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.     

Effects of N-methyl-D-aspartate (NMDA) antagonist MK-801 on breathing pattern in rats

In anaesthetized, bivagotomized and artificially ventilated rats, the respiratory effects of systemic injection of MK-801, a non-competitive N-methyl-D-aspartate antagonist, were studied. In all the experiments (n = 11), the injection increased the inspiratory duration and decreased the expiratory duration. In 4 experiments, the inspiratory duration was drastically lengthened, resulting in an apneustic-like breathing pattern. These results demonstrate that apneusis is difficult but possible to induce in rats and suggest that termination of inspiration is controlled via central mechanisms in which NMDA-like receptors are involved.     

The NMDA receptor antagonist MK-801 alters lipoprivic eating elicited by 2-mercaptoacetate

Eating behavior is controlled, at least in part, by levels of circulating metabolic fuels such as glucose and free fatty acids, and drugs that interfere with the availability of these fuels can elicit eating. One such drug is 2-mercaptoacetate (2MA), an inhibitor of fatty acid oxidation. Evidence also suggests that NMDA receptors may mediate some aspects of normal eating and satiety. The present study was conducted in order to determine whether NMDA receptors may play a role in feeding elicited by 2MA. Rats received intraperitoneal injections of either saline, 2MA, the non-competitive NMDA receptor antagonist MK-801 or a combined injection of 2MA and MK-801, and subsequent intake of a fat-enriched, mash diet was measured at 1, 2, 3 and 4 h post-injection. Results showed that cumulative food intake was significantly increased by 2MA alone, as compared to saline controls, with most of the 2MA-elicited eating occurring during the first hour post-injection. While MK-801 alone did not alter food intake, it did have a biphasic effect on feeding elicited by 2MA. MK-801 initially suppressed and later enhanced eating elicited by 2MA. Although it is unclear whether MK-801 is acting centrally, peripherally or both to alter 2MA-induced eating, these results implicate NMDA receptors and the neurotransmitter glutamate in the regulation of lipid-associated eating and satiety.     

MK-801, a non-competitive NMDA receptor antagonist, produces facilitation of the micturition reflex in awake, freely-moving rats.

MK-801 (dizocilpine), a non-competitive N-methyl-D-aspartate (NMDA) receptor blocker, produced a dose-dependent (30-120 micrograms/kg, i.v.) increase in the frequency of micturition (as well as the already described behavioral effects) in awake, freely-moving rats. The contraction amplitude was also slightly increased. In contrast, MK-801 administered to urethane-anesthetized rats resulted in complete inhibition of bladder contractions. The effect of MK-801 on the frequency of bladder contractions, therefore, is anesthetic dependent. Excitatory amino acids acting at NMDA receptors may play a role in the control of micturition.     

Differential effects of the N-methyl-d-aspartate receptor antagonist MK-801 on different stages of object recognition memory in mice

The aim of the present study was to evaluate the effects of systemic administration of the N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 on different stages of non-spatial object recognition memory processing in mice. To this end we used the object recognition test, where the animal is tested for its ability to discriminate between an old, familiar, and a novel object. MK-801 (0.1 or 0.2 mg/kg) or saline was administered 1) 30 min before or 2) directly after the first, introductory, session or 3) 30 min before the recognition session. Memory retention was evaluated 1.5 h after the introductory session. MK-801 appeared to decrease memory retention when given prior to the introductory session, but not when given directly after the introductory session or before the recognition session, where MK-801 instead induced an increased interest for the novel object. These results suggest that activation of NMDA receptors is a requisite for encoding of recognition memory in mice but not for consolidation and retrieval processes. The increased interest for the novel object showing up when MK-801 was given directly after the introductory session or before the recognition session may reflect a facilitation of retention. Alternatively, the phencyclidine-like, psychotogenic properties of MK-801 could result in an amplification of the perceived salience of the novel object, and/or anxiolytic mechanisms could result in neophilic effects.     

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.     

