Chronic neonatal MK-801 treatment results in an impairment of spatial learning in the adult rat

Chronic neonatal treatment with the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 from postnatal day 8 through 19 has been shown to affect hippocampal NMDA receptor function of adult rats. Since many studies have shown that NMDA receptors play a crucial role in learning and memory, and since one of the hippocampal functions is spatial learning, we have examined whether this changed response of hippocampal neurons is associated with changes in its normal function. We therefore tested spatial learning and memory using a water maze in adult rats neonatally treated with MK-801. MK-801-treated rats were able to learn the spatial task as well as control rats but at a significantly slower rate. Performance in a visual cue task was not affected by the neonatal treatment, suggesting that the slower spatial learning is not caused by locomotor or sensory deficits. These results suggest that chronic NMDA receptor blockade during the neonatal period leads to long-lasting disturbances of hippocampal function.     

Glutamate and dopamine in nucleus accumbens core and shell: sequence learning versus performance

This study sought to determine whether neurochemical changes associated with chronic postweaning lead (Pb) exposure, namely, enhanced dopamine (DA) activity and/or blockade of NMDA function in nucleus accumbens (NAC), underlie the learning impairments also associated with this Pb regimen, and whether core or shell subregions of nucleus accumbens would be more important to such effects. If so, then mimicking these neurochemical changes in normal (control) rats should reproduce these Pb-induced learning impairments. For this purpose, the effects of DA (20-80 microg), the non-competitive NMDA antagonist MK-801 (1.0-2.5 microg) or DA+MK-801 (40+1.0, 80+2.5 microg) were infused in core or shell of nucleus accumbens in normal rats and effects on a multiple schedule of repeated learning (RL) and performance (P) evaluated. In core, MK-801 mimicked the effects of Pb exposure, selectively reducing RL accuracy with no corresponding changes in P accuracy, an effect derived from an increased frequency of perseverative errors. DA produced non-specific changes, reducing accuracy levels in RL and P components. Accuracy and rate effects of DA could be reversed by concurrent administration of the higher MK-801 dose. In shell, MK-801, primarily the lower dose, reduced accuracy in both the RL and P components, while DA did not produce any systematic effects. Collectively, these results point to a greater importance of core as compared to shell in the mediation of learning of spatial sequences, and suggest that inhibition of glutamatergic NMDA function may play a critical role in the selective learning impairments associated with chronic low level Pb exposure.     

Effects of the cognition impairer MK-801 on learning and memory in mice and rats

There is a great need for relevant animal models for investigating the effects of putative pro-cognitive compounds. Compounds that impair learning and/or memory processes without inducing adverse side effects are cognition impairers. Rats and mice with cognitive deficits induced by the prototypical N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 may provide a relevant animal model based on the mechanistic approach of blocking NMDA/glutamatergic signaling. Unfortunately, the dose range over which MK-801 induces cognitive impairment without causing sensory, locomotor, or toxicological side effects is small. We provide an overview of the effects of MK-801 in different cognitive tasks and assessed whether MK-801 reliably affects the cognitive performance of mice or rats in the spatial Morris task, T-maze alternation tasks, and non-spatial passive avoidance, social, and object recognition tasks. MK-801 disrupted or retarded memory acquisition in all tasks. The Morris task, once acquired, was insensitive to MK-801 at a dose up to 0.1 mg kg(-1) body weight. Retention deficits in the passive avoidance tests were not likely to be due to MK-801-induced changes in shock sensitivity, as measured by a shock threshold test. On the basis of published evidence and the present findings, we conclude that MK-801, administered s.c. or i.p. into rodents in doses up to 0.1 mg kg(-1), appears to fulfill the criteria of our definition of a cognition impairer in rodents, without causing sensorimotor impairments and/or signs of intoxication. In addition, MK-801-treated rodents appear to fulfill the criteria of a valid animal model of cognitive dysfunctions, with robust effects across species, housing conditions, and testing paradigms.     

