Ameliorative effects of a neuroprotective agent, T-817MA, on place learning deficits induced by continuous infusion of amyloid-beta peptide (1-40) in rats

Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive decline due to neuronal loss and neural network dysfunction. It has been postulated that progressive neuronal loss in AD is consequence of the neurotoxic properties of the amyloid-beta peptide (Abeta). In the present study, we investigated the effect of T-817MA (1-{3-[2-(1-benzothiophen-5-yl)ethoxy] propyl}-3-azetidinol maleate), a newly synthesized neurotrophic compound, on place learning deficits in rats with hippocampal damages. To induce granule cell loss in the dentate gyrus (DG) of the hippocampus, Abeta (1-40) was continuously infused (300 pmol/day) into the cerebral ventricle using a mini-osmotic pump for 5 weeks. Three weeks after the Abeta infusion, the rats were tested in a place learning task, which required them to alternatively visit two diametrically opposed areas in an open field to obtain intracranial self-stimulation reward. The results indicated that the Abeta-infused rats without treatment of T-817MA displayed learning impairment in the task; their performance level was significantly inferior to that of the vehicle rats. Treatment of T-817MA (8.4 mg/kg/day, p.o.) significantly improved the task performance of the Abeta-infused rats. Furthermore, T-817MA prevented granule cell loss due to Abeta-infusion, which was correlated to task performance of the rats. However, other cognitive enhancer, an acetylcholinesterase inhibitor, had no such effects. The results demonstrated that T-817MA ameliorated learning deficits induced by Abeta infusion, which might be attributed to neuroprotection in the hippocampus.     

D-Serine and a glycine transporter inhibitor improve MK-801-induced cognitive deficits in a novel object recognition test in rats

Compounds enhancing N-methyl-d-aspartate (NMDA) glutamate receptor function have been reported to improve cognitive deficits. Since cognitive deficits are considered to be the core symptom of schizophrenia, enhancing NMDA receptor function represents a promising approach to treating schizophrenia. In the present study, we investigated whether d-serine or a glycine transporter inhibitor N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl]sarcosine (NFPS), both of which enhance NMDA receptor function, could improve MK-801-induced cognitive deficits in rats, and compared their effects with those of the atypical antipsychotic clozapine and of the typical antipsychotic haloperidol. To assess cognitive function, we used a novel object recognition test in rats that measured spontaneous exploratory activity of a novel object when paired with a familiar object. We then evaluated the effects of the compounds on cognitive deficits induced by treatment with MK-801, the NMDA receptor antagonist. Pretreatment with clozapine (1, 5 mg/kg, i.p.) but not haloperidol (0.03, 0.1 mg/kg, i.p.) significantly improved MK-801-induced cognitive deficits. Pretreatment with D-serine at 800 mg/kg (i.p.) or NFPS (0.3, 1 mg/kg, i.p.) significantly improved MK-801-induced cognitive deficits under this test paradigm. These findings suggest that impaired preference for novel objects induced by MK-801 in the novel object recognition test could be a useful animal model for evaluating the efficacy of compounds targeting the cognitive deficits observed in schizophrenic patients. The results also suggest that enhancing NMDA receptor function is an effective way for treating the cognitive deficits associated with schizophrenia.     

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.     

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.     

Neonatal exposure to the glutamate receptor antagonist MK-801: effects on locomotor activity and pre-pulse inhibition before and after sexual maturity in rats

