The effect of MK-801 on the micturition reflex in anesthetized rats

We studied the effect of MK-801, a potent non-competitive NMDA receptor antagonist, on the micturition reflex in anesthetized rats. Pretreatment with MK-801 (0.1-1 mg/kg i.v.) dose dependently increased the bladder capacity and reduced the micturition contraction. The ability of MK-801 to inhibit bladder voiding was confirmed in additional experiments in which the compound (30-50 micrograms/kg i.v.) transiently suppressed established bladder voiding produced by continuous bladder filling. MK-801 (1 microM) did not affect nerve-mediated contractions of the rat bladder or inhibit the response to capsaicin. These findings provide pharmacological evidence for an involvement of NMDA receptors in the micturition reflex pathways.     

The discriminative stimulus effect of MK-801 in ketamine-trained rats

MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate] was assessed for its discriminative stimulus properties in rats trained to discriminate ketamine (7 mg/kg) from vehicle. MK-801 generalized to ketamine in a dose dependent manner with a maximum effect at 0.2 mg/kg, while ketamine generalized fully at 10 mg/kg. These results indicate that ketamine and MK-801 may share a common mechanism of action, which is related to the phencyclidine recognition site in the brain.     

Amnesic effect of the novel anticonvulsant MK-801

MK-801, a reported N-methyl-D-aspartate (NMDA) antagonist with affinity for the phencyclidine (PCP) receptor, injected intravenously in mice before a training trial in a passive avoidance procedure, produced a similar amnesic effect to that produced by the standard amnesic agent scopolamine. Compared to vehicle-treated mice, each drug produced significant amnesia, yet the potency of MK-801 was 40 times that of scopolamine. This result with the MK-801 is consistent with previous reports that drugs which act at PCP recognition sites within the brain produce memory impairing effects in rodents.     

Effects of olanzapine and clozapine on radial maze performance in naive and MK-801-treated mice

Attention, working memory and long-term memory dysfunctions are the most commonly seen cognitive impairments in schizophrenic patients. Conflicting results exist regarding the effects of antipsychotics on cognitive abnormalities. The aim of this study was to investigate the effects of atypical antipsychotic drugs olanzapine (0.4, 0.8 and 1.25?mg/kg, i.p.) and clozapine (0.5 and 1?mg/kg, i.p.) on spatial working memory in naive and MK-801 (0.2?mg/kg, i.p.) treated BALB-c mice in an 8-arm radial arm maze (RAM) task. None of the antipsychotic drugs studied altered number of errors in naive mice, whereas MK-801 significantly increased working memory errors in RAM test. Olanzapine and clozapine potently reversed MK-801 induced increasement of working memory errors. Olanzapine and clozapine prolonged latency of the animals in naive mice. The MK-801-induced enhancement in the speed of mice in performing the RAM task was blocked by olanzapine but not clozapine. Our study shows that atypical antipsychotics olanzapine and clozapine might improve cognitive deficits in schizophrenic patients.     

Effects of MK-801 stereoisomers on schedule-controlled behavior in rats

Behavioral effects of (+)MK-801 (0.03–0.32 mg/kg) and (–)MK-801 (0.32–3.20 mg/kg) were evaluated in rats using a multiple fixed-ratio, fixed-interval (FR20, FI2) schedule of food presentation. Both enantiomers produced dose-dependent decreases in response rate under the FR20 and in this respect (+)MK-801 was approximately ten times as potent as (–)MK-801. Under the FI2 schedule component, the (+) enantiomer produced substantial increases as well as decreases in response rate whereas the (–) enantiomer produced only decreases. When 0.178 mg/kg (+)MK-801 and 1.78 mg/kg (–)MK-801 were administered for 11 consecutive days, tolerance developed to the decrease in response rate under the FR20 schedule component. Tolerance to the effects of the (+) enantiomer under the FI2 schedule component was indicated by progressively larger increases in response rate than those observed during acute administration. These results support potential therapeutic applications of MK-801.In conducting the research described in this report, the investigators adhere to the Guide for the Care and Use of Laboratory Animals, as promulgated by the Committee on Care and Use of Laboratory Animals of the Institute of Laboratory Animal Resources, National Research Council. The views of the authors do not purport to reflect the position of the Department of the Army or the Department of Defense (para 4–3, AR 360–5).     