Subsensitivity of lead-exposed rats to the accuracy-impairing and rate-altering effects of MK-801 on a multiple schedule of repeated learning and performance

Exposure to lead (Pb) has been reported to inhibit MK-801 binding and to alter other NMDA receptor complex-associated functions. These reported changes are provocative since both NMDA receptor antagonism and Pb exposure are known to impair learning processes. Whether the Pb-induced changes in NMDA function relate to the learning impairments associated with Pb exposure, however, has not been explored. The contention of this study was that if changes in NMDA function produced by Pb serve as the basis of Pb-associated learning impairments, then such changes should be of sufficient biological magnitude and clinical relevance to induce alterations in sensitivity at the level of the whole animal, i.e., changes in behavioral sensitivity to glutamatergic compounds. Thus, in this study, dose-effect curves of control and Pb-treated rats working on a multiple schedule of repeated learning (repeated acquisition, RA) and performance (P) were compared following acute administration of MK-801, the non-competitive NMDA antagonist. Based on the nature of the reported effects of Pb on NMDA systems, it was expected that the curves of Pb-exposed rats would be right-shifted relative to controls, if differential behavioral sensitivity was evident. Rats were chronically exposed to 0, 50 or 250 ppm Pb acetate in drinking water from weaning and trained on the multiple RA and P schedule beginning at 55 days old. The RA component required the rat to learn a new 3-member sequence of responses during each experimental session (center right left, RLC, CLR, RCL, or LRC), while the correct sequence of responses for the P component was constant across sessions (LCR), requiring performance of an already learned response. Acute administration of MK-801 (0.05–0.3 mg/k, i.p.) resulted in decrements in accuracy in both the RA and P components of the schedule, indicative of non-specific effects on behavior rather than selective effects on learning. The declines in accuracy during the RA component of the schedule were primarily the result of increased perseverative responding, i.e., repetitive responding on a single lever. Both the decline in RA accuracy and the increases in perseverative responding produced by MK-801 were attenuated by Pb exposure. Moreover, dose-effect curves relating MK-801 dose to changes in rates of responding were significantly shifted to the right in Pb-exposed rats relative to controls. Taken together, these data demonstrate a subsensitivity of Pb-exposed rats to both the accuracy-impairing and response rate-altering properties of MK-801. Furthermore, they suggest that Pb-induced changes in NMDA receptor complex function could be involved in the learning impairments that result from exposures to Pb.     

Large cortical lesions produce enduring forelimb placing deficits in un-treated rats and treatment with NMDA antagonists or anti-oxidant drugs induces behavioral recovery

Previous studies have utilized a lesion model of cortical injury that produces transient behavioral impairments to investigate the recovery of function process. To better understand the recovery process, it would be beneficial to use a lesion model that produces more severe, enduring, behavioral impairments. The purpose of experiment 1 was to validate whether large lesions of the sensorimotor cortex (SMC), which included the rostral forelimb and caudal forelimb regions, produced enduring behavioral deficits. Rats were given large unilateral electrolytic lesions of the SMC, administered either the N-methyl-D-aspartate (NMDA) antagonist, MK-801 or saline 16 h after injury, and tested on a battery of behavioral tests. Enduring behavioral deficits were observed, for at least 6 months, on two tests of forelimb placing while transient deficits were observed on the foot-fault and somatosensory neutralization tests. Administration of MK-801 facilitated recovery on the somatosensory neutralization test; however, it did not induce recovery on either forelimb placing test. A second experiment was performed to determine if earlier administration of MK-801, the NMDA antagonist magnesium chloride (MgCl(2)), or the anti-oxidant N-tert-butyl-alpha-phenylnitrone (PBN) could induce behavioral recovery in this chronic model. Treatment with these drugs induced behavioral recovery on the forelimb placing tests, whereas, the saline-treated rats did not show any signs of behavioral recovery for at least 3 months. Anatomical analysis of the striatum showed that MK-801 and MgCl(2) but not PBN reduced the extent of lesion-induced striatal atrophy. These results suggest that administration of MK-801, MgCl(2), or PBN shortly after cortical injury can induce recovery of function when recovery is otherwise not expected in un-treated rats.     