Peripheral administration of an N-methyl-D-aspartate receptor antagonist (MK-801) changes dorsal horn neuronal responses in rats

Due to the discovery of peripheral N-methyl-D-aspartate (NMDA) receptors, the effects of peripherally administrated MK-801, a non-competitive NMDA receptor antagonist, and phosphate buffered saline were tested by using the response changes of wide-dynamic range cells in the lumbar enlargement of the spinal cord in Sprague-Dawley rats. MK-801 (1 microM, 50 microl) administered directly into the subcutaneous tissue of the receptive field (n = 7), produces a reversible reduction of responses to noxious and innocuous stimuli by a peripheral action. There was no change in the responses to cutaneous stimuli following injection of phosphate buffered saline (n = 7) or following administration of MK-801 into the contralateral foot (n = 7). The present study suggests that MK-801 produces a local anesthetic like effect in the peripheral tissue.     

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.     

MK-801, a non-competitive antagonist of NMDA receptor, prevents methamphetamine-induced decrease of striatal dopamine uptake sites in the rat striatum.

We investigated the effects of MK-801, a non-competitive antagonist of NMDA receptor, on methamphetamine-induced decrease in dopamine (DA) uptake sites in the rat striatum. Repeated administrations of an escalating dose of methamphetamine (2.5, 5, 7.5, 10 mg/kg s.c. x2, every other day for a week) produced decreased DA uptake sites assayed by binding with [3H]GBR 12935 in the striatum. Co-administration of MK-801 and methamphetamine significantly prevented the methamphetamine-induced decrease in striatal [3H]GBR 12935 binding. Administration of MK-801 alone did not affect [3H]GBR 12935 binding. These results suggest that some neurochemical effects of methamphetamine may be mediated via mechanism involving excitatory amino acids.     

MK-801, an antagonist of NMDA receptors, inhibits injury-induced c-fos protein accumulation in rat brain

Unilateral lesions of the rat hippocampus produced by needle insertion lead to ipsilateral accumulation of c-fos protein in dentate granule cells and neurons in the piriform cortex, as well as in glial-like cells in the corpus callosum and in ependymal cells lining the lateral ventricle adjacent to the lesion site. C-fos protein was detected immunocytochemically using two different antibodies in formalin-fixed brain sections. The N-methyl-D-aspartate (NMDA) antagonist MK-801 produced a dose- and time-dependent inhibition of c-fos protein accumulation in dentate granule cells and in neurons in the piriform cortex, but did not affect glial or ependymal c-fos protein accumulation. MK-801 at 4 mg/kg injected two hours before lesion inhibited c-fos accumulation. Thus, c-fos protein accumulation in hippocampal neurons and in neurons in the piriform cortex induced after traumatic brain injury involves activation of NMDA receptors.     

Chronic neonatal NMDA receptor blockade with MK-801 alters monoamine metabolism in the adult rat.

Administration of non-competitive N-methyl-D-aspartate (NMDA) antagonists in rodents leads to a characteristic motor syndrome which has been related to changes in monoamine metabolism in a variety of brain regions. We examined the question whether chronic MK-801 treatment in neonatal rats from postnatal day 8 through 19, which has been shown previously to alter NMDA receptor function, would also affect monoamine metabolism in striatum and frontal cortex of adult rats. Monoamines and their metabolites were determined 5 months after the treatment using high-performance liquid chromatography with electrochemical detection. Dihydroxyphenylacetic acid (DOPAC) concentration was elevated (greater than 40%) in both regions tested, while 5-hydroxyindoleacetic acid (5-HIAA) concentration was significantly elevated only in the cortex (19%), and 3-methoxy-4-hydroxyphenylglycol (MHPG) only in the striatum (47%). These results demonstrate that the long-lasting effects of chronic neonatal MK-801 treatment are not restricted to glutamate transmission, but include monoamine transmission as well.     