Neonatal lesions of the ventral hippocampus in rats lead to post- but not pre-pubertal behavioral changes suggesting adolescent onset of dopaminergic hypersensitivity and providing an animal model of schizophrenia. Neonatal exposure to glutamate receptor antagonists produces accelerated apoptosis leading to neuronal loss in central nervous system structures including the hippocampus. This suggested that neonatal MK-801 might lead to behavioural changes like those reported following ventral hippocampal lesions. Thus, rats received MK-801 (0, 0.5, 1.0 mg/kg ip) on postnatal day 3 (P3) and were tested pre- (P35) and post-pubertally (P56). MK-801 produced an increase in TUNEL staining in the hippocampus and other forebrain structures, confirming the induction of apoptosis. Results showed little difference in locomotor activity between neonatal saline- and MK-801-treated groups during habituation or following saline injection but increased activity was seen in the 0.5 mg/kg MK-801 group following amphetamine (1.5 mg/kg i.p.) at P35 but not P56. In tests of pre-pulse inhibition (PPI), neonatal saline and MK-801 groups showed stable startle amplitudes, minimal responding to the pre-pulse stimuli alone, an increase in PPI with increases in pre-pulse intensity, and reduced PPI with apomorphine (0.1 mg/kg s.c.). At P56, neonatal MK-801 groups tested following vehicle showed less sensitivity to changes in pre-pulse intensity. It was concluded that neonatal MK-801 increases apoptotic cell loss in the hippocampus but does not produce behavioural effects like those seen after neonatal ventral hippocampal lesions. However, neonatal MK-801 did lead to increases in locomotor activity in juveniles but not adults and reduced sensitivity to pre-pulse intensity in PPI tests in adulthood.     

NC-1900, an arginine-vasopressin analogue, ameliorates social behavior deficits and hyperlocomotion in MK-801-treated rats: therapeutic implications for schizophrenia

We previously reported that chronic administration of N-methyl-D-aspartate (NMDA) antagonists reduced the density of vasopressin V1a receptors in several brain regions in rats that demonstrated social interaction deficits and increased locomotor activity. These observations indicate the ability of arginine-vasopressin (AVP), or its analogues, to modulate behavioral abnormalities associated with blockade of NMDA receptors. The present study was performed to investigate the effect of NC-1900, an AVP analogue, on social behavior and locomotor activity in rats treated with MK-801, a non-competitive NMDA receptor antagonist. Male Wistar rats were administered MK-801 (0.13 mg/kg/day ip) or saline for 14 days. Social behavior and locomotor activity were measured 45 min after the injection of NC-1900 (10 ng/kg sc) or saline together with the last MK-801 or vehicle administration. Social interaction was quantified by an automated video-tracking system, and stereotyped behavior and ataxia were manually measured. Acute administration of NC-1900 partially reversed MK-801-induced hyperlocomotion and deficits in social interaction, while NC-1900 itself did not affect these behavioral measures in animals chronically treated with vehicle saline. These results suggest that the central AVP system may interact with glutamatergic and dopaminergic transmissions, and indicate potential therapeutic effects of AVP analogues on positive and negative symptoms of schizophrenia.     

Dizocilpine reduces head diameter of dendritic spines in the hippocampus of adolescent rats

Cognitive deficits are the core symptoms of schizophrenia. Spine deficits have been found in hippocampus of schizophrenia patients, and were associated with cognitive impairments. N-methyl-d-asparate receptors (NMDARs) had been known to play a critical role in synaptic pruning and stabilization during adolescence. In the present study, male adolescent rats were exposed to dizocilpine (MK-801) (0.2 mg/kg i.p qd) or 0.9% saline for 14 days. Then spatial memory, spine morphological changes and RhoA, Rac1, Cdc42 mRNA levels in hippocampus were measured. As a result, MK-801 impaired spatial memory in the adolescent rats, as well as reduced the proportion of mushroom spines and increased the proportion of stubby spines in hippocampus. MK-801 also reduced the expression levels of Rac1 and Cdc42 mRNA and upregulated RhoA mRNA in hippocampus. These results imply that subchronic MK-801 administration during adolescence might disturb the expression of RhoA, Rac1 and Cdc42 mRNA, and then lead to the decay of the spines in hippocampus, which could be involved in cognitive impairments in schizophrenia.     

