Effects Of MK-801 Research Articles

Comparison of effects of the different dosage MK-801 on recognition memory in rats

Objective To observe the behavioral effects of acute administration of dizocilpine(MK-801) in rats, and to determine an appropriate doses of the drug to mimicking memory deficits of schizophrenia. Methods 192 rats were randomly divided into model groups and control group, and given different doses of MK-801 or saline.Locomotor activity, pre-pulse inhibition (PPI) test and novel object recognition test were studied respectively. Results The spontaneous activity increased in a dose-dependent manner after the treatment of MK-801.The total distances of locomotor activity in 0.3 mg/kg group((127.04±32.35)m) exhibited a significant difference compared with control group((35.34±12.81)m, P<0.05). MK-801 decreased PPI in dose-dependent manner(P<0.01). MK-801 0.1 mg/kg((103.45±68.04)%) and 0.3 mg/kg ((41.55±62.93)%) groups showed significant differences compared to control group((200.39±30.97)%) in PPI.The discrimination index of 0.03 mg/kg group((15.78±6.23)%) and 0.1 mg/kg group((22.42±3.85)%) were lower than that in control group((39.42±3.86)%, P<0.05). Conclusion It is necessary for select right doses for model different endophenotypes of schizophrenia by MK-801.0.03 mg/kg of MK-801 is a relatively appropriate dosage to cause recognition memory damage. Key words: Schizophrenia; Dizocilpine maleate; Recognition memory

Effects of MK-801 and amphetamine treatments on allergic lung inflammatory response in mice

Glutamate acts as a neurotransmitter within the Central Nervous System (CNS) and modifies immune cell activity. In lymphocytes, NMDA glutamate receptors regulate intracellular calcium, the production of reactive oxygen species and cytokine synthesis. MK-801, a NMDA receptor open-channel blocker, inhibits calcium entry into mast cells, thereby preventing mast cell degranulation. Several lines of evidence have shown the involvement of NMDA glutamate receptors in amphetamine (AMPH)-induced effects. AMPH treatment has been reported to modify allergic lung inflammation. This study evaluated the effects of MK-801 (0.25mg/kg) and AMPH (2.0mg/kg), given alone or in combination, on allergic lung inflammation in mice and the possible involvement of NMDA receptors in this process. In OVA-sensitized and challenged mice, AMPH and MK-801 given alone decreased cellular migration into the lung, reduced IL-13 and IL10 levels in BAL supernatant, reduced ICAM-1 and L-selectin expression in granulocytes in the BAL and decreased mast cell degranulation. AMPH treatment also decreased IL-5 levels. When both drugs were administered, treatment with MK-801 reversed the decrease in the number of eosinophils and neutrophils induced by AMPH in the BAL of OVA-sensitized and challenged mice as well as the effects on the expression of L-selectin and ICAM-1 in granulocytes, the IL-10, IL-5 and IL-13 levels in BAL supernatants and increased mast cell degranulation. At the same time, treatment with MK-801, AMPH or with MK-801+AMPH increased corticosterone serum levels in allergic mice. These results are discussed in light of possible indirect effects of AMPH and MK-801 via endocrine outflow from the CNS (i.e., HPA-axis activity) to the periphery and/or as a consequence of the direct action of these drugs on immune cell activity, with emphasis given to mast cell participation in the allergic lung response of mice.

Does increasing the ratio of AMPA-to-NMDA receptor mediated neurotransmission engender antidepressant action? Studies in the mouse forced swim and tail suspension tests

