Lurasidone reverses MK-801-induced impairment of learning and memory in the Morris water maze and radial-arm maze tests in rats

We have previously shown that lurasidone, a novel atypical antipsychotic, potently reverses learning impairment induced by the N-methyl-D-aspartate receptor antagonist MK-801 in the rat passive avoidance test. However, the effects of lurasidone in other learning and memory tasks remain to be investigated. We investigated the effects of lurasidone and other marketed antipsychotics (risperidone, clozapine, aripiprazole, and haloperidol) on MK-801-induced impairment of learning and memory in the Morris water maze (MWM) and radial-arm maze (RAM) tests in rats. Learning and memory impairment in the MWM test, as measured by escape latency, escape distance, and diving behavior, and in the RAM test, as measured by reference and working memory errors, was induced by MK-801 (i.p.) at doses of 0.15 and 0.2 mg/kg, respectively. In the MWM test, lurasidone (1 and 3 mg/kg p.o.) potently reversed MK-801-induced learning impairment. In the RAM test, lurasidone (1 and 3 mg/kg p.o.) potently reversed MK-801-induced reference memory impairment and moderately but not significantly attenuated MK-801-induced working memory impairment. Risperidone (0.3 and 1mg/kg p.o.), clozapine (3 and 10 mg/kg p.o.), aripiprazole (0.3 and 1mg/kg p.o.), and haloperidol (0.3 and 1mg/kg p.o.) did not reverse MK-801-induced impairment of learning and memory in both tasks. Lurasidone, but not the other antipsychotics tested in this study, reverses MK-801-induced impairment of learning and memory in both the MWM test and the RAM test. These results suggest that lurasidone would be more effective in treating schizophrenics with cognitive dysfunction than current antipsychotics.     

Antipsychotic drugs reverse MK-801-induced cognitive and social interaction deficits in zebrafish (Danio rerio)

Schizophrenia is a severe mental illness characterized by positive and negative symptoms and cognitive deficits. Reduction of glutamatergic neurotransmission by NMDA receptor antagonists mimics symptoms of schizophrenia. Modeling social interaction and cognitive impairment in animals can be of great benefit in the effort to develop novel treatments for negative and cognitive symptoms of schizophrenia. Studies have demonstrated that these behavioral changes are, in some cases, sensitive to remediation by antipsychotic drugs. The zebrafish has been proposed as a candidate to study the in vivo effects of several drugs and to discover new pharmacological targets. In the current study we investigated the ability of antipsychotic drugs to reverse schizophrenia-like symptoms produced by the NMDA receptor antagonist MK-801. Results showed that MK-801 (5 μM) given pre-training hindered memory formation while both atypical antipsychotics sulpiride (250 μM) and olanzapine (50 μM) improved MK-801-induced amnesia. The same change was observed in the social interaction task, where atypical antipsychotics reversed the MK-801-induced social interaction deficit whereas the typical antipsychotic haloperidol (9 μM) was ineffective to reverse those behavioral deficits. Therefore, MK-801-treated zebrafish showed some behavioral features observed in schizophrenia, such as cognitive and social interaction deficits, which were reverted by current available atypical drugs.     

Differential effects of antipsychotics on hippocampal presynaptic protein expressions and recognition memory in a schizophrenia model in mice

We compared the effects of subchronic clozapine and haloperidol administration on the expression of SNAP-25 and synaptophysin in an animal model of schizophrenia based on the glutamatergic hypothesis. Mice were first treated with a non-competitive NMDA antagonist MK-801 (0.3 mg/kg/day) or saline for 5 days, and then clozapine (5 mg/kg/day), haloperidol (1 mg/kg/day) or saline was administered for two weeks. The locomotion test, as a behavioral model of the positive symptoms of schizophrenia, was applied after MK-801/saline administration on day 6 for acute effects and after antipsychotic/saline administration on day 19 for enduring effects on mice activity. Memory function was assessed by the Novel Object Recognition (NOR) test, one day after the last day of antipsychotic/saline administration (day 20). Western Blotting technique was used to determine SNAP-25 and synaptophysin expressions in the hippocampus and frontal cortex. Both antipsychotics reversed the enhanced locomotion effects of MK-801. MK-801 and haloperidol decreased recognition memory performance. On the other hand, clozapine did not compromise memory. It also did not reverse the negative effects of MK-801 on memory performance. MK-801 did not change SNAP-25 and synaptophysin expressions in the hippocampus and frontal cortex. Clozapine increased hippocampal SNAP-25, decreased hippocampal synaptophysin expression, whereas frontal SNAP-25 and synaptophysin expressions remained unchanged. Haloperidol had no effects on levels of SNAP-25 and synaptophysin in the frontal cortex and hippocampus. These findings support the idea that the differential effects of clozapine might be related to its plastic effects and synaptic reorganization of the hippocampus.     

