Potentiation of the Ambulation-increasing effect induced by combined administration of MK-801 with ethanol in mice

Although both MK-801 (dizocilpine: 0.1 mg/kg, IP) and ethanol (1.6 nd 2.4 g/kg, PO) only slightly increased ambulatory activity in mice, their combination produced a marked enhancement of the ambulation-increasing effect. The combination of MK-801 (0.03 mg/kg) with ethanol (1.6 and 2.4 g/kg) also elicited a significant increase in the mouse's ambulation. A significant enhancement of the effect was produced by the combination of ketamine (3 and 10 mg/kg) with ethanol only (2.4 g/kg). The ambulation increment induced by the combination of MK-801 (0.1 mg/kg) plus ethanol (1.6 g/kg) was dose-dependently inhibited by YM-09151-2 (0.0001–0.01 mg/kg IP), SCH 23390 (0.001–1 mg/kg IP), reserpine (0.1–1 mg/kg, IP) and ceruletide (0.00001–0.001 mg/kg, IP), and the highest dose of each drug was effective for complete inhibition of the ambulation. Naloxone (0.05–5 mg/kg IP), apomorphine (0.001–0.1 mg/kg IP) and -methyl-p-tyrosine (50–200 mg/kg, IP) partially reduced the ambulatory activity induced by the combination of MK-801 with ethanol. These results suggest that the dopaminergic system, particularly via presynaptic changes in the release of stored dopamine, as well as the opioid system, are involved in the interaction of MK-801 with ethanol.     

Behavioral interactions caused by combined administration of morphine and MK-801 in rats

Rationale: The NMDA antagonist MK-801 reportedly blocks experience-dependent changes in sensitivity to morphine, including tolerance to its analgesic actions and sensitization to its locomotor-stimulating effects. However, evidence in the existing literature suggests that some of MK-801’s effects are additive (or synergistic) with those of morphine. Objectives: Experiments were conducted to characterize the effects of acute and repeated administration of the combination of MK-801 and morphine on analgesia, locomotor activity, and drug discrimination in rats. Methods: In each experiment, rats were first tested repeatedly after treatment with the combination of MK-801 and morphine, and then after treatment with either drug alone. Results: The analgesic effects of MK-801 combined with morphine were greater than those of morphine alone, but tolerance to the combination of drugs developed at a similar rate as to morphine alone. The locomotor-stimulating effects of MK-801 combined with morphine were also greater than those of either drug alone, and locomotor sensitization developed to the combination of drugs but not to either drug alone at the low doses used. Rats learned to discriminate a combination of MK-801 and morphine from vehicle as quickly as they learned to discriminate morphine alone from vehicle, but those trained with the combination of MK-801 and morphine responded primarily at the vehicle-appropriate lever when given either drug alone. Conclusions: Since behavioral adaptations readily occur in the presence of MK-801, it appears that NMDA antagonists fail to invariably block the cellular plasticity that underlies such adaptations. Rather, the expression of adaptations in drug sensitivity appears related, at least in part, to the continued presence of the discriminative stimulus cues that are present during conditioning. Although NMDA receptors are important for some forms of cellular plasticity, the present studies illustrate the difficulty in interpreting behavioral studies in which MK-801 is given with morphine. Received: 24 November 1999 / Accepted: 25 March 2000     

Behavioral effects of MK-801 in the rat

Several experiments were conducted to study the effects of the noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, MK-801, on learning and memory in the rat. Rats displayed impaired performance on several sensorimotor tests and appeared grossly intoxicated when treated IP with 0.2 mg/kg MK-801, but not when treated with lower doses (0.05 or 0.1 mg/kg). Postacquisition performance on two spatial learning tasks involving working memory protocols (reinforced alternation and radial arm maze) was impaired by MK-801 at intoxicating doses (0.2 mg/kg) but not at lower doses (0.05 or 0.1 mg/kg). Using a position habit reversal task, we found that rats could learn to reverse a position habit while under the influence of a nonintoxicating dose of MK-801 (0.1 mg/kg), but when tested on the following day performed as if they did not recall what they had learned. Thus, acute administration of a nonintoxicating dose of MK-801 disrupts the retention of new information learned under the influence of the drug but does not interfere with the performance of tasks that are well learned before the drug is administered. Whether the performance deficits on the spatial learning tasks observed only following intoxicating doses of MK-801 reflect an effect on memory is not clear.     