Monoamine-based antidepressant drugs increase α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) function and decrease N-methyl-d-aspartate receptor (NMDAR) function. The NMDAR antagonist ketamine shows potent antidepressant action in humans and the antidepressant-like effects of ketamine and monoamine-based antidepressants in rodents depend on increased AMPAR throughput. Further, the antidepressant-like effects of monoamine-based antidepressants are enhanced by AMPAR potentiation and by NMDAR antagonism. This has led to a hypothesis that antidepressant efficacy involves an increases ratio of AMPAR-to-NMDAR-mediated neurotransmission. To further elucidate the interaction of AMPAR, NMDAR and monoamine transmission we tested combinations of the AMPAR positive allosteric modulator (AMPA potentiator), (R,R)-N,N-(2,20-[biphenyl-4-40-diyl]bis[propane-2,1-diyl])dimethanesulfonamide (PIMSD), with: the uncompetitive NMDAR antagonist MK-801; nicotine, which has potent glutamate-releasing properties; and the selective serotonin reuptake inhibitor escitalopram using the mouse forced swim (mFST) and tail suspension tests (mTST). MK-801, nicotine or escitalopram did not induce antidepressant-like effects in either of the two tests. PIMSD enhanced the effect of MK-801 in the mFST, supporting the hypothesis that increasing AMPAR-to-NMDAR-mediated neurotransmission conveys antidepressant action. Nicotine-induced glutamate release simultaneously activates NMDARs and AMPARs and showed no net effect in the mFST when given alone. However, increasing the ratio of AMPAR-to-NMDA-R transmission by favouring AMPAR throughput with PIMSD revealed an antidepressant-like action of nicotine in the mFST. PIMSD also enhanced the effect of escitalopram treatment in the mFST and mTST, supporting existing evidence and suggesting a synergistic effect of simultaneously facilitating monoamine transmission and increasing the ratio of AMPAR-to-NMDAR throughput. No synergistic effects of the PIMSD+MK-801 or PIMSD+nicotine were found in the mTST, indicating a differential sensitivity of mFST and mTST when investigating glutamate-based antidepressant mechanisms. This study corroborates existing evidence that there may be an unexploited therapeutic potential in treating depression by directly increasing the ratio of AMPAR-to-NMDAR neurotransmission, possibly in combination with monoamine-based mechanisms.

Reconsolidation and extinction of an appetitive pavlovian memory

When memories are retrieved, they can enter a labile state during which the memory may be modified and subsequently restabilized through the process of reconsolidation. However, this does not occur in all situations, and certain “boundary conditions” determine whether a memory will undergo reconsolidation. Naïve male lister hooded rats were trained for 5days to press a lever in order to retrieve a food reward associated with a pavlovian light stimulus. Three days post-training, animals were injected with either MK-801 (0.1mgkg−1; i.p.) or saline vehicle, 30min before they were placed back into the training context for a retrieval session. Lever pressing was reinforced only by the light stimulus and was restricted to either 10, 30 or 50 presentations of the light conditioned stimulus. After 48h, animals were again returned to the boxes and light-reinforced lever-pressing activity was recorded. MK-801-treated animals in the 10CS group significantly reduced lever pressing at test, compared to saline controls. In contrast, MK-801-treated rats in the 50CS group demonstrated a significant increase. There was no effect of MK-801 in the 30CS group. Additionally, there were no effects of MK-801 in an analogous, pure instrumental, setting when the cue lights were omitted. The opposing effects of MK-801 under different parametric conditions likely reflect impairments of appetitive pavlovian memory reconsolidation and extinction, respectively. These results demonstrate a competition between reconsolidation and extinction. However, there are also conditions under which MK-801 fails to impair either process.

Visuospatial working memory is impaired in an animal model of schizophrenia induced by acute MK-801: An effect of pretraining

Deficient working memory was proposed as an endophenotype of schizophrenia. Such deficits are also commonly found in animal models of schizophrenia-like behavior of various origins. An allothetic place avoidance alternation task was proposed as a behavioral test of visuospatial working memory. This study tested the hypothesis that working memory in this test would be impaired by acute pre-test treatment with MK-801 (dizocilpine) in an animal model possessing high phenomenological and predictive validity. Furthermore, the study sought to determine the effect of pretraining to the task prior to treatment on the subsequent learning in the animal model. The results show that both doses of MK-801 (0.12mg/kg and 0.15mg/kg) significantly impaired working memory in the alternation paradigm, and both doses also increased locomotor activity. Notably, in previously pretrained animals, the significant effect of MK-801 on working memory was absent, despite persistent hyperlocomotion. These results showed that a deficit in working memory was detectable in this animal model of schizophrenia-like behavior, but its occurrence depended on the previous experience of animals with familiarization in the task.

