Effects of zotepine,haloperidol and clozapine on MK-801-induced stereotypy and locomotion in rats

Summary In the present study we compared the effects of the atypical neuroleptic zotepine to haloperidol and clozapine on stereotypies and locomotion induced in rats by the N-methyl-D-aspartate (NMDA) antagonist MK-801. Zotepine caused a dose-dependent reduction of MK-801-induced stereotypies and locomotion. Zotepine at a dosis of 2.5 mg/kg body weight showed a similar effect to 0.25 mg/kg haloperidol in reducing sterotypies and locomotion. Clozapine (5.0 mg/kg) reduced significantly locomotion and non-significantly stereotypies. These results add support to the assumption that MK-801-induced behavior provides an adequate animal model to test the potential efficacy of typical and atypical neuroleptics in the treatment of psychoses.     

Nitric oxide donor molsidomine attenuates psychotomimetic effects of the NMDA receptor antagonist MK-801

There is experimental evidence indicating that the non-competitive NMDA receptor antagonist MK-801 impairs cognition and produces a series of schizophrenia-like symptoms in rodents (hypermotility, stereotypies, and ataxia). The present study was designed to investigate the efficacy of the nitric oxide (NO) donor molsidomine in counteracting these MK-801-induced behavioral effects in the rat. In a first study, post-training administration of molsidomine (at 4 but not 2 mg/kg) successfully antagonized MK-801-induced performance deficits in a recognition memory test. In a subsequent study, molsidomine (2 and 4 mg/kg) was shown to be unable to reverse MK-801-induced hypermotility but attenuated stereotypies (continuous movement whole cage, body sway, and head weaving) produced by MK-801. Moreover, at 4 mg/kg this NO donor counteracted MK-801-induced ataxia. Our findings indicate that molsidomine attenuates behavioral effects related to the hypofunction of the NMDA receptor suggesting that NO might be involved in the psychotomimetic effects of non-competitive NMDA receptor antagonists.     

Dystonia induced by combined treatment with L-dopa and MK-801 in parkinsonian monkeys.

We examined whether the N-methyl-D-aspartate antagonist MK-801 (dizocilpine) would reverse parkinsonism or potentiate the effects of L-dopa in primates treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In contrast to its effect in rodent models, treatment with MK-801 (0.1 mg/kg) caused bradykinesia and ataxia in parkinsonian primates, but no locomotor stimulation. Coadministration of MK-801 (0.1 mg/kg) with L-dopa (20 mg/kg) induced marked dystonia accompanied by bradykinesia and ataxia. Dystonia was not induced by either treatment given alone. These findings indicate that MK-801 should not be advocated as an adjunct to dopamine agonist therapy in Parkinson's disease.     

Anticonvulsant effects of diazepam and MK-801 in soman poisoning

An animal model was developed to evaluate the anticonvulsant effects of diazepam and MK-801 in soman poisoning and to examine the possible mechanism of soman-induced convulsions. The oxime HI-6 (125 mg/kg, i.p.) was given to male rats, to increase survival, 30 min prior to 180 micrograms/kg, s.c. (equivalent to 1.6 x LD50) of soman, which produced 100% occurrence of convulsions. Initially, diazepam was studied with or without the concomitant administration of various doses of atropine sulfate 30 min prior to soman challenge. Diazepam (1.25-10.0 mg/kg, i.m.) alone did not prevent soman-induced convulsions. In the presence of 2, 4, 8, and 16 mg/kg of atropine, the anticonvulsant ED50 doses of diazepam were 0.490, 0.257, 0.132 and 0.136 mg/kg, respectively. Atropine sulfate at a dose of 16 mg/kg prevented the soman-induced hypersecretion, showed some anticonvulsant activity and provided a good motor recovery. MK-801 by itself, at or above 1 mg/kg, prevented convulsions, but markedly potentiated the lethal effects produced by soman. With atropine (16 mg/kg), the anticonvulsant ED50 for MK-801 was 0.037 mg/kg, which indicated that MK-801 was about 4 times as potent as diazepam, and the lethal interactions between MK-801 and soman were suppressed. The findings indicate that, in soman poisoning, diazepam and MK-801 are effective anticonvulsants in the presence of the anticholinergic atropine sulfate. The possible sequence of events and neuropharmacological mechanism of soman-induced convulsions are discussed.     