The investigation of neonatal MK-801 administration and physical environmental enrichment on emotional and cognitive functions in adult Balb/c mice

N-methyl-d-aspartate (NMDA) receptors play an important role in brain maturation and developmental processes. It is known that growing up in an enriched environment has effects on emotional and cognitive performance. In our study, we evaluated the effects of physically enriched environment on the emotional and cognitive functions of the adult brain in the setting of previous NMDA receptor hypoactivity during the critical developmental period of the nervous system. In this study, NMDA receptor blockade was induced 5-10 days postnatally (PD5-10) using MK-801 in mice Balb/c (twice a day 0.25 mg/kg, for 5 days, intraperitoneal). MK-801 was given to developing mice living in a standard (SE) and an enrichment environment (EE) and once the animals reached adulthood, emotional behaviors were evaluated using an open field test (OF) and an elevated plus maze (EPM) test whereas cognitive processes were evaluated using the Morris water-maze (MWM). The EE group showed decreased locomotor activity (p < 0.05) in the OF and increased exploratory behaviour (p < 0.01) and decreased fear of heights/anxiety-like behaviour (p < 0.05) in the EPM test. The EE had positive effects on spatial learning in the MWM (p < 0.05). Blockade of the NMDA receptor increased the fear of height (p < 0.05), decreased exploratory behaviour and locomotor activity (p < 0.001). Also, it led to decreased spatial learning (p < 0.05). The decreases in spatial learning and exploratory behaviours and the increase in fear of heights/anxiety-like behaviour with NMDA receptor blockade was not reversed by EE. NMDA receptor blockade during the critical period of development led to deterioration in the emotional and cognitive processes during adulthood. An enriched environmental did not reverse the deleterious effects of the NMDA receptor blockade on emotional and cognitive functions.     

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.     

Cessation of repeated administration of MK-801 changes the anticonvulsant effect against flurothyl-induced seizure in mice

The effects of acute and repeated administration of MK-801 on flurothyl (FE)-induced seizure were investigated in mice. In the acute effect of MK-801 (0.01-0.1 mg/kg ip) in naive and FE-kindled mice, there were no changes on the latencies of clonic seizures. However, MK-801 dose-dependently inhibited both latencies and incidence of tonic seizures in mice and suppressed the grade of seizure severity in FE-kindled mice. Repeated administration of MK-801 at doses of 0.01 and 0.1 mg/kg 2 h prior to each exposure to FE for 8 days did not show any effects on the latencies of clonic seizure. However, seizure severity was significantly exacerbated in the 0.1 mg/kg treated group when mice were re-exposed to FE without MK-801 1 week after the last administration. A week after the repeated administration of MK-801 at a dose of 0.1 mg/kg for 8 days without exposure to FE, mice were exposed to FE 2 h after readministration of MK-801 until tonic seizure occurred. The latencies of clonic seizures were almost the same in the acute experiment in naive controls. The latency of tonic seizure was significantly delayed compared to the acute experiment with MK-801 at a dose of 0.1 mg/kg. These findings suggested that MK-801 possessed an anticonvulsant action against FE-induced tonic seizure. However, the efficacy of this acute effect of MK-801 was impaired at 1 week of withdrawal after repeated administrations. This may be related in part to the changes in sensitivity to NMDA receptors.     

Subchronic MK-801 behavioural deficits in rats: partial reversal by the novel nitrate GT 1061

Cognitive deficits are a core feature of schizophrenia that may be linked to abnormalities in GABA and nitric oxide (NO). Subchronic treatment with glutamate receptor antagonists produces similar deficits, providing a useful model to examine potential therapeutics. The present study investigated the effects of subchronic MK-801 (intraperitoneally; 0.5 mg/kg twice daily for 7 days) on amphetamine-induced locomotor activity and reversal learning in the water maze in rats, and the ability of the novel compound GT 1061 (4-methyl-5-(2-nitroxyethyl) thiazole HCl), containing dual pharmacophores producing NO- and GABA-mimetic activity, to ameliorate these effects. MK-801 enhanced locomotor responses to amphetamine. GT 1061 (0.1; not 0.0001, 0.001, 0.01, 1.0 mg/kg) further enhanced locomotion; the pro-GABA drug chlormethiazole (0.1, 1.0 mg/kg) had no significant effect. In saline-pretreated rats GT 1061 (0.1; not 0.0001, 0.001 mg/kg) increased amphetamine-induced locomotion; chlormethiazole (0.1, 1.0 mg/kg) had no effect. In the water maze, MK-801 impaired reversal learning after platform relocation. GT 1061 (0.001, 0.01, 0.1; not 0.0001 or 1.0 mg/kg) attenuated this impairment; chlormethiazole had no significant effect. These ameliorative effects of GT 1061 may be linked to the activation of NO- and GABA-dependent signaling and suggests a new direction for treating cognitive dysfunction in schizophrenia.     