Two learning tasks provide evidence for disrupted behavioural flexibility in an animal model of schizophrenia-like behaviour induced by acute MK-801: A dose–response study

Schizophrenia is a chronic and devastating illness. Exact causes of the disease remain elusive; however, neurodevelopmental changes in the brain glutamate system are recognized to play an important role. Several animal models of the disease are induced by a systemic blockade of N-methyl-d-aspartate (NMDA) receptors. This study examined the animal model of schizophrenia-like behaviours induced by acute treatment with MK-801, a non-competitive NMDA-receptor antagonist. Behavioural flexibility is an ability to adapt to the changes in environment, and schizophrenia is often accompanied by its decrease. The study tested the effect of MK-801 on behavioural flexibility in an active place avoidance task and the Morris water maze (MWM). Flexibility was tested under reversal conditions, i.e., after changing the location of the target. Each spatial task addressed different functions; continuous coordinate-frame segregation was present in the active place avoidance and precise place representation in the MWM. Results showed that reversal was altered in both tasks by MK-801 at doses of 0.10–0.15mgkg−1. Some impairment was observed in the active place avoidance task at 0.08mgkg−1. Swimming towards a visible platform was impaired only by the highest dose (0.15mgkg−1). The results demonstrate that a significant impairment of behavioural flexibility accompanies this acute animal model of schizophrenia-like behaviours, and that active place avoidance had higher sensitivity for such deficits than the MWM. This suggests the usefulness of the reversal paradigm in both tasks for examining novel drugs with antipsychotic and procognitive actions.

Effect of MK-801, a non-competitive NMDA receptor antagonist, on motor deficits induced by focal cerebral ischemia in the rat

زمینه و هدف : از آنجائی که گیرنده­های NMDA به عنوان یک هدف درمانی در سکته مغزی پیشنهاد شده­اند، در این مطالعه اثر MK-801 ، آنتاگونیست غیر رقابتی گیرنده NMDA بر اختلالات حسی- حرکتی ناشی از ایسکمی در مدل انسداد شریان مغزی میانی ( MCAO ) مورد بررسی قرار گرفت . مواد و روش كار: در این مطالعه تجربی، تعداد 30 سر موش صحرایی نر از نژاد ویستار (350-300 گرم) بطور تصادفی در 5 گروه کنترل، شم، ایسکمی و دو گروه ایسکمی تحت تیمار با 801 MK - با دوزهای 5/0 و 1 میلی گرم/کیلوگرم مورد بررسی قرار گرفتند. القاء ایسکمی با انسداد شریان مغزی میانی ( MCAO ) صورت گرفت . بررسی وضعیت حرکتی حیوانات با استفاده از تست روتارود و آزمون تخته شیبدار در طول سه روز مطالعه انجام شد. آنالیز داده ها با استفاده از نرم افزار SPSS و آزمون آنالیز واریانس یک طرفه و تست تعقیبی توکی انجام شد . یافته ها: القاء ایسکمی باعث کاهش مدت زمان باقی ماندن بر روی استوانه در حال حرکت روتارود و نیز کاهش زاویه تخته شیبدار در گروه ایسکمی نسبت به گروه شم گردید (001/0> P ). ت زریق MK-801 با دوزهای 5/0 و 1 میلی گرم/کیلو گرم در طی سه روز بصورت وابسته به دوز باعث افزایش مدت زمان باقی ماندن بر روی روتارود و نیز افزایش زاویه سطح شیبدار نسبت به گروه ایسکمی گردید (001/0> P ). نتيجه‌گيري: تزریق MK-801 اختلالات حسی- حرکتی ناشی از ایسکمی ناحیه ای مغزی را بهبود می بخشد ، بنابراین استفاده از این دارو ممکن است ارزش درمانی برای بیماری سکته مغزی داشته باشد. واژه های كليدي : MK-801 - رسپتور NMDA - ایسکمی مغزی - انسداد شریان مغزی میانی