The effect of the interaction between N-methyl-D-aspartate receptor blockade and growth environment during the last maturation period of the nervous system on anxiety-related behaviour in adulthood in the rat

The cerebral glutamate system and NMDA-mediated glutamate transmission are known to play main roles in processes related to cognitive skills and emotional responses. The impact of the physical environment on emotional responses and the role of NMDA-mediated glutamate transmission in this interaction remain unknown. The present study aimed to investigate the role of NMDA receptors during the last maturation period of the nervous system in the effect of physical environmental conditions on anxiety responses induced by change (novelty), open field and height in adulthood. NMDA receptor blockade performed between postnatal 20?C30 days with MK-801 treatment. Starting from postnatal day 20, rats were subcutaneously injected with MK-801 twice a day at the nape of the neck for a period of 10 days (dizocilpine either at a dose of 0.25 mg/kg or in a volume of 0.1 mL/20 g body weight). The open field apparatus and elevated plus maze were used to evaluate anxiety related behaviours in adulthood. In conclusion, enriched physical environmental conditions eliminated the anxiolytic effects of NMDA receptor blockade observed in rats reared under standard physical environmental conditions.     

Effects of chronic administration of MK-801 upon local cerebral glucose utilisation and ligand binding to the NMDA receptor complex

Although clinical use of N-methyl-D-aspartate (NMDA) receptor antagonists will involve prolonged drug administration, knowledge of the functional consequences of chronic NMDA receptor blockade is limited. Local cerebral glucose utilisation was measured in conscious rats in 74 discrete brain regions after chronic administration of (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine (MK-801) (0.5 mg/kg i.p.). Chronic treatment with MK-801 caused small, significant changes in glucose use in 4 of the 74 brain areas; parietal cortex (-13%), frontal cortex (-10%), subthalamic nucleus (-14%) and nucleus accumbens (-17%). These focal alterations in glucose use were not associated with changes in ligand binding to various sites within the NMDA receptor complex (i.e. agonist recognition site, glycine site, ion channel site) which were assessed autoradiographically. The acute effects of MK-801 on glucose utilisation were significantly enhanced after chronic MK-801 in 7 brain regions (e.g. frontal and parietal cortices) and attenuated in 6 brain regions (e.g. nucleus accumbens, hippocampus, posterior cingulate cortex). Neither local enhancement nor attenuation of the acute response to MK-801 was due to alterations in ligand binding to sites within the NMDA receptor complex. The data clearly indicate that the functional consequences of NMDA blockade are altered after chronic MK-801 treatment in an anatomically organised, though complex manner. These adaptive functional changes after chronic MK-801 treatment cannot be attributed readily to alterations in the NMDA receptor complex in affected regions.     

D-Serine and a glycine transporter inhibitor improve MK-801-induced cognitive deficits in a novel object recognition test in rats

Compounds enhancing N-methyl-d-aspartate (NMDA) glutamate receptor function have been reported to improve cognitive deficits. Since cognitive deficits are considered to be the core symptom of schizophrenia, enhancing NMDA receptor function represents a promising approach to treating schizophrenia. In the present study, we investigated whether d-serine or a glycine transporter inhibitor N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl]sarcosine (NFPS), both of which enhance NMDA receptor function, could improve MK-801-induced cognitive deficits in rats, and compared their effects with those of the atypical antipsychotic clozapine and of the typical antipsychotic haloperidol. To assess cognitive function, we used a novel object recognition test in rats that measured spontaneous exploratory activity of a novel object when paired with a familiar object. We then evaluated the effects of the compounds on cognitive deficits induced by treatment with MK-801, the NMDA receptor antagonist. Pretreatment with clozapine (1, 5 mg/kg, i.p.) but not haloperidol (0.03, 0.1 mg/kg, i.p.) significantly improved MK-801-induced cognitive deficits. Pretreatment with D-serine at 800 mg/kg (i.p.) or NFPS (0.3, 1 mg/kg, i.p.) significantly improved MK-801-induced cognitive deficits under this test paradigm. These findings suggest that impaired preference for novel objects induced by MK-801 in the novel object recognition test could be a useful animal model for evaluating the efficacy of compounds targeting the cognitive deficits observed in schizophrenic patients. The results also suggest that enhancing NMDA receptor function is an effective way for treating the cognitive deficits associated with schizophrenia.     