The selective 5-HT(6) receptor antagonist Ro 04-6790 attenuates psychotomimetic effects of the NMDA receptor antagonist MK-801

There are experimental evidences indicating that the non-competitive NMDA receptor antagonist MK-801 impairs cognition and produces a series of schizophrenia-like symptoms in rodents (hypermotility, stereotypies and ataxia). The present study was designed to investigate the efficacy of the selective 5-HT(6) receptor antagonist Ro 04-6790 in counteracting these MK-801-induced behavioural effects in the rat. The effects of Ro 04-6790 in antagonizing MK-801-induced memory deficits were assessed using the object recognition task. The ability of this 5-HT(6) receptor antagonist in counteracting hypermotility, stereotypies and ataxia produced by MK-801 were evaluated in a motor activity cage. Post-training administration of Ro 04-6790 (10 and to some extent also 3mg/kg) antagonized MK-801-induced performance deficits in a recognition memory test. In a subsequent study, Ro 04-6790 (3 and 10 mg/kg) reversed hypermotility and ataxia produced by MK-801. This 5-HT(6) receptor antagonist also alleviated MK-801-induced certain stereotypies. Our findings indicate that Ro 04-6790 attenuates behavioural effects related to the hypofunction of the NMDA receptor suggesting that this compound might be involved in the psychotomimetic effects of non-competitive NMDA receptor antagonists.     

The N-methyl-D-aspartate antagonist MK-801 protects against serotonin depletions induced by methamphetamine, 3,4-methylenedioxymethamphetamine and p-chloroamphetamine.

The non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 blocks the ability of D-methamphetamine (MA) to deplete striatal dopamine (DA). We now report that MK-801 attenuates decreases in serotonin (5-HT) concentration induced by MA and two other amphetamine analogues, 3,4-methylenedioxymethamphetamine (MDMA) and p-chloroamphetamine (PCA). Rats were injected with saline (1.0 ml/kg) or MK-801 (0.5, 1.0 or 2.5 mg/kg) followed by either saline (1.0 mg/kg), MA (4, 2 or 1 injection(s); 10.0, 20.0 or 40.0 mg/kg), MDMA (20.0 or 40.0 mg/kg) or PCA (5.0 or 10.0 mg/kg). In some experiments, two injections of MK-801 or saline were used. Seventy-two hours after the last injection rats were sacrificed and concentrations of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA) and DA were determined in hippocampus and striatum. MA caused a depletion of 5-HT to 33% of control in hippocampus and to 50% of control in striatum after the 4 x 10.0 mg/kg dose regimen. When MK-801 (2.5 mg/kg) was co-administered with MA, concentrations of 5-HT did not differ from control levels in either brain region. MDMA depleted 5-HT to approximately 58% of control in hippocampus and 66% of control in striatum at the 40 mg/kg dose.(ABSTRACT TRUNCATED AT 250 WORDS)     

MK-801-induced stereotypy and its antagonism by neuroleptic drugs

Summary MK-801 [(+)-5-methyl-10,11-dihydroxy-5H-dibenzo-(a,d)cyclo-hepten-5, 10-imine hydrogen maleate], which blocks glutamatergic transmission at the NMDA-receptor-gated ion chanel, induced stereotypies which are similar to those found after intrastriatal injections of AP-5, e.g. sniffing and locomotion. Tests in familiar or unfamiliar environment (non-stressful or stressful situation) did not qualitatively change MK-801-induced effects. Haloperidol (0.1mg/kg, IP) delayed the onset and shortened the duration of MK-801 (0.16; 0.33mg/ kg, IP)-induced stereotypy whereas clozapine (5 mg/kg, SC) potently antagonized it. However, exact quantification of sniffing, measured in an experimental chamber designed for this purpose, revealed an antagonism by both drugs, haloperidol as well as clozapine.Stereotypy is considered to represent an animal model of schizophrenia, and the antagonism of stereotypy with classical (haloperidol) as well as with atypical (clozapine) antipsychotic drugs is in accordance with the glutamate hypothesis of schizophrenia.     