Induction of S100B Gene Expression in Long-Term Potentiation in the Hippocampal CA1 Field Depends on Activity of NMDA Receptors

The effects of NMDA receptor blocker MK-801 on the increase in S100B protein mRNA content induced by long-term posttetanic potentiation in the hippocampal sections were studied. The level of S100B mRNA after 30-min tetanization in the presence of 10 μM MK-801 constituted 132% of the basal level, which was significantly (226%) lower than the control level. Hence, gene expression, induced by long-term posttetanic potentiation, in the glial cells (similarly as in the neurons) depended significantly on NMDA receptors.

Hippocampal serotonin depletion unmasks differences in the hyperlocomotor effects of phencyclidine and MK-801: quantitative versus qualitative analyses

Antagonism of N-methyl-D-aspartate (NMDA) receptors by phencyclidine (PCP) is thought to underlie its ability to induce a schizophrenia-like syndrome in humans, yet evidence indicates it has a broader pharmacological profile. Our previous lesion studies highlighted a role for serotonergic projections from the median, but not dorsal, raphe nucleus in mediating the hyperlocomotor effects of PCP, without changing the action of the more selective NMDA receptor antagonist, MK-801. Here we compared locomotor responses to PCP and MK-801 in rats that were administered 5,7-dihydroxytryptamine (5,7-DHT) into either the dorsal or ventral hippocampus, which are preferentially innervated by median and dorsal raphe, respectively. Dorsal hippocampus lesions potentiated PCP-induced hyperlocomotion (0.5, 2.5 mg/kg), but not the effect of MK-801 (0.1 mg/kg). Ventral hippocampus lesions did not alter the hyperlocomotion elicited by either compound. Given that PCP and MK-801 may induce different spatiotemporal patterns of locomotor behavior, together with the known role of the dorsal hippocampus in spatial processing, we also assessed whether the 5,7-DHT-lesions caused any qualitative differences in locomotor responses. Treatment with PCP or MK-801 increased the smoothness of the path traveled (reduced spatial d) and decreased the predictability of locomotor patterns within the chambers (increased entropy). 5,7-DHT-lesions of the dorsal hippocampus did not alter the effects of PCP on spatial d or entropy – despite potentiating total distance moved – but caused a slight reduction in levels of MK-801-induced entropy. Taken together, serotonergic lesions targeting the dorsal hippocampus unmask a functional differentiation of the hyperlocomotor effects of PCP and MK-801. These findings have implications for studies utilizing NMDA receptor antagonists in modeling glutamatergic dysfunction in schizophrenia.

1175 – The effect of mk-801 on the erk-creb signal system in prenatally stressed offspring rats

Studies revealed that prenatal stress (PS) may increase the vulnerability to depression in their offspring, and ERK-CREB signal system might play a role in its mechanism. The present study investigated the effect of MK-801 on depressive-like behavior and its impacts on ERK2, CREB, Bcl-2 mRNA expression in PS female rat offspring. The pregnant rats were randomly divided into three groups, the control group (Con) was left undisturbed, the PS-saline group (PS-saline) and the PS-MK-801 group (PS-MK-801) were subjected to restraint stress on days 14–20 of pregnancy three times daily for 45 min, and received an i.p. administration of saline or MK-801(sigma, 0.2 mg/kg) 30 min before the first stress respectively. Forced swimming test was undertaken to assess depressive-like behavior in one month female offspring. ERK2, CREB, Bcl-2 mRNA in the hippocampus, frontal cortex, and striatum were detected by RT-PCR. PS-saline spent significantly more immobile time compared to Con and PS-MK-801 (P < 0.05). ERK2 and CREB mRNA expression in hippocampus and frontal cortex was significantly decreased in PS-saline compared to Con and PS-MK-801 (P < 0.05), while in striatum CREB mRNA expression in PS-saline was lower than Con (P < 0.05). Bcl-2 mRNA expression in hippocampus and striatum was significantly decreased in PS-saline (P < 0.05), and in frontal cortex, its expression was significantly lower in PS-saline and PS-MK-801 (P < 0.05). PS may suppress ERK-CREB signal pathway in female offspring rats, which could be partly prevented by MK- 801. (Supported by National Natural Science Foundation of China, No: 30970952).