Long-term behavioural, molecular and morphological effects of neonatal NMDA receptor antagonism

Brief N-methyl-D-aspartate (NMDA) receptor blockade in neonatal rats has been reported to increase neuronal apoptosis. We replicated this finding using MK-801 (0.5 mg/kg) administered twice on postnatal day 7, and then studied the long-term consequences. In adulthood, treated rats showed reduced volume and neuronal number within the hippocampus, and altered hippocampal NMDA receptor (NR1 subunit) expression. Synaptophysin mRNA was decreased in the thalamus (laterodorsal nucleus). Adult MK-801-treated females had prepulse inhibition deficits and increased locomotor activity. The data show that a transient and limited glutamatergic intervention during development can have chronic behavioural, structural and molecular effects. The effects are reminiscent of alterations reported in schizophrenia and, as such, are consistent with hypotheses advocating a role for NMDA receptor hypofunction, and aberrant apoptosis, in the neurodevelopmental pathogenesis of the disorder.     

Effects of MK-801 on DNA synthesis in neonatal rat brain regions under normoxic and hypoxic conditions

Global metabolic insults such as ischemia/hypoxia, damage neural cells through release of excitatory amino acids and their subsequent actions at the N-methyl-D-aspartate (NMDA) receptor. NMDA receptors are highly expressed in neonatal rat brain, and the current study examines the effects of receptor blockade with MK-801 on DNA synthesis under normoxic and hypoxic conditions. At one day of age, hypoxia alone caused a decrease in [3H]thymidine incorporation into DNA throughout the brain, whereas MK-801 alone decreased incorporation selectively in regions known to be enriched in NMDA receptors. MK-801 afforded no protection from hypoxia and instead exacerbated the effects of hypoxia in the cerebellum. At 8 days of age, hypoxia alone or MK-801 alone still produced the same patterns of inhibition of DNA synthesis, but MK-801 neither prevented nor exacerbated the effects of hypoxia; animals receiving MK-801 showed a significant incidence of hypoxia-induced mortality. These data suggest that excitatory actions exerted at the NMDA receptor serve to maintain cell replication in neonatal brain and, as distinct from the situation for excitatory amino acid-induced cell death, these receptors do not participate in adverse effects of hypoxia on DNA synthesis.     

NC-1900, an arginine-vasopressin analogue, ameliorates social behavior deficits and hyperlocomotion in MK-801-treated rats: therapeutic implications for schizophrenia

We previously reported that chronic administration of N-methyl-D-aspartate (NMDA) antagonists reduced the density of vasopressin V1a receptors in several brain regions in rats that demonstrated social interaction deficits and increased locomotor activity. These observations indicate the ability of arginine-vasopressin (AVP), or its analogues, to modulate behavioral abnormalities associated with blockade of NMDA receptors. The present study was performed to investigate the effect of NC-1900, an AVP analogue, on social behavior and locomotor activity in rats treated with MK-801, a non-competitive NMDA receptor antagonist. Male Wistar rats were administered MK-801 (0.13 mg/kg/day ip) or saline for 14 days. Social behavior and locomotor activity were measured 45 min after the injection of NC-1900 (10 ng/kg sc) or saline together with the last MK-801 or vehicle administration. Social interaction was quantified by an automated video-tracking system, and stereotyped behavior and ataxia were manually measured. Acute administration of NC-1900 partially reversed MK-801-induced hyperlocomotion and deficits in social interaction, while NC-1900 itself did not affect these behavioral measures in animals chronically treated with vehicle saline. These results suggest that the central AVP system may interact with glutamatergic and dopaminergic transmissions, and indicate potential therapeutic effects of AVP analogues on positive and negative symptoms of schizophrenia.     