Comparative effects of N and MK-801 on the abstinence syndrome in morphine-dependent mice

The effects of N^{G-monomethyl-l-arginine} (l-NMMA), an inhibitor of nitric oxide (NO) synthase and MK-801, an NMDA receptor antagonist on abrupt and naltrexone-precipitated abstinence symptoms were determined in male Swiss-Webster mice rendered dependent on morphine by subcutaneous implantation of a pellet containing 75 mg of morphine base for 3 days. Mice which served as controls were implanted with placebo pellets. Six hours after pellet removal, mice were injected intraperitoneally with either the vehicle or MK-801 (0.03, 0.1 and 0.3 mg/kg). Thirty minutes later the animals were injected with naltrexone subcutaneously (50 μg/kg) and the intensity of abstinence symptoms were determined. Of the three doses of MK-801 used, only 0.1 mg/kg dose inhibited the jumping behavior precipitated by naltrexone in morphine-dependent mice. Whereas the lower dose (0.03 mg/kg) of MK-801 increased, the higher doses of MK-801 (0.1 and 0.3 mg/kg) displayed a decrease in the formation of fecal boli. Administration of MK-801 did not affect the body weight loss observed during abrupt withdrawal (induced by removal of the pellets) in morphine-dependent mice. MK-801 at 0.1 mg/kg dose further decreased the body temperature during abrupt withdrawal in morphine-dependent mice. Other two doses of MK-801 (0.03 and 0.3 mg/kg) did not modify the hypothermia observed during abrupt morphine withdrawal. On the other hand, l-NMMA (0.02 to 4.0 mg/kg) injected intraperitoneally 15 min prior to the naltrexone administration blocked the stereotyped jumping response in a dose-dependent manner. Higher doses of l-NMMA 2.0 and 4.0 mg/kg also decreased the number of fecal boli formation. l-NMMA (0.2 to 4.0 mg/kg) also significantly reduced the abrupt withdrawal-induced body weight loss in morphine-dependent mice. Thus MK-801 has very little effect, which is not dose-dependent, on abrupt and antagonist-precipitated withdrawal in morphine-dependent mice. However, the l-NMMA has more profound dose-dependent effects on both the abrupt and antagonist-precipitated withdrawal in morphine-dependent mice. It is concluded that the inhibitors of NO synthase may be more beneficial than NMDA receptor antagonists in managing the symptoms of morphine abstinence syndrome.     

Reduction of motor seizures in rats induced by the ethyl bicyclophosphate trimethylolpropane phosphate (TMPP)

1. Trimethylolpropane phosphate (TMPP) is a potent cage convulsant, reported to act through binding to the picrotoxinin and/or benzodiazepine receptor sites of the gamma-aminobutyricA (GABA(A)) ionophore complex. 2. Adult male Fischer-344 rats were pretreated by intraperitoneal (i.p.) injection with either diazepam (DZP) [0.5-5.0 mg/kg], Phenobarbital (PB) [5-20 mg/kg], dizocilpine maleate (MK-801) [0.5-3.0 mg/kg], Tiagabine (TGB) [0.5-5.0 mg/kg], 6,7-dinitro-quinoxaline-2,3-dione (DNQX), [5-20 mg/kg], or scopolamine [SCP] (0.25-1.0 mg/kg) 30 min prior to i.p. injection with a convulsive dose of TMPP (0.6 mg/kg). 3. Rats were rated for occurrence of convulsive activity for 120 min post-injection. Time from TMPP injection to observation of subclinical seizures, generalized (tonic-clonic) seizures, and lethality was rated for each pretreatment group. 4. In general, DZP = PB > TGB in reduction of TMPP subclinical and/or clinical seizures. MK-801, at dose levels inducing near sedation, was also effective in modulation of TMPP-induced seizures. SCP or DNQX were generally ineffective in reducing or eliminating TMPP-induced seizures.     

Combined treatment with MK-801 and nicardipine reduces global ischemic damage in the gerbil.