The influence of N-desmethylclozapine and clozapine on recognition memory and BDNF expression in hippocampus

Clozapine, which is the most effective treatment option for treatment-refractory schizophrenia, has been reported to have both positive and negative effects on specific cognitive symptoms in patients with schizophrenia and in animal models of cognition. Clozapine has a major metabolite, N-desmethylclozapine (NDMC), which has been suggested to be more effective than clozapine itself to improve cognition. Enhancement of brain derived neurotrophic factor (BDNF) expression in the hippocampus has been proposed to contribute to the cognitive-enhancing effects of antipsychotic drugs. The aims of this study were to investigate the change in short and long term memory as assessed by the novel object recognition (NOR) test and BDNF expression in hippocampus produced by an acute hypoglutamatergic model of memory impairment in schizophrenia induced by administration of the NMDA receptor non-competitive antagonist, MK-801 and the ability of clozapine and NDMC to prevent the deleterious effects of MK-801. Both short (1 h) and long-term (24 h) memory were impaired in MK-801 (0.1 mg/kg) - and clozapine (5 mg/kg)-, but not NDMC (5 mg/kg)-treated rats. Neither NDMC (5 mg/kg) nor clozapine (5 mg/kg) reversed the effect of MK-801. Western blotting studies showed that BDNF levels in hippocampus were not different in rats administered MK-801 alone, clozapine or NDMC alone. These results show that in this model clozapine affects memory negatively, while NDMC does not. The absence of impairment of NOR with NDMC is consistent with previous evidence that it has a more benign effect on cognition than does the parent compound, and may support the efforts to study its effects on other cognitive functions. These findings do not provide any support for the role of BDNF in the MK-801-induced impairment in NOR or for differences between clozapine and NDMC.     

Ameliorative effect of N-desmethylclozapine in animal models of social deficits and cognitive functions

One of the major circulating metabolites of clozapine, N-desmethylclozapine (NDMC), has been demonstrated to exhibit partial agonistic activity at M(1) muscarinic receptors. Some of the unique therapeutic effects of clozapine might involve the pharmacological effects of this metabolite. The purpose of the present study was therefore to examine whether NDMC improved behavioral abnormalities in animal models of social deficits and cognitive deficits of schizophrenia. NDMC (3mg/kg) and clozapine (1-3mg/kg) each improved the reduction of social interaction caused by a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, 5R,10S-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801) (0.1mg/kg), without affecting locomotor activity in rats. NDMC (3-10mg/kg) and clozapine (1-3mg/kg) each also resulted in better discrimination of a novel from a familiar object 24h after a training trial in a rat object recognition test. These findings suggest that NDMC can improve behavior in animal models of social deficits and cognitive deficits of schizophrenia as well as clozapine.     

A behavioural pattern analysis of hypoglutamatergic mice – effects of four different antipsychotic agents

In a hypoglutamatergic rodent model, we have observed certain behaviours that might have relevance for the cognitive impairments seen in autism and schizophrenia. Thus, hypoglutamatergic mice show defective habituation, impaired attention, a meagre behavioural repertoire and a general behavioural primitivization. The aim of the present study was to characterise and quantify changes in movement pattern in mice rendered hypoglutamatergic by means of MK-801 treatment, using an automated video tracking system. Further, the effects of four different antipsychotic drugs, the classical neuroleptic haloperidol, the atypical antipsychotic clozapine, the DA D2/5-HT2A antagonist risperidone and the selective 5-HT2A-receptor antagonist M100907, were compared with respect to effects on NMDA antagonist-induced movement pattern alterations. We found that each receptor antagonist had a unique effect on the MK-801-induced behavioural primitivization. Haloperidol was unable to affect the monotonous behaviour induced by MK-801, while risperidone, clozapine and M100907 produced movement patterns of high intricacy.     