The anticonflict effect of MK-801, an NMDA antagonist: investigation by punishment procedure in mice

The NMDA antagonist MK-801 at 0.3 mg/kg, i.p. increased the punished response under a MULT VI 1.5/FR 5-punishment schedule of food reinforcement in mice. Furthermore, although neither MK-801 (0.1 mg/kg, i.p.) nor diazepam (0.25 mg/kg, s.c.) was without effect when separately administered, a significant increase in the punished response appeared after the combined administration of these two drugs. The present results suggest that MK-801 not only shows an anticonflict effect, but also enhances the anticonflict effect of benzodiazepine anxiolytics in mice.     

Kindled rats are more sensitive than non-kindled rats to the behavioural effects of combined treatment with MK-801 and valproate.

The effects of combined treatment with low doses (0.025-0.05 mg/kg i.p.) of the non-competitive NMDA receptor antagonist, MK-801 (dizocilpine), and the antiepileptic drug, valproate, were studied in amygdala-kindled and non-kindled rats. MK-801, 0.05 mg/kg, did not exert anticonvulsant effects in fully kindled rats but increased the anticonvulsant potency of valproate, 100 mg/kg i.p. However, the increase in anticonvulsant activity was paralleled by a marked increase in adverse effects such as motor impairment and hyperactivity, resulting in a considerable reduction of the therapeutic index of the combined treatment compared to valproate alone. Furthermore, MK-801 potentiated the adverse effects but not the anticonvulsant activity of 50 mg/kg valproate. Combined treatment with MK-801 and valproate induced much less marked adverse effects in non-kindled rats than in kindled rats. The competitive NMDA receptor antagonist, CGP 37849 1 mg/kg i.p., did not alter the effects of valproate in kindled rats. The data on combined treatment with MK-801 and valproate substantiate the conclusion that kindling alters the susceptibility to manipulations of NMDA receptor-mediated events.     

Procedural examination of behavioural sensitisation to morphine: lack of blockade by MK-801, occurrence of sensitised sniffing, and evidence for cross-sensitisation between morphine and MK-801

Rats were tested in an open field, a "sniffing box" and an eight-arm maze, to examine in detail the behavioural changes induced by morphine (10mg/kg, i.p.) and MK-801 (0.1mg/kg, i.p.), either alone or in combination, during a 10 day treatment and subsequent drug challenges. In addition to locomotion, a number of other behaviours such as sniffing, rearing and exploration were examined. After morphine challenge, sensitised locomotion and rearing were found in the open field, and sensitised sniffing and turning were observed in the sniffing box. In addition, in the sniffing box, saline challenge produced significant conditioned sniffing and turning, and after a challenge with MK-801, sensitised sniffing and turning were seen in the group pretreated with morphine, suggesting a cross-sensitisation between morphine and MK-801 (but not vice versa). In the eight-arm maze, sensitised locomotion was found after morphine challenge. Morphine and MK-801 changed the preference for particular angles run during trials in a characteristic manner. In none of the behavioural measures was MK-801 able to block the development (and expression) of sensitisation to morphine. In several cases, rather, MK-801 enhanced the acute morphine effects. Sensitisation of sniffing suggests that sensitisation has also developed within the nigrostriatal dopamine system and not only within the mesolimbic dopamine system, as is generally discussed in the context of the most commonly assessed behaviour, locomotion. This finding argues for the additional use of the sniffing box in sensitisation experiments.     