Methylphenidate and MK-801, an N-methyl-d-aspartate receptor antagonist: shared biological properties

Methylphenidate (MPH), a dopamine reuptake inhibitor, is used increasingly to treat attention deficit and hyperactivity disorders in children. Given that dopaminergic mechanisms, contribute to the structural and functional maturation of brain circuitry, consideration of the potential influence of MPH in disrupting such processes seems warranted. Following a similar logic regarding the relevance of glutamate neurotransmission in mediating aspects of brain maturation, we and others have previously utilized in vivo and in vitro studies of the developing rodent brain to establish that MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist has both neuroprotective and pro-apoptotic actions. In this study we used a neonatal murine model of excitotoxin-induced cortical injury to compare such actions between MPH and MK-801, and found that MPH shared some biological properties with MK-801. Specifically, both drugs were neuroprotective against excitotoxic challenge resulting in neonatal brain lesions and in vitro neuronal death, but both drugs also exacerbated programmed neural cell death. However, this profile of action was not shared by the dopamine reuptake blocker GBR-12783, a molecule which like MPH binds to and blocks the dopamine transporter, but which is structurally dissimilar to MPH, suggesting that inhibition of dopamine reuptake alone cannot explain the results from our MPH studies. The implications of our findings are that when studied in our developmental mouse model both drugs demonstrate similar capacities to be either neuroprotective or pro-apoptotic, depending on the specific biologic setting in which they act. Additional studies to identify some potential positive as well as negative consequences of exposure to these drugs during brain development in clinical settings are warranted.     

Differential effects of MK-801, a N-methyl-D-aspartate non-competitive antagonist, on the dorsal horn neuron hyperactivity and hyperexcitability in neuropathic rats

N-methyl-D-aspartate (NMDA) involvement in altered spinal neuron activity following peripheral nerve injury has been investigated in rats with chronic constriction of the sciatic nerve. Extracellular single neuron recordings were performed, in anesthetized, paralyzed rats, from the sciatic spinal cord segments (lumbar, L5-L6) ipsilateral to the constriction, and the effect of iontophoresized MK-801, an NMDA receptor non-competitive antagonist, was tested on baseline hyperactivity and hyperresponsiveness to noxious stimulation. The results show that baseline activity was unaffected whereas the noxious evoked responses were significantly modified, there being amplitude reduction and after-discharges suppression. The different role of NMDA in the abnormal pain states related to the abnormal neuronal activities is discussed.     

Comparison of the spinal anti-nociceptive effects of ES-242-1 and MK-801, two different NMDA antagonists, in rats

The purpose of this study was to determine whether ES-242-1, a novel N-methyl-D-aspartate (NMDA) receptor antagonist of microbial origin, has anti-nociception at the spinal level and to evaluate how its anti-nociceptive effect differs from that of MK-801, a non-competitive NMDA receptor antagonist. Agents were injected intrathecally (0.1, 1.0 and 10 microg) through a previously implanted PE tube in rats. Formalin (2%, 100 microl) was injected subcutaneously into the left hindpaw 15 min after each antagonist administration. Licking time as a nociceptive behavior was measured in three stages after formalin-injection, such as early phase (0-9 min), late first phase (10-29 min) and late second phase (30-60 min). In the early phase, the largest dose of ES-242-1 significantly decreased total licking time, although MK-801 did not show any significant reduction. With the treatment of 1.0 and 10 microg MK-801, total licking time in both late first and second phases was significantly suppressed, although the smallest dose (0.1 microg) of ES-242-1 showed a significant reduction in the late second phase. These results indicate that ES-242-1 is highly effective against tonic pain, such as inflammatory pain.     

Studies on the spinal interaction of morphine and the NMDA antagonist MK-801 on the hyperesthesia observed in a rat model of sciatic mononeuropathy.