BACKGROUND AND PURPOSE: Excessive activation of the N-methyl-D-aspartate receptor by glutamate produces an influx of Ca2+, which in turn is thought to lead to ischemic cell death. In this study we evaluated the combined treatment of the N-methyl-D-aspartate antagonist dizocilpine (MK-801) and the dihydropyridine Ca2+ channel blocker nicardipine for the reduction of hippocampal CA1 neuronal loss. METHODS: Global ischemia was induced by bilateral carotid artery occlusion in the gerbil. Body temperature was maintained between 36.5 degrees C and 37.5 degrees C during surgery. MK-801 (5.0 mg/kg) was injected 15 minutes after occlusion whereas nicardipine was given by injection and via a micro-osmotic pump (1.0 mg/kg/day) for 3 days. RESULTS: Postischemic treatment with MK-801 reduced CA1 cell loss by 27.0%, whereas nicardipine reduced CA1 cell loss by 13.3%. Combined postischemic treatment with these drugs yielded an additive, protective effect (44.5% reduction of CA1 loss) that did not appear to result from postischemic hypothermia as assessed by skull and rectal temperature recordings. CONCLUSIONS: Our results demonstrate that MK-801 plus nicardipine significantly attenuates CA1 cell death after forebrain ischemia in the gerbil. Excitatory amino acid antagonists in combination with Ca2+ channel antagonists may be an effective therapy in patients exposed to global ischemic insult.     

The evaluation of antimuscarinic-induced convulsions in fasted rats after food intake

The present study was performed to evaluate convulsions after food intake in fasted rats pretreated with scopolamine or atropine and to determine whether these convulsions respond to drugs found effective in fasted mice. Scopolamine (2.4 mg/kg) and atropine (2.4 mg/kg) were given intraperitoneally (i.p.) to rats fasted for 52h. Both drugs induced convulsions after animals were allowed to eat ad lib. Another group of fasted rats pretreated with saline, MK-801 (0.1mg/kg), clonidine (0.1mg/kg), chlorpromazine (2 and 4 mg/kg), valproate (200mg/kg), diazepam (1.5 and 2mg/kg) or gabapentin (50mg/kg) were treated i.p. with saline or scopolamine (2.4 mg/kg) and were allowed to eat ad lib. Clonidine, MK-801, chlorpromazine (4 mg/kg) and diazepam (2 mg/kg) reduced the incidence of scopolamine-induced convulsions in fasted rats. Gabapentin could only prolong the onset of convulsions. Neither treatment was effective against myoclonus of hindlimbs. Present results showed that fasted rats also develop antimuscarinic-induced convulsions which do not completely respond to treatments found effective in convulsions of fasted mice.     

MK-801 protects against seizures induced by the cholinesterase inhibitor soman

MK-801, a novel anticonvulsant which is a potent N-methyl-d-aspartate antagonist, attenuated or blocked seizures and convulsions induced by the irreversible organophosphorus anticholinesterase inhibitor soman. Guinea pigs chronically instrumented for electrocorticogram recording were given a low dose (1 mg/kg) or a high dose (5 mg/kg) of MK-801 or saline vehicle 30 min prior to receiving 2 x LD50 of soman. All animals were treated with atropine methylnitrate and pralidoxime chloride 30 sec after soman injection. All saline control subjects exhibited severe seizures and convulsions shortly after receiving soman. Low dose MK-801 greatly attenuated and high dose MK-801 completely blocked seizure activity. Animals treated with MK-801 recovered faster and had a much greater probability of survival for 48 hr after soman exposure than did controls. This is the first demonstration of the involvement of the excitatory amino acid neurotransmitter system in seizures and convulsions induced by a cholinesterase inhibitor.     

MK-801 and ketamine induce heat shock protein HSP72 in injured neurons in posterior cingulate and retrosplenial cortex.

MK-801 and ketamine are noncompetitive N-methyl-D-aspartate (NMDA) receptor blockers that decrease brain injury in animal models of focal and global ischemia. Recent reports, however, suggested that MK-801 itself can damage neurons. Here we show that MK-801 (0.1 to 5.0 mg/kg) and ketamine (40 to 100 mg/kg) typically induce heat shock protein HSP72 mainly in layer 3 neurons of the posterior cingulate and retrosplenial cortex of the rat. These HSP72-immunoreactive neurons contain abnormal cytoplasmic vacuoles visualized by electron microscopy. The HSP72 immunoreactivity is maximal at 24 hours with 1.0-mg/kg doses of MK-801 and disappears by 2 weeks. Based on these data, we propose: (1) MK-801 and ketamine injure selected neurons, which express HSP72 in response to that injury. (2) Since HSP72 is induced for 1 to 2 weeks, the prolonged psychological side effects of MK-801, ketamine, phencyclidine, and related drugs could be related to this injury. (3) The neuroprotective effect of MK-801 is probably not related to HSP72 induction. (4) HSP72 immunocytochemistry is useful for studying nonlethal neuronal injury from a wide variety of brain insults.     