氟哌啶醇对MK-801致小鼠高活动性与前脉冲抑制损害的作用

目的观察氟哌啶醇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(prepulse inhibition,PPI)损害的作用。方法昆明种小鼠152只分组(n=8或n=10)进行下述对照观察:观察不同剂量氟哌啶醇(0.03、0.1、0.3 mg/kg)腹腔注射对昆明种小鼠探究行为和自主活动的影响;以0.25 mg/kg MK-801诱导小鼠自主活动增加,观察上述剂量氟哌啶醇对MK-801致小鼠高活动性的影响;以0.5 mg/kg MK-801诱导小鼠PPI损害,观察氟哌啶醇(0.1、0.3、1 mg/kg)对基线水平PPI以及MK-801损害后PPI的作用。结果与对照组比较,氟哌啶醇剂量为0.1 mg/kg和0.3 mg/kg时,小鼠的探究行为及自主活动总路程减少(P<0.05);但剂量为0.03 mg/kg时,对小鼠的探究行为及自主活动均无影响(P>0.05)。氟哌啶醇剂量为0.1~0.3 mg/kg时,呈剂量依赖性抑制由MK-801引起的自主活动增加(F=27.23,P<0.01),0.1mg/kg的氟哌啶醇的抑制程度为22%(P<0.01),0.3 mg/kg的氟哌啶醇的抑制程度为65%(P<0.00...     

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.     

MK-801 induced stereotypies in rats are decreased by haloperidol and increased by diazepam

Summary The effects of haloperidol and diazepam were investigated on stereotypies (wall contacts and turn rounds) induced by the non-competitive NMDA antagonist MK-801 in rats. Haloperidol (0.03, 0.10, 0.25 and 0.40mg/kg body weight) caused a dose-dependent antagonism whereas diazepam (3.0 and 5.0 mg/ kg) caused a dose-dependent agonism of the stereotypies induced by 0.30 mg/ kg MK-801 (all drugs given intraperitoneal). Conversely, diazepam (5.0 mg/kg) given alone reduced significantly the number of spontaneous wall contacts and turn rounds. The paradoxial stimulation of MK-801 induced stereotypies by diazepam could be explained by a shift between positive and negative corticostriatothalamic feedback loops envolving GABAergic neurons in favour of the former.     

Septohippocampal GABAergic neurons mediate the altered behaviors induced by n‐methyl‐D‐aspartate receptor antagonists

We hypothesize that selective lesion of the septohippocampal GABAergic neurons suppresses the altered behaviors induced by an N‐methyl‐D ‐aspartate (NMDA) receptor antagonist, ketamine or MK‐801. In addition, we hypothesize that septohippocampal GABAergic neurons generate an atropine‐resistant theta rhythm that coexists with an atropine‐sensitive theta rhythm in the hippocampus. Infusion of orexin‐saporin (ore‐SAP) into the medial septal area decreased parvalbumin‐immunoreactive (GABAergic) neurons by ～80%, without significantly affecting choline‐acetyltransferase‐immunoreactive (cholinergic) neurons. The theta rhythm during walking, or the immobility‐associated theta induced by pilocarpine, was not different between ore‐SAP and sham‐lesion rats. Walking theta was, however, more disrupted by atropine sulfate in ore‐SAP than in sham‐lesion rats. MK‐801 (0.5 mg/kg i.p.) induced hyperlocomotion associated with an increase in frequency, but not power, of the hippocampal theta in both ore‐SAP and sham‐lesion rats. However, MK‐801 induced an increase in 71–100 Hz gamma waves in sham‐lesion but not ore‐SAP lesion rats. In sham‐lesion rats, MK‐801 induced an increase in locomotion and an impairment of prepulse inhibition (PPI), and ketamine (3 mg/kg s.c.) induced a loss of gating of hippocampal auditory evoked potentials. MK‐801‐induced behavioral hyperlocomotion and PPI impairment, and ketamine‐induced auditory gating deficit were reduced in ore‐SAP rats as compared to sham‐lesion rats. During baseline without drugs, locomotion and auditory gating were not different between ore‐SAP and sham‐lesion rats, and PPI was slightly but significantly increased in ore‐SAP as compared with sham lesion rats. It is concluded that septohippocampal GABAergic neurons are important for the expression of hyperactive and psychotic symptoms an enhanced hippocampal gamma activity induced by ketamine and MK‐801, and for generating an atropine‐resistant theta. Selective suppression of septohippocampal GABAergic activity is suggested to be an effective treatment of some symptoms of schizophrenia. © 2012 Wiley Periodicals, Inc.     

Endogenous kynurenic acid disrupts prepulse inhibition.