Effects of neonatal repeated MK-801 treatment on delayed nonmatching-to-position responses in rats

This study was carried out to investigate the long-term effects of chronic neonatal antagonism of N-methyl-D-aspartate (NMDA) receptors, a subtype of glutamate receptors, on working memory. Rats were tested on the delayed nonmatching-to-position task in adulthood after repeated treatment of a noncompetitive NMDA antagonist MK-801 in postnatal days 7-20. As a result, this treatment led to deficits in learning and/or performance of delayed nonmatching-to-position responses, suggesting that chronic neonatal NMDA antagonism persistently impairs working memory. Furthermore, it decreased body and brain weight, and induced stereotyped head-rotation behavior. As working memory deficits are shown in several mental disorders such as schizophrenia and developmental disorders, rats with chronic neonatal NMDA antagonism might be useful for a better understanding of these disorders.     

MK-801 prevents hippocampal neurodegeneration in neonatal hypoxic-ischemic rats

In cerebral asphyxia, enhanced postsynaptic stimulation of N-methyl-D-aspartate (NMDA) receptor by excessive glutamate may mediate neuronal injury and death. The neuroprotective potential of the novel, potent NMDA receptor antagonist MK-801 was assessed by evaluating hippocampal behavioral and histologic outcomes in an experimental rat model of neonatal hypoxia/ischemia. Seven-day-old rats with and without MK-801 pretreatment were subjected to unilateral carotid ligation followed by 2 hours of hypoxia. At age 30 days, spontaneous alternation behavior was measured using a conventional wooden T maze. Hypoxic-ischemic animals pretreated with saline demonstrated a significant impairment in spontaneous alternation behavior compared with that of normal control rats and the hypoxic-ischemic rats pretreated with MK-801. Hippocampal neuronal damage in the CA1 and CA3 regions was prevented in animals pretreated with MK-801 vs saline-treated controls. Therefore, while saline-treated rats with hippocampal lesions showed defective memory and hippocampal neuronal destruction, pretreatment with MK-801 protected rats. Thus, MK-801 appears to protect hippocampal neurons from hypoxia/ischemia and may be potentially beneficial in preventing neonatal asphyxial brain damage.     

Delayed application of MK-801 attenuates development of morphine tolerance in rats

To investigate the possible involvement of enduring or delayed changes at the N-methyl-D-aspartic acid (NMDA) receptor in the mechanisms of morphine tolerance, rats were treated with the specific NMDA receptor antagonist, MK-801 (0.15 mg/kg) 2 h after morphine injection (20 mg/kg) during a 4-day induction period of tolerance. On the fifth day rats were injected only with morphine (15 mg/kg), and analgesia was assessed using the hot-plate test. Morphine tolerance was significantly reduced by MK-801. These findings suggest that long-lasting or delayed changes at the NMDA receptor underlie the development of morphine tolerance. Moreover, because MK-801 was delivered 2 h after morphine and therefore could not serve as a cue for morphine administration, these findings indicate that the attenuating effect of MK-801 on the development of morphine tolerance is not attributable to state-dependent learning.     