Anticataleptic effects of the N-methyl-D-aspartate antagonist MK-801 in rats

The N-methyl-D-aspartate (NMDA) antagonist MK-801 was administered to rats in three doses (0.08, 0.16, 0.33 mg/kg) in order to examine its effects on catalepsy that was induced by haloperidol (0.5 mg/kg). The degree of catalepsy was assessed 30 and 60 min after application of drugs by placing the rat on a horizontal bar, on a podium and on a vertical grid. Animals having received saline and haloperidol showed a higher degree of catalepsy than animals having received MK-801 and haloperidol (except for the lowest dose of MK-801). These findings may suggest a therapeutic potential of MK-801 and possibly of other NMDA antagonists in the treatment of Parkinson's disease.     

Phencyclidine-like discriminative stimulus properties of MK-801 in rats

The discriminative stimulus properties of the N-methyl-D-aspartate (NMDA) antagonist MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine) were investigated in rats trained to discriminate phencyclidine (PCP; 1.25 mg/kg i.p.) from saline on a standard two-lever fixed ratio 32 schedule of food reinforcement. MK-801 was generalized from PCP in a dose-dependent manner, with an ED50 of 0.10 mg/kg i.p. The ED50 for PCP was 0.7 mg/kg io.p. MK-801 is, therefore, a very potent PCP-like drug which may share cellular mechanisms and other effects with PCP, including the antagonism of NMDA.     

MK-801 antagonizes the lethal action of centrally and peripherally administered cypermethrin in mice and rats.

The present study investigated the effect of MK-801, an N-methyl-D-aspartate antagonist, on the convulsant lethal action of cypermethrin administered centrally or peripherally. Cypermethrin produced severe convulsions and death in a dose-dependent manner. MK-801 (0.5, 1 and 2 mg kg-1, intraperitoneally) significantly increased the onset time of convulsions and decreased the mortality in the peripherally treated cypermethrin group. MK-801 (1.0 and 2.0 mg kg-1) attenuated the convulsant action of cypermethrin (50 micrograms, intracerebroventricularly) significantly. Survival rate was also increased significantly. However, MK-801 (0.5 mg kg-1) did not produce any significant protective effect against centrally administered cypermethrin. These results suggest excitatory amino acids to be a target for pyrethroid-induced neurotoxicity.     

MK-801 potently inhibits alcohol withdrawal seizures in rats

The ability of MK-801, an N-methyl-D-aspartate (NMDA)-channel antagonist, to suppress alcohol withdrawal seizures generated audio-genically was studied in adult male rats using a cross-over experimental design. MK-801 treatment reduced overall seizure score and proportion of rats seizing. In comparison to other seizure models, alcohol withdrawal seizures seem to be particularly sensitive to MK-801, suggesting that mechanisms which result in seizure susceptibility after withdrawal of chronic ethanol exposure may be dependent upon sensitization or upregulation of NMDA processes.     

Locomotor hyperactivity induced by MK-801 in rats.

The MK-801-induced hyperactivity in rats was antagonized by haloperidol and, to a lesser degree, by SCH 23390, a dopamine D-1 antagonist, and sulpiride, a dopamine D-2 antagonist. Combined treatment with MK-801 + D-amphetamine, or MK-801 + apomorphine caused a stronger locomotor hyperactivity than each of those drugs given alone. The stereotypy evoked by D-amphetamine or apomorphine was not changed by MK-801. Atropine potentiated the effect of MK-801. Prazosin, idazoxan or ritanserin did not affect the MK-801-induced hyperactivity. It was reduced by pretreatment with alpha-methyl-p-tyrosine (alpha-MT) and completely abolished by pretreatment with reserpine, or with reserpine+alpha-MT. Also combined administration of MK-801 + clonidine increased the activity of rats pretreated with reserpine+alpha-MT. Our results indicate that the dopamine system is mainly involved in the locomotor hyperactivity induced by MK-801.     