Topiramate antagonizes MK-801 in an animal model of schizophrenia

The phencyclidine (PCP) model of schizophrenia suggests that N-methyl-D-aspartate (NMDA) receptor hypofunction and its consequences may play an important role in the pathophysiology of this psychiatric disorder. Moreover, the schizophreniform psychosis caused by PCP resembles schizophrenia in all of the relevant domains of psychopathology, especially negative symptoms and cognitive dysfunction. Because of interest in the PCP model and possible NMDA receptor hypofunction in schizophrenia, animal behaviors elicited by PCP and its analogues have been characterized. These preclinical models may serve to identify candidate compounds that possess therapeutic efficacy in schizophrenia. Ideally, negative symptoms and cognitive dysfunction would also serve as therapeutic targets for these novel medications. In the current study, the ability of topiramate to attenuate the severity of a specific behavior elicited by MK-801 (dizocilpine), a high affinity analogue of PCP was studied in mice. Topiramate was chosen because it addresses two of the predicted pathological consequences of NMDA receptor hypofunction. Specifically, topiramate potentiates GABAergic neurotransmission and antagonizes the excitotoxic actions of glutamate at the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate (KA) classes of glutamate-gated channels. Topiramate was shown to inhibit MK-801-elicited "popping" behavior in a complex dose-dependent manner.     

The behavioural effects of MK-801 in rats: involvement of dopaminergic, serotonergic and noradrenergic systems.

The non-competitive NMDA receptor antagonist, MK-801 (dizocilpine), induces in rats a characteristic behavioural syndrome with ataxia, stereotypies and hyperlocomotion. At least part of this behavioural syndrome is thought to be related to interactions between glutamatergic and dopaminergic neurotransmission. Based on recent biochemical evidence that serotonin (5-HT) might also be involved in the effects of MK-801 several 5-HT receptor ligands were tested for effects on MK-801-induced behaviours. The 5-HT1A receptor ligands, ipsapirone and NAN-190, which are known to display antagonist-like properties in functional models of postsynaptic 5-HT1A receptor activity attenuated or blocked the hyperlocomotion and head weaving observed after administration of MK-801, whereas the 5-HT2 receptor antagonist, ritanserin, was ineffective in this respect. The dopamine receptor antagonist, haloperidol, and the alpha 1-adrenoceptor antagonist, prazosin, also attenuated behaviours induced by MK-801. In contrast to its effects on stereotypies induced by MK-801, ipsapirone potentiated rather than attenuated the stereotyped behaviour induced by the dopamine receptor agonist, apomorphine, indicating that antagonism of MK-801-induced stereotypies by ipsapirone may not be related to the dopaminergic system. The data indicate that, in addition to catecholaminergic systems, serotonergic neurotransmission is significantly involved in the mechanisms by which MK-801 alters behaviour in rats.     

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.     

Psychopharmacological effects of MK-801 in infant and preweanling rat pups.

-Neonatal (3-4-day-old) and preweanling (17-18-day-old) Sprague-Dawley rat pups were tested following SC administration of saline, 0.01, 0.05, 0.1, 0.5, or 1.0 mg/kg MK-801. In neonatal rat pups, reductions in a number of behaviors (forward locomotion, mouthing) were seen at the higher (0.5 and 1 mg/kg) doses. In contrast, evidence of behavioral stimulation in forward locomotion at 30 min postinjection was seen at a lower dose (0.1 mg/kg). In preweanling rat pups, marked sedative effects of MK-801 were seen at higher doses (decreases in forward locomotion, headlift and sniff), with signs of behavioral stimulation (increases in forward locomotion and mouthing) evident at low doses. Thus, as in adults, low doses of MK-801 may be behaviorally stimulatory and higher doses inhibitory to both neonatal and preweanling pups, although the stimulatory effects appear to be somewhat less pronounced in these young animals than has been previously reported in adulthood.     

MK-801 prevents the enhanced behavioural response to apomorphine elicited by repeated electroconvulsive treatment in mice

Repeated administration of electroconvulsive stimuli (ECS) to mice once daily for a period of 7 days results in an enhanced locomotor response induced by apomorphine (1.0 mg/kg, IP). Pretreatment (30 min) with the N-methyl-d-aspartate (NMDA) receptor antagonist, MK-801 (0.01–1.0 mg/kg IP), suppressed ECS-induced seizure activity in a dose-dependent manner. MK-801 (0.01 and 0.033 mg/kg, IP) given 30 min before each ECS dose-dependently decreased apomorphine-mediated responses. Administration of MK-801 (0.033 mg/kg IP) 30 min after each convulsion had the same effect. These results indicate that MK-801 can abolish the ECS-induced enhancement of dopamine-mediated behaviour possibly by interfering with postictal processes. Thus, NMDA receptors seem to be involved in the behavioural changes and presumably also in the neural adaptations produced by repeated ECS.     