Effect of cannabidiol in a MK-801-rodent model of aspects of schizophrenia

Cannabidiol is a non-psychoactive phytocannabinoid which, based on several previous preclinical and clinical reports, is purported to have antipsychotic potential. The purpose of this investigation was to further investigate if these effects would be seen using an MK-801-induced rat model of aspects of schizophrenia. MK-801 is an NMDA receptor-antagonist known to produce hyperactivity, deficits in prepulse inhibition and social withdrawal, behaviours which correlate well with some of the positive, cognitive and negative symptoms of schizophrenia. Following a 4-day acclimatisation to the holding room, rats were acclimatised to startle chambers on day 5 and their prepulse inhibition (PPI) determined on day 6 following treatment with cannabidiol or vehicle and MK-801 or vehicle. On day 9, rats were acclimatised to the social interaction testing arena and on day 10, were tested for social interaction and locomotor activity following the same treatments. Cannabidiol treatment alone disrupted PPI and produced hyperactivity but had no effect on social behaviour. Cannabidiol had no effect on MK-801-induced disruption of PPI or hyperactivity but showed potential towards inhibiting MK-801-induced social withdrawal. As a comparator, we also tested the effect of the atypical antipsychotic clozapine which only partially reversed MK-801-induced disruption of PPI but was able to reverse MK-801-induced hyperactivity and social withdrawal. In conclusion, cannabidiol showed both propsychotic activity and partial antipsychotic activity in an MK-801-induced model of aspects of schizophrenia. Further behavioural studies would be required using a range of species, strains, animal models and testing paradigms to conclusively establish the antipsychotic potential of cannabidiol.     

Chronic nicotine and dizocilpine effects on nicotinic and NMDA glutamatergic receptor regulation: interactions with clozapine actions and attentional performance in rats

Blockade of NMDA glutamate receptors with dizocilpine (MK-801) has been shown to cause substantial cognitive deficits and has been used to model symptoms of schizophrenia. Nicotine or nicotinic agonists, in contrast, may enhance cognitive or attentional functions and be of therapeutic potential in schizophrenia. Nicotinic–glutamatergic interactions, therefore, may have important implications in cognitive functions and antipsychotic treatments. Clozapine, a widely used antipsychotic drug, has been shown in some studies to be effective in ameliorating the cognitive deficits associated with schizophrenia. However, there is some evidence to suggest that clozapine similar to haloperidol may impair sustained attention in rats. In this study, we sought to determine whether chronic nicotine or dizocilpine may modify the effects of acute clozapine on attentional parameters and whether the behavioral effects would correlate with nicotinic or NMDA receptor densities in discrete brain regions. Adult female rats trained on an operant visual signal detection task were given 4 weeks of nicotine (5 mg/kg/day), dizocilpine (0.15 mg/kg/day), the same doses of both nicotine and dizocilpine as a mixture, or saline by osmotic minipump. While on chronic treatment, rats received acute injections of various doses of clozapine (0, 0.625, 1.25, 2.5 mg/kg, sc) 10 min prior to tests on attentional tasks. The pumps were removed on day 28 and 24 h later the animals were sacrificed for measurements of receptor densities in specific brain regions. The percent correct hit as a measure of sustained attention was significantly impaired by clozapine in a dose-related manner. Neither chronic nicotine nor dizocilpine affected this measure on their own or modified the effects of clozapine. Both nicotine and dizocilpine affected the receptor bindings in a region specific manner and their combination further modified the effects of each other in selective regions. Attentional performance was inversely correlated with alpha-bungarotoxin binding in the frontal cortex only. In conclusion, the data suggest attentional impairments with clozapine alone and no modification of this effect with nicotine or dizocilpine. Moreover, cortical low affinity nicotinic receptors may have a role in attentional functions.     

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.     

Effects of antipsychotic treatments and D-serine supplementation on the electrophysiological activation of midbrain dopamine neurons induced by the noncompetitive NMDA antagonist MK 801