Arcaine and MK-801 make recall state-dependent in rats

RATIONALE: Conditioned fear to context causes freezing and cardiovascular changes in rodents and has been used to measure anxiety. It also activates the dorsolateral column of the periaqueductal gray (dlPAG). Microinjections of cannabinoid agonists into the dlPAG produced anxiolytic-like effects in the elevated plus maze, but the effects of these treatments on fear conditioning remains unknown. OBJECTIVE: The objective of this study was to verify if intra-dlPAG injection of the CB1 cannabinoid receptor agonist anandamide (AEA) or the anandamide transport inhibitor AM404 would attenuate behavioral (freezing) and cardiovascular (increase of arterial pressure and heart rate) responses of rats submitted to a contextual fear-conditioning paradigm. MATERIALS AND METHODS: Male Wistar rats with cannulae aimed at the dlPAG were re-exposed to a chamber where they had received footshocks 48 h before. Fifteen minutes before the test, the animals received a first intra-dlPAG injection of vehicle or AM251, a CB1 receptor antagonist (100 pmol/200 nl), followed 5 min later by vehicle, AEA (5 pmol/200 nl) or AM404 (50 pmol/200 nl). Freezing and cardiovascular responses were recorded for 10 min. RESULTS: Freezing and cardiovascular responses were reduced by administration of either AEA or AM404 into the dlPAG before re-exposition to the aversively conditioned context. These effects were abolished when the animals were locally pretreated with AM251. The latter drug, even at a higher dose (300 pmol), was ineffective when administered alone into the dlPAG. CONCLUSION: The results suggest that facilitation of endocannabinoid-mediated neurotransmission in the dlPAG, through activation of local CB1 receptors, attenuates the expression of contextual fear responses.     

The effect of acute tryptophan depletion on probabilistic choice

Choice behaviour can be viewed as a response to reinforcement determined by an interaction between the quantities, delays and probabilities of two outcomes. The variation in the perceived value of a reinforcer with alteration of these factors (discounting) can be modelled mathematically by hyperbolic discounting functions. Making risky choices is a feature of impulsivity and has been associated with reduced serotonin (5-hydroxytryptamine, 5-HT) function. In this study, we investigated the possible role of 5-HT in modulating probability discounting using the technique of acute tryptophan (TRP) depletion in subjects undertaking an imaginary gambling task. The gambling task consisted of choosing between two 'roulette-like' dials: 'A' which provided a smaller but nearly certain 'win' and 'B' which gave a 'win' 2.5 times the amount with a probability that was systematically varied. A series of reward sizes on dial 'A' was presented ranging from 10 pence to 10,000 pounds. The probability of winning on dial 'B' at which the subjects valued the two dials equally (indifference point) was determined as a measure of willingness to take a risk. Subjects were more likely to take a risk for smaller rewards but the indifference points in the 15 subjects who received TRP depletion did not differ from 13 who had the control drink. On a surprise retesting 1 week later there was a trend (p < 0.07) for subjects to be more willing to take risks the second time, particularly in the case of small rewards. This study does not support a role for 5-HT in modulating probabilistic choice in agreement with recent evidence from experiments with animals; however, the imaginal nature of the task and modest numbers may have influenced the result.     