Parallel Effect of Nicotine and MK-801 on Brain Metabolism: An In vivo Non Invasive Near-Infrared Spectroscopy Analysis in Rats

Oxygenated haemoglobin, deoxyhaemoglobin and total blood volume are measured with our recently developed Near-Infrared Spectroscopy [NIRS] apparatus allowing in vivo non invasive real time monitoring of brain metabolism in anaesthetized rats. These measurements are indicative of the state of vascular activity and the state of the oxygen saturation, thus of the level of metabolism in the living tissue. Nicotine is a natural alkaloid derived from tobacco that has been implicated in various effects ranging from addiction to toxic effects and neuro-protective actions. Here we analyse the influence of nicotine as well as that of the non competitive NMDA receptor antagonist MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine maleate)] upon brain metabolism in anaesthetized rats. In the first 30min after treatment, nicotine decreases significantly although in a transient manner oxygenated haemoglobin and total blood volume while increasing significantly deoxyhaemoglobin. In addition, MK-801 performed in another group of rats was followed by changes in these three parameters that were similar to those monitored in nicotine treated rats. The NIRS methodology appears to be apt to analyzing non-invasively and in real time the influence of systemic pharmacological treatments upon brain metabolism. In particular the data gathered show similarity of action of the two chemicals studied on influencing metabolic brain “behaviour” proposing that their central protective action may pass via the observed similar changes in brain metabolism. These changes could be a common mechanism of adaptation and protection towards neurotoxicity: mechanism that should be also considered in the intent of developing new pharmaceutical approaches for neuro-protective treatments.

MK-801 Protects against Intracellular Ca2+ Overloading and Improves N-methyl-d-aspartate Receptor Expression in Cerebral Cortex of Methylmercury-Poisoned Rats

Overexposure to methylmercury (MeHg) has been known to induce neurotoxicity. The objective of this study is to explore mechanisms that contribute to MeHg-induced nerve cell apoptosis focusing on the alteration of intracellular Ca(2+) homeostasis and expression of N-methyl-D-aspartate receptors (NMDARs) subunits in rat cerebral cortex and whether MK801, a non-competitive NMDAR antagonist, could attenuate MeHg-induced neurotoxicity. Fifty rats were randomly divided into five groups of 10 animals in each group: control group, MK801 control group, MeHg-treated group (4 and 12μmol/kg) and MK801 pre-treated group. Administration of MeHg at a dose of 12μmol/kg for 4weeks significantly increased in intracellular [Ca(2+)](i) and total Hg levels and that enhanced neurocyte apoptosis rate in cerebral cortex. In addition, the inhibitory effect of MeHg on Na(+)-K(+)-ATPase and Ca(2+)-ATPases might be one of the reasons that cause a significant increase of [Ca(2+)](i) in neurocyte. Over activated by increased cytosolic Ca(2+) loading, calpains degraded NMDAR subunits leading ultimately to nerve cell damage. However, pretreatment with MK801 at a dose of 0.3μmol/kg could prevent Ca(2+) homeostasis dysregulation and alleviate the neurocyte apoptosis. In conclusion, the neuroprotective effects of MK801 appeared to be mediated not only via its NMDA receptor binding properties but also by maintaining intracellular calcium homeostasis.