BACKGROUND: Recent studies show that endogenous levels of kynurenic acid (KYNA) are increased in the cerebrospinal fluid of schizophrenic patients. Prepulse inhibition (PPI) of the acoustic startle reflex is an operational measure of sensorimotor gating that is reduced in neuropsychiatric disorders, such as schizophrenia. Previous studies show that administration of N-methyl-D-aspartate (NMDA) receptor antagonists, such as phencyclidine or MK-801, leads to deficits in sensorimotor gating that mimic those observed in schizophrenic patients. METHODS: The present study examined the effects of the endogenous NMDA receptor antagonist KYNA on startle and PPI in rats. Elevation of endogenous brain levels of KYNA was achieved through intraperitoneal (IP) administration of kynurenine (100 mg/kg), the precursor of KYNA, or by intravenous administration of PNU 156561A (10 mg/kg). RESULTS: A fourfold increase in brain KYNA levels, as induced by kynurenine or PNU 156561A, significantly reduced PPI. There were no differences in startle magnitudes between control rats and drug-treated rats. The disruption of PPI was restored by administration of the antipsychotic drugs haloperidol (.2 mg/kg, IP) or clozapine (7.5 mg/kg, IP). CONCLUSIONS: The present results suggest that brain KYNA serves as an endogenous modulator of PPI and are consistent with the hypothesis that KYNA contributes to the pathophysiology of schizophrenia.     

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.     

Chronic neonatal N-methyl-D-aspartate receptor blockade induces learning deficits and transient hypoactivity in young rats

A blockade of N-methyl-D-aspartate (NMDA)-type of glutamate receptor in rodents is believed to provide a pharmacological model of schizophrenia-related psychosis. Since neurodevelopmental abnormality, at least partly, could contribute to the pathogenesis of schizophrenia, the aim of this study was to recapitulate cognitive impairments accompanying this disorder in rats by a chronic neonatal treatment with a noncompetitive NMDA antagonist MK-801. Rat pups were treated with a low dose of MK-801 (0.05 mg/kg s.c.) chronically from early postnatal period (PD 7-49) known to be critical for glutamatergic system maturation. Locomotor activity in the "open-field" test, anxiety level in the elevated plus-maze test, and learning capacity in food rewarded spatial task were examined in young animals. Chronic MK-801 treatment produced a decrease of spontaneous motor and exploratory activity in 16- to 28-day-old rats. At the same time, a hyperlocomotion in response to acute administration of MK-801 was observed as well. Spatial learning of MK-801-treated rats was found to be negatively affected. Treated rats were able to respond to stress stimuli in the adequate manner but their anxiety level was found to be lower than in controls. Behavioral disturbances appeared to be temporary, and no such abnormalities could be detected at the age of 16 weeks. Thus, even mild chronic neonatal blockade of NMDA receptors may lead to a specific pattern of cognitive abnormalities presumably resulting from impairments of sensory information processing at the cortical-basal ganglia level.     

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)     

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.     

Modifications of inhibitory transmission onto pyramidal neurons by postnatal exposure to MK-801: Effects of enriched environment

Early enriched environment (EE) prevents several deficits associated with postnatal MK-801 [N-Methyl-d-Aspartate (NMDA) receptor antagonist] treatment such as cognitive and locomotor deficits. We sought physiological correlates to such changes by looking at inhibitory synaptic inputs onto pyramidal cells in a prefrontal cortex slice preparation. Pharmacologically isolated γ-amino-butyric acid _A (GABA_A) receptor-mediated currents were measured using whole-cell patch clamp recordings. Wistar rats were raised in standard or EE from birth up to the time of experiments and were injected with saline or MK-801 (1 mg/ kg) on postnatal days (P) 6–10. We recorded miniature inhibitory post-synaptic currents (mIPSCs) of pyramidal cells in layer II/III of prefrontal cortex and measured their frequency, amplitude and kinetics. In control animals, the amplitude and frequency of mIPSCs increased strikingly during development from P21 to P28. MK-801 accelerated the development of mIPSCs frequency but caused a significant decrease in the amplitude of mIPSCs on P28 suggesting a significant reduction of inhibition onto pyramidal cells. EE per se led to a significant increase in both frequency and amplitude of mIPSCs, but its application to MK-801-treated rats resulted in moderate rescue of GABAergic transmission on P28. We conclude that postnatal MK-801 leads to reduced inhibitory transmission onto pyramidal cells of prefrontal cortex at adolescence which may underlie behavioural and morphological differences detected in vivo in rats. EE presentation from birth rather prevents GABAergic alterations associated with postnatal MK-801 treatment at adolescence.     