This study evaluated the effects of intrathecally coadministered morphine and the N-methyl-D-aspartate (NMDA) antagonist (+)5-methyl-10,11-dihydro-5H- dibenzocyclohepten-5,10-imine maleate (MK-801) on the thermally evoked hindpaw withdrawal latency (PWL) in rats with one paw (ipsilteral) rendered hyperesthetic by the unilateral application of loose ligatures to the sciatic nerve (delta PWL (+/- S.D.) = PWLhyperesthetic paw - PWLnormal paw = -3.1 +/- 1.2 s). Intrathecal morphine produced a dose-dependent (0.1-10 micrograms; P less than 0.0001) elevation in the thermal response latency of both the contralateral (normal) and ipsilateral (hyperesthetic) paw. delta PWL did not vary with morphine, indicating that the dose-response curves were parallel but shifted to the right for the hyperesthetic paw. For the normal paw, MK-801 (10 micrograms) was without effect upon the response latency; whereas, the response latency of the hyperesthetic paw was elevated to the same as the normal paw, i.e. the hyperesthesia was selectively abolished (delta PWL (+/- S.D.) = -0.067 +/- 2.73). Co-administration of MK-801 with morphine did not alter the effects of morphine in the normal paw, but reduced the delta PWL for each dose of morphine. These results suggest that NMDA antagonism (1) does not alter the thermal sensitivity in the normal paw, (2) selectively abolishes the hypersensitivity of the hypersthetic paw and (3) has a simple additive interaction with the antinociceptive effects of morphine in the hyperesthetic paw.     

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.     

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 an NMDA-receptor antagonist,MK-801, on central locomotor programming in the rabbit

Summary NMDA has been shown to disclose spinal fictive locomotor activity in various in vitro preparations. In the present work the NMDA-mediated effects of endogenously released excitatory aminoacids (EAA) on fictive locomotion in the adult rabbit preparation were assessed in vivo using systemic injections of a non competitive NMDA-antagonist, MK-801. In acute low spinal and curarized preparations, the amplitude of the spontaneous fictive locomotor activities recorded from hindlimb muscle nerves after nialamide-DOPA pretreatment was much decreased in flexor and extensor nerves after MK-801 administration (0.25 mg/kg i.v.) whereas the locomotor period increased slightly. The more potent locomotor bursts, evoked by repetitive sural nerve stimulation at 10 Hz during 10 s, were differently affected after MK-801: the main effect was a lengthening of the locomotor period and a less drastic drop in the burst amplitude. These changes in the burst period were maximal for activities evoked by A fibre group stimulation (+100%) and less when C fibres were recruited (+70%). In decerebrate curarized preparations where the locomotor sequences were evoked either by sural nerve stimulation or by stimulation of the mesencephalic locomotor region, MK-801 (0.25 mg/kg i.v.) caused the same drop in burst amplitude (by at least 50%) as in the spinal preparation but, in constrast, it reinforced rhythmic bursting: this was revealed by a clear shortening (up to-65%) of the locomotor period and by the prolongation of rhythmic bursting after stimulation. All these effects obtained in decerebrate preparations were maximal 20–30 min after MK-801 injection. Among the spinal reflexes tested by dorsal root stimulation, the mono- and disynaptic reflexes were unaffected by MK-801; the effect was limited to flexor and extensor polysynaptic reflexes which were depressed. With regard to the lumbar locomotion generators, the interpretation of the above results leads us to propose three levels of NMDA-mediated controls of locomotion by endogenously released EAA: two frequency modulations respectively responsible for the activation of the spinal locomotion generator by group A cutaneous afferents and for the strong supraspinal depression of this spinal generator; finally an amplitude modulation, achieved at a spinal, probably interneuronal level, that can amplify the out-puts of the rhythmic generated signals without modifying the pattern.     

The topography of MK-801-induced locomotor patterns in rats

Locomotor patterns in rats given systemic injections of the novel, noncompetitive N-methyl-D-aspartate (NMDA) antagonist, MK-801 were characterized using Digiscan Animal Activity Monitoring System. At low systemic doses, MK-801 produced an activity pattern most similar to patterns previously described for less potent noncompetitive NMDA antagonists; this was typified by hyperactive locomotor behavior, with increases in distance travelled, speed, and clockwise/anticlockwise locomotion, and a marked decrease in rearing behavior. Although MK-801 elicited some motor patterns similar to those previously described for sympathomimetic agents, including hyperactivity and increased stereotypy, it did not produce increased rearing behavior, the most prominent sympathomimetic effect. These results demonstrated that the topography of locomotion elicited by low systemic doses of MK-801 is most similar to locomotor patterns previously described for noncompetitive NMDA receptor antagonists.     

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.