The NMDA receptor antagonist MK-801 does not protect against serotonin depletions caused by high doses of DL-fenfluramine.

The non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (MK-801) has been shown to block methamphetamine (MA) induced damage to the dopamine (DA) and serotonin (5HT) systems of the brain. DL-Fenfluramine (FEN) is another potential neurotoxin but its long-term depletions are more selective to the 5HT system. To determine whether MK-801 protects against damage induced by FEN, we treated rats with FEN (4 injections of 12.5 mg/kg, at 1 h intervals) in conjunction with either saline or MK-801 (2 injections of 2.5 mg/kg, administered 15 min before and 90 min after the first FEN injection). Two weeks post-treatment, MK-801 alone caused a small but significant decrease in 5HT tissue concentrations in striatum and amygdala. FEN significantly reduced 5HT in all 8 brain regions studied. MK-801 + FEN did not protect against FEN-induced 5HT depletions in nucleus accumbens/olfactory tubercle, septum, frontal cortex, somatosensory cortex or hippocampus. MK-801 + FEN enhanced 5HT depletions in striatum, hypothalamus and amygdala. The differential protective effect of MK-801 between MA and FEN are discussed in terms of a possible dopaminergic mechanism.     

Guanosine selectively inhibits locomotor stimulation induced by the NMDA antagonist dizocilpine

Guanosine has been shown to modulate glutamate system by stimulating astrocytic glutamate uptake. Recent evidence suggest that the locomotor effects of NMDA receptor antagonists, an animal model of schizophrenia, is associated with activation of non-NMDA glutamatergic receptors caused by increased glutamate release. The present work was undertaken to evaluate whether guanosine could have influence on the hyperlocomotion induced in mice by dizocilpine (MK-801), a NMDA antagonist. We also evaluated the effect of guanosine on the hyperlocomotion induced by the indirect dopamine agonist amphetamine, and by the non-selective adenosine receptor antagonist caffeine. Guanosine (7.5 mg/kg) produced an attenuation of about 60% on the hyperlocomotion induced by dizocilpine (0.25 mg/kg), whereas it did not affect the hyperlocomotion induced by amphetamine (5 mg/kg) or caffeine (30 mg/kg). Guanosine pre-treatment did not affect total spontaneous locomotion in all experiments. To test neuronal pathway selectivity, we evaluated MK-801 against guanosine in a working memory paradigm (spontaneous alternation task). Guanosine did not reverted the impairment caused by MK-801 in the spontaneous alternation test, and when administered alone also presented an amnesic effect. The results are discussed based on the current hypothesis of locomotor activation induced by the psychoactive drugs studied. Further studies are necessary to evaluate if guanosine could have clinical utility for the treatment of schizophrenia.     

Effect of postnatal iron administration on MPTP-induced behavioral deficits and neurotoxicity: behavioral enhancement by L-Dopa-MK-801 co-administration