Effect of transient blockade of N-methyl-D-aspartate receptors at neonatal stage on stress-induced lactate metabolism in the medial prefrontal cortex of adult rats: role of 5-HT1A receptor agonism

Decreased activity of the medial prefrontal cortex (mPFC) has been considered a basis for core symptoms of schizophrenia, an illness associated with a neurodevelopmental origin. Evidence from preclinical and clinical studies indicates that serotonin (5-HT)1A receptors play a crucial role in the energy metabolism of the mPFC. This study was undertaken to determine (1) if transient blockade of N-methyl-D-aspartate receptors during the neonatal stage inhibit energy demands in response to stress, as measured by extracellular lactate concentrations, in the mPFC at the young adult stage, and (2) if tandospirone, a 5-HT1A partial agonist, reverses the effect of the neonatal insult on energy metabolism. Male pups received MK-801 (0.20 mg/kg) on postnatal days (PDs) 7-10. On PD 63, footshock stress-induced lactate levels were measured using in vivo microdialysis technique. Tandospirone (0.1, 1.0, and 5.0 mg/kg) was administered once daily for 14 days before the measurement of lactate levels. Neonatal MK-801 treatment suppressed footshock stress-induced lactate production in the mPFC, but not caudate-putamen, whereas basal lactate levels were not significantly changed in either brain region. The MK-801-induced suppression of footshock stress-induced lactate production in the mPFC was attenuated by tandospirone at 1.0mg/kg/day, but not 0.1 or 5.0 mg/kg/day, which is an effect antagonized by coadministration of WAY-100635, a selective 5-HT1A antagonist. These results suggest a role for impaired lactate metabolism in some of the core symptoms of schizophrenia, for example, negative symptoms and cognitive deficits. The implications for the ability of 5-HT1A agonism to ameliorate impaired lactate production in the mPFC of this animal model are discussed.     

Glutamate antagonism during secondary deafferentation enhances cognition and axo-dendritic integrity after traumatic brain injury

The combination of central fluid percussion traumatic brain injury (TBI) followed 24 h later by a bilateral entorhinal cortical deafferentation (BEC) produces profound cognitive morbidity. We recently showed that MK-801 given prior to TBI in this insult improved spatial memory for up to 15 days. In the present study we examine whether MK-801 treatment of the BEC component in the combined insult model affects cognitive recovery. Two strategies for drug treatment were tested. Fifteen minutes prior to the BEC lesion in the combined insult, rats were given i.p. doses of either 3 mg/kg (acute group) or 1 mg/kg (chronic group) MK-801. The acute group received no further injections, whereas the chronic group received 1 mg/kg MK-801 i.p. twice a day for 2 days post-BEC lesion. Two additional groups of animals received BEC lesion alone and either acute or chronic MK-801 treatment identical with the combined insult cases. Each group was then assessed for spatial memory deficits with the Morris water maze at days 11–15 and 60–64 postinjury. Both acute and chronic MK-801 treatment in the combined insult group significantly reduced spatial memory deficits at 15 days postinjury relative to untreated injured cases (P < .01). This reduction appeared more robust at 15 days and persisted for up to 64 days in the chronically treated group (P < .05). By contrast, neither acute nor chronic MK-801 treatment affected memory performance with the BEC insult alone. Immunocytochemical localization of parvalbumin showed that chronic administration of MK-801 in the combined insult cases attenuated the injury-induced dendritic atrophy of inhibitory neurons in the dentate gyrus and area CA1. Synaptophysin immunobinding revealed that chronic MK-801 treatment of the BEC component of the combined insult normalized the distribution of presynaptic terminals within the dentate gyrus. These results suggest that cognitive deficits produced by head trauma involving both neuroexcitation and deafferentation can be attenuated with chronic application of glutamatergic antagonists during the period of deafferentation injury and that this attenuation is correlated with axo-dendritic integrity. Hippocampus 1998;8:390–401. © 1998 Wiley-Liss, Inc.     

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。