Temporal patterns of motor behavioural improvements by MK-801 in Mongolian gerbils submitted to different duration of global cerebral ischemia

The purpose of this study was to investigate the temporal pattern of NMDA receptors antagonist-MK-801 on motor behaviour parameters in gerbils submitted to different duration of global cerebral ischemia. The common carotid arteries of gerbils were occluded for 5, 10 or 15min. Gerbils were given MK-801 (3mg/kg i.p.) or saline immediately after the occlusion in normothermic conditions prior to testing. Motor activity was registered 1, 2, 4, 7, 14, 21 and 28 days after reperfusion during 60min by open field test. At the same time, the effect of NMDA receptor blockade was followed in vivo by monitoring the neurological status of whole animals or at the cellular level by standard light and confocal microscopy on brain slices. Post-ischemic gerbils quickly developed hypermotor response with the most intensity in animals submitted to 15min ischemia. MK-801 administrated immediately after ischemia significantly decreased this hyperactivity. In all ischemic-treated animals, behavioural suppression by MK-801 was observed already 1 day after occlusion and was lasting as far as observed ischemia-dependent hypermotor responses. Beneficial effect of MK-801 was also confirmed by morphological and neurological status data. These findings suggest that sustained ischemia-induced hyperactivity is related to abnormalities in NMDA glutamatergic function, as well as its manifestation could be completely abolished by NMDA receptor blockade immediately after ischemic insult.     

Delayed onset of enhanced MK-801-induced motor hyperactivity after neonatal lesions of the rat ventral hippocampus.

BACKGROUND: Abnormalities in the glutamatergic system, glutamate/dopamine/gamma-aminobutyric acid interactions, and cortical development are implicated in schizophrenia. Moreover, patients with schizophrenia show symptom exacerbation in response to N-methyl-D-aspartate (NMDA) antagonist drugs. Using an animal model of schizophrenia, we compared the impact of neonatal and adult hippocampal lesions on behavioral responses to MK-801, a noncompetitive NMDA antagonist. METHODS: Neonatal rats were lesioned on postnatal day 7. Their motor activity in response to MK-801 was tested at a juvenile age, in adolescence, and in adulthood. We also measured binding of [(3)H]MK-801 and the expression of NR1 messenger RNA (mRNA) in the medial prefrontal cortex and nucleus accumbens. Adult rats received similar lesions and were tested 4 and 8 weeks after the lesion. RESULTS: As juveniles, neonatally lesioned rats did not differ from control rats in responsiveness to MK-801, whereas in adolescence and adulthood they showed more pronounced hyperactivity than control rats. The adult lesion did not alter behaviors elicited by MK-801. Neonatally lesioned rats showed no apparent changes in [(3)H]MK-801 binding or expression of the NR1 mRNA. CONCLUSIONS: These results suggest that an early lesion of the ventral hippocampus affects development of neural systems involved in MK-801 action without changes at the NMDA receptor level, and they show that the behavioral changes manifest first in early adulthood.     

Behavioural evaluation of long-term neurotoxic effects of NMDA receptor antagonists

High doses of NMDA antagonists e.g. (+)MK-801 evoke neurodegeneration in retrosplenial cortex in rodents. To assess functional consequences of such treatment, three paradigms of two-way active avoidance learning (with visual or auditory conditioned stimuli) and additionally a spatial learning paradigm — radial maze — were used. Female rats were treated i.p. with 5 mg/kg of (+)MK-801. Recumbence, severe hypothermia and loss of body weight were observed for 3–7 days. Despite that, there were no statistically significant differences in performance of avoidance reaction between saline and (+)MK-801 treated animals trained 10–40 days after the drug administration. However, in the radial maze test (+)MK-801 impaired reference (but not working) memory in the experiment that started 8 days after the treatment. Similar effect was observed on reversal learning. The clinically used NMDA receptor antagonist memantine at the doses of 20 and 40 mg/kg had also no such long term negative effect on working memory during training (even positive effect was seen at 20 mg/kg) but at 40 mg/kg impaired learning on the first day of reversal. This indicates that (+)MK-801 neurotoxicity in the retrosplenial cortex is connected with subtle alterations in the learning performance that may be seen in some tests only. Moreover, memantine doses greatly exceeding therapeutically relevant range produce minimal functional alteration. An additional experiment revealed that the same dose of memantine results in two fold higher serum levels of the antagonist in female than male rats. Hence, considering that profiling studies are done in male rats, a safety factor of over 16 fold can be calculated for memantine.     