Two experiments were performed to investigate the interactive effects of postnatal iron administration and adult MPTP treatment upon the function of C57 Bl/6 mice tested at adult age and to ascertain the possible ameliatory effects of a subthreshold dose of L-Dopa co-administered with different doses of the uncompetitive glutamate antagonist, MK-801. Experiment I indicated that postnatal iron induced marked deficits (hypoactivity), initially, in all three parameters of motor activity at the 5.0 and 7.5 mg/kg doses, and to a lesser extent at the 2.5 mg/kg dose. Later combination with MPTP (2x40 mg/kg) potentiated severely these deficits. During the final period of testing a marked hyperactivity was obtained for the two higher dose groups; this effect was abolished in mice administered MPTP. Experiment II indicated that the deficits in motor activity parameters induced by postnatal iron at 7.5 mg/kg were alleviated in a dose-related manner by the co-administration of the uncompetitive glutamate antagonist, MK-801, with a subthreshold dose of L-Dopa. Postnatal iron (7.5 mg/kg) administration followed by low doses of MPTP (2x20 mg/kg) 3 months later virtually abolished all motor activity. The combination of these compounds increased also the motor activity of mice treated with MPTP (2x20 mg/kg) or mice treated with the combination of postnatal iron and MPTP. The combination of MK-801 with L-Dopa increased locomotor (0.3 mg/kg), rearing (0.1 and 0.3 mg/kg) and total activity (0.3 mg/kg) of iron-treated mice during the initial, hypoactive 30-min period of testing. Locomotor activity (0.1 mg/kg) of MPTP-treated mice was increased too during this period. During the final 30-min period of testing all three parameters of activity (locomotion, 0.3 mg/kg; rearing and total activity, 0.1 and 0.3 mg/kg) were enhanced in the iron-treated mice, locomotion (0.1 mg/kg) and rearing (0.1 mg/kg) in the iron plus MPTP treated mice and only locomotion (0.1 mg/kg) in the MPTP-treated mice. In control mice (vehicle+saline), the higher doses of MK-801 (0.1 and 0.3 mg/kg) enhanced both locomotor and total activity. Analyses of total iron concentration in the frontal cortex and basal ganglia of Fe(2+) and vehicle treated mice indicated that marked elevations basal ganglia iron levels of the 5.0 and 7.5 mg/kg groups, later injected either saline or MPTP, were obtained (Experiment I). In Experiment II, iron concentrations in the basal ganglia were elevated in both the Fe(2+)-sal and Fe(2+)-MPTP groups to 170 and 177% of Veh.-sal values, respectively. There was a significant increase in the frontal cortex of iron-treated mice later administered either saline or MPTP (2x40 mg/kg) in Experiment I as well as in those given iron followed by MPTP (2x20mg/kg) in Experiment II. The implications of iron overload in parkinsonism seem confirmed by the interactive effects of postnatal administration of the metal followed by adult MPTP treatment upon motor activity and the activity-enhancing effects of co-administration of L-Dopa with MK-801.     

Systemic administration of MK-801 protects against ischemia-induced hippocampal neurodegeneration in the gerbil

The neuroprotective effects of MK-801, a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors, were evaluated in models of cerebral ischemia using Mongolian gerbils. Bilateral occlusion of the carotid arteries for a period of 5 min resulted in a consistent pattern of degeneration of hippocampal CA1 and CA2 pyramidal neurons, which was quantified using an image analyzer. Systemic administration of MK-801 (0.01-10 mg/kg, i.p.) 1 hr prior to the occlusion caused a dose-dependent protection of the CA1 and CA2 neurons. The ED50 value for neuroprotection by MK-801 was calculated to be 0.3 mg/kg, and at doses greater than or equal to 3 mg/kg the majority of animals were completely protected against the ischemic insult. Systemic administration of MK-801 (1 or 10 mg/kg, i.p.) 1 hr prior to unilateral occlusion of the right carotid artery resulted in significant protection against hippocampal neurodegeneration following 10 min of occlusion, and increased the survival rate after 30 min of occlusion. The potent neuroprotective effects of MK-801 in these cerebral ischemia models add further weight to the evidence that NMDA receptors are involved in the mechanism of ischemia-induced neuronal degeneration.     

MK-801 (Dizocilpine): Synergist and conditioned stimulus in bromocriptine-induced psychomotor sensitization