The acute administration of the noncompetitive glutamate N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (MK 801) is known to increase central dopaminergic activity in rats and to elicit schizophreniform behavior in human. The current study was undertaken to compare the effects of different acute or chronic neuroleptic treatments, on the response of ventral tegmental area dopamine (DA) neurons to MK 801, using the in vivo electrophysiological paradigm in anesthetized preparations. Sprague Dawley male rats were treated, acutely or chronically during 3 weeks, with saline, olanzapine (10 mg/kg), haloperidol (1 mg/kg) or the combination of haloperidol with D-serine (1 mg/kg/300 mg/kg), a gliotransmitter coagonist of the NMDA receptor that has been shown to improve the efficacy of typical neuroleptics. In control animals, the acute administration of MK 801 (0.5 mg/kg, i.v.) increased significantly both the firing and burst activity of DA neurons by 20 and 26%, respectively, the latter effect being partially reversed by the selective 5-HT2A antagonist M 100,907 (0.4 mg/kg, i.v.). The acute preadministration of haloperidol (1 mg/kg, i.p.) and olanzapine (10 mg/kg, i.p.) failed to prevent or reverse the activatory effect of MK 801 on firing activity. On the other hand, MK 801-induced burst activity, was partially prevented by olanzapine, but not by haloperidol pretreatment. All antipsychotic treatments, when administered chronically, prevent the activatory effect of MK 801 on both firing and burst activity, and occasionally convert the response to MK 801 on burst activity to an inhibitory response, the latter occurring more predominantly in rats treated with the combination haloperidol/D-serine. These results suggest that a chronic antipsychotic regime alters the function of the NMDA receptors that tonically control the firing activity of midbrain dopaminergic neurons.     

奥氮平对谷氨酸功能低下的精神分裂症小鼠模型的作用

目的 观察奥氮平对谷氨酸功能低下小鼠模型表现出的高活动性及前脉冲抑制(PPI)缺失的作用.方法 昆明种小鼠165只.(1)取36只小鼠分为4组:溶媒空白对照组(腹腔注射溶媒,以下简称对照组),3种奥氮平剂量(0.1 mg/kg体质量,0.2 mg/kg体质量,0.3 mg/kg体质量,腹腔注射)组,每组8～10只;观察奥氮平对小鼠探究行为和自主活动的影响.(2)取49只小鼠分为5组:对照组,地卓西平马来酸盐(MK-801)模型组(溶媒+MK-801,0.25 mg/kg体质量,腹腔注射),3种剂量(同上)奥氮平干预组(奥氮平+MK-801 0.25 mg/kg体质量,腹腔注射),每组9～10只;观察奥氮平对MK-801致小鼠自主活动增加的影响.(3)取80只小鼠分为8组:对照组,MK-801模型组(溶媒+MK-801,0.5 mg/kg体质量,腹腔注射),3种奥氮平剂量给药组(奥氮平+生理盐水,奥氮平剂量分别为0.3 mg/kg体质量,1 mg/kg体质量,3 mg/kg体质量),3种奥氮平剂量(同上)干预组(奥氮平+MK-801 0.5 mg/kg体质量,腹腔注射),每组10只;观察奥氮平对基线前脉冲抑制(PPI)及MK-801引起的PPI缺失的影响.结果 (1)与对照组比较,奥氮平剂量为0.2 mg/kg体质量和0.3mg/kg体质量时,小鼠的探究行为及自主活动总路程减少(P均＜0.05);但剂量为0.1 mg/kg时,对小鼠的探究行为(P=0.363)及自主活动(P=0.196)无影响.(2)奥氮平剂量为0.1～0.3 mg/kg体质量时,呈剂量依赖性抑制MK-801引起的自主活动增加(P均＜0.05).(3)奥氮平剂量为0.3～3mg/kg体质量时,对基线的PPI无影响(P均＞0.05),剂量为1～3 mg/kg时呈剂量依赖性修复了MK-801引起的PPI缺失(P均＜0.05).结论 奥氮平能够特异性地抑制谷氨酸功能低下小鼠模型表现出的高活动性和PPI缺失,与奥氮平的临床药理作用一致.     

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.     

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

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

Effects of antipsychotics on the behavioral deficits in human dominant-negative DISC1 transgenic mice with neonatal polyI:C treatment

Interactions of environmental and genetic factors may play a role in the pathoetiology of schizophrenia. We have recently developed a novel animal model of mental disorders such as schizophrenia by inducing abnormal immune response during the perinatal period in mice with overexpression of the human dominant-negative form of disrupted-in-schizophrenia 1 (DN-DISC1). In the present study, we investigated the effects of antipsychotics on the behavioral deficits in this animal model for mental disorders with gene-environment interaction. Neonatal DN-DISC1 transgenic (DN-DISC1 tg) mice were repeatedly injected with polyriboinosinic-polyribocytidylic acid (polyI:C) for 5 days from postnatal days 2 to 6. The behavioral analyses were performed in adulthood. Clozapine (3 mg/kg) or haloperidol (1 mg/kg) was administered orally once a day from 1 week before starting a series of behavioral experiments and continued until the end of the study. Cognitive impairment in polyI:C-treated DN-DISC1 tg mice was improved by repeated administration of clozapine while haloperidol had no effect. Both antipsychotics suppressed the augmentation of MK-801-induced hyperactivity in the model mice. Neither clozapine nor haloperidol ameliorated the impairments of social behaviors in polyI:C-treated DN-DISC1 tg mice. These results suggest that the polyI:C-treated DN-DISC tg mice are quite unique as an animal model for mental disorders. Furthermore, this mouse model may be useful for the screening of potential antipsychotic compounds that could be more effective than clozapine in ameliorating negative symptoms and cognitive impairment in schizophrenia.     