UCCB01-125, a dimeric inhibitor of PSD-95, reduces inflammatory pain without disrupting cognitive or motor performance: Comparison with the NMDA receptor antagonist MK-801

Excessive N-Methyl-d-aspartate receptor (NMDAR)-dependent production of nitric oxide (NO) is involved in the development and maintenance of chronic pain states, and is mediated by postsynaptic density protein-95 (PSD-95). By binding to both the NMDAR and neuronal NO synthase (nNOS), PSD-95 mediates a specific coupling between NMDAR activation and NO production. NMDAR antagonism shows anti-nociceptive action in humans and animal models of chronic pain but is associated with severe disturbances of cognitive and motor functions. An alternative approach to modulate the NMDAR-related activity is to perturb the NMDAR/PSD-95/nNOS complex by targeting PSD-95, thereby decreasing NO production without interfering with the NMDAR ion channel function. Here, we compared the effects of a dimeric PSD-95 inhibitor, UCCB01-125, and the NMDAR antagonist, MK-801, on mechanical hypersensitivity in the complete Freund's adjuvant (CFA) model of inflammatory pain. To examine side-effect profiles we also compared the effects of UCCB01-125 and MK-801 in tests of attention, long-term memory, and motor performance. When administered concurrently with CFA, both MK-801 and UCCB01-125 prevented the development of CFA-induced mechanical hypersensitivity 1 and 24 h after treatment. Moreover, UCCB01-125 was found to reverse CFA-induced hypersensitivity when administered 24 h after CFA treatment, an effect lasting for at least 3 days. At the dose reducing hypersensitivity, MK-801 disrupted attention, long-term memory, and motor performance. By contrast, even high doses of UCCB01-125 were devoid of side-effects in these tests. The data suggest that PSD-95 inhibition is a feasible strategy to prevent both development and maintenance of chronic inflammatory pain, while avoiding NMDAR antagonism-related side-effects.

Acute N-methyl-d-aspartate receptor hypofunction induced by MK801 evokes sex-specific changes in behaviors observed in open-field testing in adult male and proestrus female rats

Schizophrenia is a complex constellation of positive, negative and cognitive symptoms. Acute administration of the non-competitive antagonist of the N-methyl-d-aspartate receptor (NMDAR) dizocilpine (MK801) in rats is one of few preclinical animal models of this disorder that has both face and/or construct validity for these multiple at-risk behavioral domains and predictive power for the efficacy of therapeutic drugs in treating them. This study asked whether and to what extent the rat NMDAR hypofunction model also embodies the sex differences that distinguish the symptoms of schizophrenia and their treatment. Thus, we compared the effects of acute MK801, with and without pretreatment with haloperidol or clozapine, on seven discrete spontaneous open-field activities in adult male and female rats. These analyses revealed that MK801 was more effective in stimulating ataxia and locomotion and inhibiting stationary behavior in females while more potently stimulating stereotypy and thigmotaxis and inhibiting rearing and grooming in males. Haloperidol and clozapine pretreatments had markedly different efficacies in terms of behaviors but strong similarities in their effectiveness in male and female subjects. These results bear intriguing relationships with the complex male/female differences that characterize the symptoms of schizophrenia and suggest possible applications for acute NMDAR hypofunction as a preclinical model for investigating the neurobiology that underlies them.

Delayed Effects of NMDA Receptor Antagonist MK-801 on Storage and Reconsolidation of Spatial Memory in Rats

We studied the effects of NMDA receptor antagonist MK-801 on the storage and reconsolidation of spatial memory in Morris water maze in adult rats. MK-801 (50 μg/kg) administered 24 h after the completion of training was shown to improve the resistance of spatial memory to spontaneous extinction, while reminder against the background of MK-801 suppresses its ameliorating effect on memory storage. The detected behavioral effects of MK-801 persisted over 60 days after administration and can be associated with its influence on coupled neurogenesis/apoptosis processes induced during memory trace formation in adult animals.