The effects of haloperidol and clozapine on the disruption of sensorimotor gating induced by the noncompetitive glutamate antagonist MK-801

The amplitude of the acoustic startle response in rats is decreased if the startle stimulus is preceded by a nonstartle-eliciting auditory stimulus. This sensory gating phenomenon, known as prepulse inhibition, is diminished in schizophrenic individuals. In rats, the noncompetitive glutamate antagonist MK-801 disrupts prepulse inhibition. The present study examined whether the disruption by MK-801 is reversible in rats pretreated with the classical antipsychotic haloperidol or the atypical antipsychotic clozapine. Male Sprague-Dawley rats were placed into a startle chamber and presented with auditory stimuli consisting of either 95 or 105 dB tones presented alone or preceded by a 70 dB tone. Rats treated with 0.1 mg/kg MK-801 demonstrated a significant disruption of prepulse inhibition. Haloperidol (0.1 and 0.5 mg/kg) and clozapine (1.0 and 5.0 mg/kg) each consistently failed to antagonize the MK-801-induced blockade of prepulse inhibition. The effects of haloperidol and clozapine on prepulse inhibition were also examined in saline-treated rats. Clozapine and, to some extent, haloperidol produced a dose-related facilitation of prepulse inhibition. Although preliminary, this finding raises the possibility that the enhancement of prepulse inhibition by antipsychotics might provide a useful rodent model for screening potential antipsychotic drugs.     

Effect of MK-801 on the decrease in tryptophan hydroxylase induced by methamphetamine and its methylenedioxy analog

The role of N-methyl-D-aspartate (NMDA) receptors in the decrease in neostriatal tryptophan hydroxylase (TPH) activity induced by repeated high doses of methamphetamine or 3,4-methylenedioxymethamphetamine (MDMA) was evaluated. Rats received 4 injections of methamphetamine (15 mg/kg) or MDMA (10 mg/kg) at 6 h intervals, and were killed 18-20 h after the last administration. These treatments with methamphetamine or MDMA reduced neostriatal TPH activity to 26 and 34% of control, respectively. Coadministration of MK-801 (2.5 mg/kg) significantly attenuated the methamphetamine-induced decrease in TPH activity (66% of control), but did not alter the effect of MDMA. This study suggests that excitatory amino acids may participate in the methamphetamine-induced decline in central TPH activity, and that the mechanism by which MDMA and methamphetamine decreases TPH activity may differ.     

Comparative neurobiological effects of ibogaine and MK-801 in rats

Ibogaine is a plant-derived alkaloid with putative 'anti-addictive' properties. Although ibogaine binds to multiple targets in the brain, recent evidence suggests the drug acts as an N-methyl-D-aspartate (NMDA) antagonist similar to MK-801. The purpose of the present study was to compare neurochemical and neuroendocrine effects of ibogaine and MK-801 in vivo. Male rats received either i.p. saline, ibogaine (10 and 100 mg/kg), or MK-801 (0.1 and 1 mg/kg). Groups of rats (N=6-8/group) were decapitated 30 or 60 min after injection. Brains were harvested for analysis of dopamine (DA) and its metabolites, while trunk blood was collected for analysis of plasma corticosterone and prolactin. Ibogaine produced marked dose-dependent reductions in tissue DA with concurrent increases in the metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). This profile of ibogaine-induced effects on DA metabolism was consistently observed in the cortex, striatum, olfactory tubercle, and hypothalamus. MK-801, on the other hand, did not reduce DA levels in any brain region but did cause modest region-specific elevations in DA metabolites. Ibogaine and MK-801 caused comparable elevations in circulating corticosterone, but only ibogaine increased prolactin. The present findings show that the effects of ibogaine on DA neurotransmission and neuroendocrine secretion are not fully mimicked by MK-801. Thus, the wide spectrum of in vivo actions of ibogaine can probably not be explained simply on the basis of antagonism at NMDA receptors.     