氯氮平对谷氨酸功能低下精神分裂症小鼠模型的作用

目的 观察氯氮平对地卓西平马来酸盐（MK-801）所致谷氨酸功能低下精神分裂症小鼠模型的高活动性及刻板行为的作用。方法 昆明种小鼠130只。（1）取34只小鼠分为4组：溶媒空白对照组（腹腔注射溶媒，以下简称对照组）；3种氯氮平剂量（1．0，1．5，2．0mg／kg体质量，腹腔注射）组；每组8～10只，观察氯氮平对小鼠探究行为和自主活动的影响。（2）取46只小鼠分为5组，分别为对照组、MK-801模型组（溶媒＋MK-801，0．25mg／kg体质量，腹腔注射）及3种剂量（同上）氯氮平组分别加MK-801（0．25mg／kg体质量，腹腔注射），每组8～10只，观察氯氮平对MK-致801小鼠自主活动增加的影响。（3）取50只小鼠，每组10只，给药方案同“（2）”，观察氯氮平对MK-801引起的刻板行为的影响。结果 （1）与对照组比较，氯氮平剂量为1．5mg／kg体质量和2．0mg／kg体质量时，小鼠的探究行为及自主活动总路程减少（P均〈0．001）；但剂量为1．0mg／kg时，对小鼠的探究行为及自主活动均无影响（P均〉0．05）。（2）氯氮平剂量为1．0～2．0mg／kg体质量时，呈剂量依赖性抑制由MK-801引起的自主活动增加（均P〈0．05）。（3）氯氮平剂量为1．5～2．0mg／kg体质量时，呈剂量依赖性抑制MK-801引起的刻板行为（均P〈0．05）。但低剂量（1．0mg／kg体质量）氯氮平对MK-801引起的刻板行为无明显影响（P〉0．05）。结论 氯氮平对MK-801所致谷氨酸功能低下精神分裂症小鼠模型不同脑区的作用有选择性，低剂量时抑制由中脑边缘、中脑皮质系统介导的高活动性，较高剂量时抑制由中脑边缘、中脑皮质系统及黑质纹状体系统控制的高活动性及刻板行为。     

Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of the antibiotic drug minocycline

BACKGROUND: The N-methyl-d-aspartate (NMDA) receptor antagonist phencyclidine (PCP)-induced cognitive deficits have been used as an animal model for schizophrenia. This study was undertaken to determine whether the antibiotic drug minocycline could improve PCP-induced cognitive deficits in mice. METHODS: Saline (10 ml/kg/day, s.c., once daily on day 1-5, 8-12) or PCP (10 mg/kg/day, s.c., once daily on day 1-5, 8-12) were administered to mice for 10 days. Subsequently, vehicle (10 ml/kg/day, i.p.) or minocycline (4.0 or 40 mg/kg/day, i.p.) was injected for 14 consecutive days. One day after the final injection, a novel object recognition test was performed. RESULTS: PCP-induced cognitive deficits in mice were significantly improved by subsequent subchronic (14 days) administration of minocycline (40 mg/kg), but not minocycline (4.0 mg/kg). CONCLUSIONS: This study suggests that minocycline could be a potential therapeutic drug for cognitive deficits in schizophrenic patients.     

Impact of schizophrenia and chronic antipsychotic treatment on [123I]CNS-1261 binding to N-methyl-D-aspartate receptors in vivo.