Behavioural evaluation of long-term neurotoxic effects of NMDA receptor antagonists

High doses of NMDA antagonists e.g. (+)MK-801 evoke neurodegeneration in retrosplenial cortex in rodents. To assess functional consequences of such treatment, three paradigms of two-way active avoidance learning (with visual or auditory conditioned stimuli) and additionally a spatial learning paradigm - radial maze - were used. Female rats were treated i.p. with 5 mg/kg of (+)MK-801. Recumbence, severe hypothermia and loss of body weight were observed for 3-7 days. Despite that, there were no statistically significant differences in performance of avoidance reaction between saline and (+)MK-801 treated animals trained 10-40 days after the drug administration. However, in the radial maze test (+)MK-801 impaired reference (but not working) memory in the experiment that started 8 days after the treatment. Similar effect was observed on reversal learning. The clinically used NMDA receptor antagonist memantine at the doses of 20 and 40 mg/kg had also no such long term negative effect on working memory during training (even positive effect was seen at 20 mg/kg) but at 40 mg/kg impaired learning on the first day of reversal. This indicates that (+)MK-801 neurotoxicity in the retrosplenial cortex is connected with subtle alterations in the learning performance that may be seen in some tests only. Moreover, memantine doses greatly exceeding therapeutically relevant range produce minimal functional alteration. An additional experiment revealed that the same dose of memantine results in two fold higher serum levels of the antagonist in female than male rats. Hence, considering that profiling studies are done in male rats, a safety factor of over 16 fold can be calculated for memantine.     

Differential effects of ketamine and MK-801 on the induction of long-term potentiation.

Ketamine and MK-801 are phencyclidine (PCP)-like noncompetitive antagonists of the N-methyl-D-aspartate (NMDA) receptor that produce a use-dependent blockade of the NMDA receptor-coupled channel. Recent studies have suggested that the binding properties of these drugs to the NMDA receptor in-vitro are different. In the present study, the effects of ketamine and MK-801 on the induction of long-term potentiation (LTP) were compared at perforant path--granule cell synapses in anaesthetized rats. LTP was observed in animals treated with either saline or MK-801, but not in those treated with ketamine. These results reveal that ketamine and MK-801 differentially modulate the induction of LTP, and we propose that this differential modulation may be related to the different binding properties of the drugs.     

NMDA receptor blockade and hippocampal neuronal loss impair fear conditioning and position habit reversal in C57Bl/6 mice

The interpretation of learning and memory deficits in transgenic mice has largely involved theories of NMDA receptor and/or hippocampal function. However, there is little empirical data that describes what NMDA receptors or the hippocampus do in mice. This research assessed the effects of different doses of the NMDA receptor antagonist, MK-801, or different-sized hippocampal lesions on several behavioral parameters in adult male C57Bl/6 mice. In the first set of experiments, different doses of MK-801 (0.05-0.3mg/kg, s.c.) were assayed in fear conditioning, shock sensitivity, locomotion, anxiety, and position habit reversal tests. Contextual and cued fear conditioning, and position habit reversal were impaired in a dose-dependent manner. Locomotor activity was increased immediately after injection of the highest dose of MK-801. A second set of experiments determined the behavioral effects of a moderate and large excitotoxic hippocampal lesion. Both lesions impaired contextual conditioning, while the larger lesion interfered with cued conditioning. Reversal learning was significantly diminished by the large lesion, while the moderate lesion had a detrimental effect at a trend level (P<0.10). These results provide important reference data for studies involving genetic manipulations of NMDA receptor or hippocampal function in mice. Furthermore, they serve as a basis for a non-transgenic mouse model of the NMDA receptor or hippocampal dysfunction hypothesized to occur in human cognitive disorders.