Postnatal choline levels mediate cognitive deficits in a rat model of schizophrenia

In the present study, we investigated whether the essential nutrient choline may protect against schizophrenic-like cognitive deficits in a rat model. Theories regarding the etiology of schizophrenia suggest that early life events render an individual more vulnerable to adult challenges, and the combination may precipitate disease onset. To model this, the adult male offspring of dams who either experienced stress during late gestation or did not were given a 5mg/kg dose of the NMDA antagonist, MK-801. The presence of both the prenatal challenge of stress and the adult challenge of MK-801 was expected to impair memory in these offspring. Memory was not expected to be impaired in rats that did not experience prenatal stress, but did receive MK-801 as adults. To study whether choline levels altered outcomes in these groups, rats were fed a choline-supplemented, -deficient, or standard diet during the period between the two challenges: beginning at weaning and continuing for 25days. All rats consumed regular rat chow thereafter. The efficacy of the model was confirmed in the standard fed rats in that only those that were prenatally stressed and received MK-801 as adults displayed impaired memory on a novelty preference test of object recognition. Contrary to this finding and consistent with our hypothesis, choline-supplemented rats that were also both prenatally stressed and given MK-801 as adults showed intact memory. Choline deficiency impaired memory in rats that were just prenatally stressed, just given MK-801 as adults, and subjected to both. Thus, a choline deficient diet may render rats vulnerable to either challenge. Taken together, we offer evidence that developmental choline levels modulate the effects of prenatal stress and/or MK-801 and thereby alter the cognitive outcome in a rat model of schizophrenia.

Disruption of social approach by MK-801, amphetamine, and fluoxetine in adolescent C57BL/6J mice

Autism is a severe neurodevelopmental disorder, diagnosed on the basis of core behavioral symptoms. Although the mechanistic basis for the disorder is not yet known, genetic analyses have suggested a role for abnormal excitatory/inhibitory signaling systems in brain, including dysregulation of glutamatergic neurotransmission. In mice, the constitutive knockdown of NMDA receptors leads to social deficits, repetitive behavior, and self-injurious responses that reflect aspects of the autism clinical profile. However, social phenotypes differ with age: mice with reduced NMDA-receptor function exhibit hypersociability in adolescence, but markedly deficient sociability in adulthood. The present studies determined whether acute disruption of NMDA neurotransmission leads to exaggerated social approach, similar to that observed with constitutive disruption, in adolescent C57BL/6J mice. The effects of MK-801, an NMDA receptor antagonist, were compared with amphetamine, a dopamine agonist, and fluoxetine, a selective serotonin reuptake inhibitor, on performance in a three-chamber choice task. Results showed that acute treatment with MK-801 led to social approach deficits at doses without effects on entry numbers. Amphetamine also decreased social preference, but increased number of entries at every dose. Fluoxetine (10mg/kg) had selective effects on social novelty preference. Withdrawal from a chronic ethanol regimen decreased activity, but did not attenuate sociability. Low doses of MK-801 and amphetamine were also evaluated in a marble-burying assay for repetitive behavior. MK-801, at a dose that did not disrupt sociability or alter entries, led to a profound reduction in marble-burying. Overall, these findings demonstrate that moderate alteration of NMDA, dopamine, or serotonin function can attenuate social preference in wild type mice.

Effect of the NMDA antagonist MK-801 on latent inhibition of fear conditioning

N-methyl-d-aspartate (NMDA) receptors seem to play a central role in learning and memory processes involved in Latent Inhibition (LI). In fact, MK-801, a non-competitive NMDA receptor antagonist, has proved its effectiveness as a drug for attenuating LI when administered before or after stimulus preexposure and conditioning stages. This paper presents three experiments designed to analyze the effect of MK-801 on LI when the drug is administered before (Experiment 1A) or after (Experiment 1B) preexposure and conditioning stages with a conditioned emotional response procedure. Additionally, we analyze the effect of the drug when it was administered before preexposure, before conditioning or before both phases (Experiment 2). The results show that the effect of the drug varied as a function of the dose (with only the highest dose being effective), the moment of administration (with only the drug administered before the experimental treatments being effective), and the phase of procedure (reducing LI when the drug was administered only at preexposure, and disrupting fear conditioning when administered at conditioning). These differences may be due to several factors ranging from the role played by NMDA receptors in the processing of stimuli of different sensorial modalities to the molecular processes triggered by drug administration.