BACKGROUND: Antipsychotic drugs modulate N-methyl-D-aspartate (NMDA) receptor function in animals. The novel single photon emission tomography (SPET) radiotracer [123I]CNS-1261 binds to the PCP/MK-801 intrachannel site of the NMDA receptor, allowing the noninvasive estimation of NMDA receptor activity in living humans. We used [123I]CNS-1261 to determine whether binding to the NMDA receptor intrachannel PCP/MK-801 site is affected by schizophrenia or by treatment with typical antipsychotics and clozapine in vivo. METHODS: Three groups of schizophrenia patients were recruited-drug free (n = 5), typical antipsychotic treated (n = 7), and clozapine treated (n = 9)-as well as a control group of healthy normal volunteers (n = 13). All underwent [123I]CNS-1261 SPET scanning. Total volume of distribution of [123I]CNS-1261 was determined within predefined user-independent regions of interest after alignment of all images to a common template. RESULTS: There was no apparent difference in total volume of distribution of [123I]CNS-1261 in drug-free patients relative to healthy control subjects. A nonsignificant reduction in total volume of distribution was observed in typical antipsychotic treated patients. A significant decline in total volume of distribution of [123I]CNS-1261 was observed in all examined brain regions in the clozapine-treated patient group relative to healthy control subjects (p < .005). CONCLUSIONS: Clozapine treatment resulted in a global reduction in [123I]CNS-1261 binding to the NMDA receptor intrachannel PCP/MK-801 site in vivo. This supports an effect of the drug on glutamatergic systems that could be exploited for future antipsychotic drug discovery.     

The dopaminergic stabiliser ACR16 counteracts the behavioural primitivization induced by the NMDA receptor antagonist MK-801 in mice: implications for cognition

The Carlsson research group has developed a series of compounds capable of stabilising the dopamine system without inducing the deleterious hypodopaminergia that encumbers the currently used antipsychotic drugs. In the present study one of these dopaminergic stabilisers, ACR16, was tested in a mouse model for cognitive deficits of schizophrenia and autism. Since we believe that hypoglutamatergia is a key element in both schizophrenia and autism we used mice rendered hypoglutamatergic by treatment with the N-methyl-D-aspartate (NMDA) antagonist MK-801. MK-801 causes both hyperactivity and a behavioural primitivization. ACR16 attenuated the MK-801-induced hyperactivity and, in addition, caused a marked improvement of behavioural quality with a movement pattern approaching that of control animals. Since we believe that the impoverishment of the behavioural repertoire caused by MK-801 may correspond to the cognitive deficits seen in schizophrenia and autism, these results suggest that ACR16 may improve cognitive status in these disorders.     

Proteome analysis after co-administration of clozapine or haloperidol to MK-801-treated rats

Summary MK-801, a glutamergic, N-methyl-D-aspartate (NMDA)-receptor antagonist that mediates neurotransmission and has psychotomimetic properties, giving schizophrenia-like symptom. The objective of this study was to investigate the effects on the thalamic and cortical proteome of one typical (haloperidol) and one atypical (clozapine) antipsychotic drug in interaction with MK-801 in rats. Rats received subcutaneous injections of MK-801 or vehicle (controls) or MK-801 together with concurrent administration of haloperdol or clozapine for eight days. Protein samples from thalamus and cortex were analyzed with two-dimensional gel electrophoresis in combination with mass spectrometry. MK-801 induced alterations in the levels of three proteins in both cortex and thalamus. Clozapine reversed all the protein changes. Haloperidol reversed two. Both antipsychotics induced new protein changes in both cortex and thalamus not seen after MK-801-treatment by alone. In conclusion, the MK-801 animal model shows potential for investigation of different antipsychotic drugs and biochemical treatment effects in schizophrenia.     

Oxiracetam prevents the MK-801 induced amnesia for the elevated plus-maze in mice

We investigated the effect of the nootropic substance oxiracetam on the impairment of memory induced in mice by the non-competitive NMDA antagonist MK-801. Memory capacities of animals having different experience were evaluated using the elevated plus-maze test. Oxiracetam was injected immediately after the acquisition session(s), MK-801 was given 30 min before the retention session which followed 24 h after the acquisition session(s). In slightly experienced animals (Section 3.1), oxiracetam (3 and 30 mg/kg, s.c.) prevented MK-801 (0.15 mg/kg, i.p.) induced memory deficits characterized by a prolongation of the transfer latency. In well-trained animals (Section 3.2), oxiracetam (30 mg/kg, s.c.) attenuated MK-801 (0.15,0. 25 and 0.4 mg/kg, i.p.) induced amnesia for a spatial orientation in the elevated plus-maze. These results show that oxiracetam interacted with the glutamatergic NMDA receptor system and forestalled the impairment of retrieval of long-term memory. The results also justify the usage of the elevated plus-maze method in the evaluation of potential anti-amnesic or nootropic drugs.