestrus. These results do not support the traditional view that hippocampal long-term potentiation is positively correlated with spatial learning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Adenosine A1 and A2 receptor agonists significantly prevent the electroencephalographic effects induced by MK-801 in rats

Both N6-cyclopentyladenosine (CPA, adenosine A1 receptor agonist) and 2-[4-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamido-adenosi ne (CGS 21680, adenosine A2 receptor agonist) inhibited the electroencephalographic (EEG) effects induced by the noncompetitive NMDA receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo-(a,d)cyclohepten-5,10-imine maleate (MK-801) in rats. While the inhibitory effects of CPA were evident at doses (0.1 and 0.5 mg/kg i.p.) devoid of intrinsic behavioral effects, CGS 21680 was effective only when administered at depressant doses (2 mg/kg i.p.). Since the effects induced by NMDA receptor antagonists may be regarded as a model of psychosis, these results suggest a possible role of adenosine receptor agonists as antipsychotics.     

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. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Comparison of the amnestic effects on NMDA receptor antagonist MK-801 and nitric oxide synthase inhibitors: L-NAME and L-NOARG in goldfish.

Investigations indicate that the induction of long-term potentiation (LTP) may be mediated by postsynaptic N-methyl-D-aspartate (NMDA) receptors and that the maintenance of LTP may be initiated by nitric oxide (NO), a retrograde messenger carrying signals backward from the postsynaptic to the presynaptic neuron. The present study compared amnestic effects of dizocilpine maleate (MK-801), an NMDA receptor antagonist, and nitro-L-arginine-methyl-ester (L-NAME) and N-nitro-L-arginine (L-NOARG), nitric oxide (NO) inhibitors, in goldfish, using active-avoidance conditioning as the learning paradigm. The results showed that MK-801 and NO inhibitors produced anterograde amnesia at doses that did not impair performance processes necessary for learning to occur. Furthermore, MK-801 did not produce retrograde amnesia, whereas L-NAME did, suggesting that MK-801 impaired learning whereas NO inhibitors impaired memory consolidation and possibly also learning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)