Protective effects of MK-801 on methylmercury-induced neuronal injury in rat cerebral cortex: Involvement of oxidative stress and glutamate metabolism dysfunction

Methylmercury (MeHg) is one of the ubiquitous environmental toxicants, which can induce oxidative stress and an indirect excitotoxicity caused by altered glutamate (Glu) metabolism. However, little is known of the interaction between oxidative stress and Glu metabolism play in MeHg poisoning rats. We have investigated the neuroprotective role of MK-801, a non-competitive N-methyl-d-aspartate receptors (NMDAR) antagonist, against MeHg-induced neurotoxicity. Fifty rats were randomly divided into five groups of 10 animals in each group: control group, MK-801 control group, MeHg-treated group (4 and 12μmol/kg) and MK-801 pre-treated group. Administration of MeHg at a dose of 12μmol/kg for four weeks significantly increased in ROS and total Hg levels and that caused lipid, protein and DNA peroxidative damage in cerebral cortex. In addition, MeHg also reduced nonenzymic (reduced glutathione, GSH) and enzymic (glutathione peroxidase, GPx and superoxide dismutase, SOD) antioxidants and enhanced neurocyte apoptosis rate in cerebral cortex. MeHg-induced ROS production appears to inhibit the activity of the glutamine synthetase (GS), leading to Glu metabolism dysfunction. Pretreatment with MK-801 at a dose of 0.3μmol/kg prevented the alterations of the activities of PAG and GS and oxidative stress. In addition, pretreatment with MK-801 significantly alleviated the neurocyte apoptosis rate and histopathological damage. In conclusion, the results suggested ROS formation resulting from MeHg- and Glu-induced oxidative stress contributed to neuronal injury. MK-801 possesses the ability to attenuate MeHg-induced neurotoxicity in the cerebral cortex through mechanisms involving its NMDA receptor binding properties and antioxidation.

Differential effects of antipsychotics on hippocampal presynaptic protein expressions and recognition memory in a schizophrenia model in mice

We compared the effects of subchronic clozapine and haloperidol administration on the expression of SNAP-25 and synaptophysin in an animal model of schizophrenia based on the glutamatergic hypothesis. Mice were first treated with a non-competitive NMDA antagonist MK-801 (0.3 mg/kg/day) or saline for 5 days, and then clozapine (5 mg/kg/day), haloperidol (1 mg/kg/day) or saline was administered for two weeks. The locomotion test, as a behavioral model of the positive symptoms of schizophrenia, was applied after MK-801/saline administration on day 6 for acute effects and after antipsychotic/saline administration on day 19 for enduring effects on mice activity. Memory function was assessed by the Novel Object Recognition (NOR) test, one day after the last day of antipsychotic/saline administration (day 20). Western Blotting technique was used to determine SNAP-25 and synaptophysin expressions in the hippocampus and frontal cortex. Both antipsychotics reversed the enhanced locomotion effects of MK-801. MK-801 and haloperidol decreased recognition memory performance. On the other hand, clozapine did not compromise memory. It also did not reverse the negative effects of MK-801 on memory performance. MK-801 did not change SNAP-25 and synaptophysin expressions in the hippocampus and frontal cortex. Clozapine increased hippocampal SNAP-25, decreased hippocampal synaptophysin expression, whereas frontal SNAP-25 and synaptophysin expressions remained unchanged. Haloperidol had no effects on levels of SNAP-25 and synaptophysin in the frontal cortex and hippocampus. These findings support the idea that the differential effects of clozapine might be related to its plastic effects and synaptic reorganization of the hippocampus.