MK-801 impedes the acquisition of a spatial memory task in rats

Several studies have reported that MK-801 impairs the acquisition of various learning and memory tasks, while others suggest that MK-801 may interfere with performance rather than having a specific effect on memory. To characterize further the effects of MK-801 on learning and memory, MK-801 (0.05 mg/kg, SC) was administered prior to or immediately after learning trials in a trial-independent water maze task. Since MK-801 may affect nonassociative variables that may influence learning and memory, motor activity and general reactivity measures were also determined for 0.0125, 0.025, or 0.05 mg/kg of MK-801 administered SC. Since MK-801 may also be used to treat children with epilepsy, we investigated the possible persistent cognitive effects on neonates. MK-801 (0.02 mg/kg, SC) was administered at postnatal days 9-15 and tested in the same task as above starting at day 36 of age. There were no persistent effects of neonatal treatment. However, in adult rats, MK-801 impaired the acquisition of the water maze task but did not affect performance during a recall task in the same apparatus. At doses affecting learning, there were no effects on motor activity or general reactivity in adult rats. These results are consistent with the conclusion that MK-801 interferes with acquisition of spatial learning in the rat.     

Serotonin depletion enhances the intracerebroventricularly administered MK-801-induced plasma interleukin-6 levels in mice

To investigate the effect of serotonin depletion on the intracerebroventricularly (i.c.v.) administered MK-801-induced plasma interleukin-6 (IL-6) levels, we pretreated mice with parachlorophenylalanine (PCPA, 300 mg/kg, i.p.) 3 d before an i.c.v. injection of MK-801 (1 microg). The i.c.v. MK-801-induced rise of plasma IL-6 level was markedly enhanced in the PCPA-pretreated mice. However, serotonin depletion by PCPA pretreatment did not affect the i.c.v. MK-801-induced increase in plasma corticosterone level. These results suggest that serotonergic system is involved in the suppressive regulation of MK-801-induced plasma IL-6 level.     

MK-801 produces antianxiety effect in elevated plus-maze in mice

The antianxiety effect of the non-competitive NMDA receptor antagonist, MK-801, was investigated in the present study in the elevated plus-maze paradigm in mice. During a 5-min session of the test, the number of entries the animal made in open/and closed arm, preference of the animal for first entry, and average time each animal spent in open and closed arm were noted as parameters for anxiety-related movements. The effect of MK-801 was further explored by studying its interaction with the specific anxiolytic agent, diazepam; the anxiogenic beta carboline agent, FG 7142; and the central benzodiazepine receptor antagonist, flumazenil (RO 15–1788). MK-801 produced anxiolytic effects at all the doses investigated. It increased the preference of the animal for open arm in a dose-dependent manner and the effect was potentiated by diazepam. Both FG 7142 and flumazenil reversed the effects of MK-801 when these agents were concomitantly administered with MK-801. The study revealed the anxiolytic effect of MK-801, a non-competitive antagonist of NMDA-receptor, and also an interaction of the NMDA-receptor and GABA/BZ-receptor complex in anxiety-related behaviour in mice.     

Sex differences in dizocilpine (MK-801) neurotoxicity in rats

The sex differences in the clinical signs and the distribution of astrocytic glial fibrillary acidic protein (GFAP) induced by an N-methyl-d-aspartate antagonist, dizocilpine (MK-801), were examined. A single intraperitoneal injection of MK-801 (5 mg/kg body weight) caused a prolonged recumbency (35-40 h), leading to a severe loss of body weight in female rats, in contrast to a light effect in males, independent of age. Early salivation or lacrimation was also severe in females and delayed bloody lacrimation was observed in females only. The pretreatment with 17β-estradiol (0.1 or 1.0 mg/kg body weight) made early signs worse in both sexes, but a remarkable mortality (20-40%) was observed in females only. The treatment with MK-801 greatly enhanced GFAP expression in retrospenial cortex of both sexes with a higher enhancement in females. The MK-801-induced expression of GFAP was further increased by the pretreatment with 17β-estradiol (1 mg/kg body weight) in females. Overall, the expression of GFAP in the retrospenial cortex of rats treated with MK-801 appeared to be higher in females than males, somewhat in parallel with more severe clinical signs in females. The results indicate the higher sensitivity of female rats to MK-801 neurotixicity, and the possible involvement of 17β-estradiol in the sex differences of the sensitivity.