The behavioural effects of MK-801: a comparison with antagonists acting non-competitively and competitively at the NMDA receptor

The selective non-competitive NMDA receptor antagonist, MK-801, potently blocked convulsions induced in the mouse by N-methyl-DL-aspartic acid (NMDLA) with an i.v. ED50 dose of 0.2 mg/kg. Similar doses of MK-801 were also effective in blocking seizures induced by pentylenetetrazol (PTZ), electroshock and by sound in audiogenic seizure-prone animals. Other less selective non-competitive NMDA receptor antagonists including phencyclidine (PCP), thienylcyclohexylpiperidine (TCP), (+)-N-allylnormetazocine [+)-NANM, (+)-SKF 10,047) and ketamine also blocked NMDLA-induced seizures with a rank order of potency of MK-801 greater than PCP greater than TCP = (+)-NANM greater than ketamine. The competitive NMDA receptor antagonist, 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) blocked NMDLA-induced seizures with an ED50 of 4.5 mg/kg, 22- and 560-fold more potently than the competitive antagonists, 2-DL-amino-7-phosphonoheptanoic acid (2-APH) and 2-DL-amino-5-phosphonovaleric acid (2-APV), respectively. MK-801 was the most potent of the non-competitive antagonists to induce a motor syndrome including head weaving, body rolling, increased locomotion and ataxia, characteristic of the behavioural response to PCP in the mouse. The syndrome was also present following injection of the competitive NMDA receptor antagonists, although they were generally less potent (probably a reflection of poor brain penetration) and less efficacious than the non-competitive antagonists. For all compounds except CPP, the anticonvulsant ED50 dose was close to the minimum effective dose to induce motor stimulation: CPP was 5- to 10-fold more potent as an anticonvulsant.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Comparison of the effects of the acute administration of dexoxadrol, levoxadrol, MK-801 and phencyclidine on body temperature in the rat

Some of the dioxolanes produce pharmacological effects that have much in common with phencyclidine and phencyclidine-like drugs. Dioxadrol can be resolved into two enantiomers, dexoxadrol and levoxadrol. Dexoxadrol has an affinity for phencyclidine receptors that is much greater than that of levoxadrol, but dexoxadrol and levoxadrol have nearly equal affinities for sigma receptors. The systematic analysis of the relative potencies of dexoxadrol and levoxadrol can be used as an approach to define effects mediated by phencyclidine vs sigma receptors. Compounds that act on phencyclidine receptors, as well as affecting behavior, alter body temperature in the rat. The purpose of the present study was to compare and contrast the effects of the acute administration of dexoxadrol, levoxadrol, MK-801 and phencyclidine on body temperature in the rat. Dexoxadrol and levoxadrol (5.0, 10.0, 20.0 or 40.0 mg/kg), MK-801 (0.12, 0.6 or 1.2 mg/kg) or phencyclidine (5.0, 10.0 or 20.0 mg/kg) were administered subcutaneously and body temperature was measured. Both dexoxadrol and MK-801 produced hyperthermia but levoxadrol did not affect body temperature. In contrast to the hyperthermic effects of dexoxadrol and MK-801, phencyclidine produced hypothermia. These findings indicate that hypothermia induced by phencyclidine is not due to interactions with phencyclidine receptors and, while dexoxadrol, MK-801 and phencyclidine may share some similar receptor binding and behavioral characteristics, they can be differentiated on the basis of their effects on body temperature.     

Cerebral oligemic hypoxia and MK-801 treatment: effect on alternation behavior in mice

It is known that glutamatergic system is one of neurotransmitter systems affected by a transiently reduced oxygen supply. The aim of the present study was to examine the effects of MK-801, a noncompetitive NMDA receptor antagonist, on spontaneous alternation in mice exposed to cerebral oligemic hypoxia. Spontaneous alternation behavior and locomotor activity were evaluated using the Y-maze task. Transient cerebral oligemia was induced by bilateral clamping of carotid arteries (BCCA) for 30 min under pentobarbital anesthesia. MK-801 was injected 48 h after BCCA or sham surgery, 30 min before the test session. Treatment with MK-801 (0.1 mg/kg ip) impaired spontaneous alternation both in sham-operated and BCCA mice. MK-801 (0.1 mg/kg ip) significantly enhanced the locomotion of mice. The effects of MK-801 were not exacerbated by BCCA. These results show that cerebral oligemic hypoxia induced by BCCA does not change alternation behavior of mice treated with MK-801.