Intraperitoneal injections of the D₂/D₃ dopamine agonist bromocriptine (5.0 mg/kg, IP) induced locomotion that became progressively stronger on successive days of testing. The sensitized response developed twice as rapidly when the non-competitive NMDA antagonist MK-801 (0.25 mg/kg, IP) was given 30 min after bromocriptine (so that the peak effects of the two drugs overlapped). In a second group of animals, MK-801 was given 30 min prior to bromocriptine (the pretreatment regimen typical of studies where MK-801 is reported to block cocaine, amphetamine or morphine sensitization) and locomotion was monitored during the pretreatment period; in this case sensitization to the locomotor-stimulating effects of MK-801 alone (in the pretreatment period) as well as sensitization to the locomotor-stimulating effects of the drug combination (following the second injection) were observed. No sensitization to the effects of MK-801 alone (pretreatment) were seen in animals that received saline rather than bromocriptine as their second injection in this experiment. Thus MK-801 does not block but rather enhances bromocriptine sensitization; it appears to do so by a synergism with the locomotor effects of bromocriptine and by becoming a conditioned stimulus for the sensitized response. These findings confirm the earlier report that NMDA receptor activation is not critical to bromocriptine-induced sensitization, and they illustrate the importance of controls for conditioning and state-dependency phenomena in studies of drug interactions in psychomotor sensitization. © 1996 Wiley-Liss, Inc.     

Neuroprotective effects of MK-801 in vivo: selectivity and evidence for delayed degeneration mediated by NMDA receptor activation

The ability of the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 to prevent neuronal degeneration in the rat striatum and hippocampus caused by intracerebral injection of excitotoxins has been examined. Excitotoxic damage was assessed after 7 d, using histological and biochemical [choline acetyltransferase (ChAT) glutamate decarboxylase (GAD)] measurements. Systemically administered MK-801 was found to protect against neurodegeneration caused by NMDA (200 nmol) and the naturally occurring NMDA receptor agonist quinolinate (120-600 nmol) but not against that induced by kainate (5 nmol) or alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA; 50 nmol), indicating a selectivity for NMDA receptor-mediated neuronal loss. Neurotoxicity caused by NMDA (200 nmol) or quinolinate (200 nmol) was prevented by MK-801 (1-10 mg/kg, i.p.) administered in a single dose after excitotoxin injection. In the striatum, significant protection of cholinergic neurons (assessed by ChAT measurements) was observed when MK-801 was given up to 5 hr after injection of NMDA or quinolinate, whereas protection of GABAergic neurons (assessed by GAD measurements) was obtained up to 2 hr. The results suggest that GABAergic neurons degenerate more rapidly than cholinergic neurons. The competitive NMDA receptor antagonist 3-[(+/-)-2-carboxypiperazin-4-yl]-propyl-1-phosphonate (100 mg/kg, i.p.) gave partial protection of striatal neurons when administered 1 hr after quinolinate injection. In the rat hippocampus, administration of 10 mg/kg MK-801 i.p. 1 hr after quinolinate injection caused almost complete protection of pyramidal and granule neurons, whereas the degeneration of CA3/CA4 pyramidal neurons caused by kainate injection was unaffected. These observations indicate that neurons in rat striatum and hippocampus do not die as an immediate consequence of exposure to high concentrations of NMDA agonists but that a delayed process is involved that requires NMDA receptor activation. In this respect, intracerebral injections of NMDA agonists may mimic the pathological changes that are thought to occur in the brain following periods of cerebral ischemia, where delayed neuronal degeneration occurs.     

Fenfluramine-induced increases in extracellular hippocampal serotonin are progressively attenuated in vivo during a four-day fenfluramine regimen in rats

The non-competitiveN-methyl-d-aspartate (NMDA) receptor antagonist dizocilpine (MK-801) has been shown to block methamphetamine (MA) induced damage to the dopamine (DA) and serotonin (5HT) systems of the brain.dl-Fenfluramine (FEN) is another potential neurotoxin but its long-term depletions are more selective to the 5HT system. To determine whether MK-801 protects against damage induced by FEN, we treated rats with FEN (4 injections of 12.5 mg/kg, at 1 h intervals) in conjunction with either saline or MK-801 (2 injections of 2.5 mg/kg, administered 15 min before and 90 min after the first FEN injection). Two weeks post-treatment, MK-801 alone caused a small but significant decrease in 5HT tissue concentrations in striatum and amygdala. FEN significantly reduced 5HT in all 8 brain regions studied. MK-801 + FEN did not protect against FEN-induced 5HT depletions in nucleus accumbens/olfactory tubercle, septum, frontal cortex, somatosensory cortex or hippocampus. MK-801 + FEN enhanced 5HT depletions in striatum, hypothalamus and amygdala. The differential protective effect of MK-801 between MA and FEN are discussed in terms of a possible dopaminergic mechanism.