MK-801与环境线索交互作用对吗啡行为敏感化的影响

为探讨MK-801与环境线索交互作用对吗啡诱导行为敏感化的影响,将42只大鼠随机分为对照组,MK-801组,吗啡组（匹配和非匹配）和MK-801+吗啡组（匹配和非匹配）。行为敏感化模型建立分为发展期,戒断期和表达期三个阶段。实验结果发现：同时给予MK-801（0.1mg·kg-1）会促进吗啡（5mg·kg-1）诱导大鼠行为敏感化的发展,而且会使MK-801成为大鼠行为敏感化表达所必需的条件性刺激。MK-801的内部线索作用过强,从而削弱了环境的外部线索作用。研究结果表明：MK-801对吗啡诱导行为敏感化的影响存在状态依赖（state-dependency）现象,提示在NMDA受体与行为敏感化关系的研究中应考虑选择刺激特性更小的药物     

Place and response learning of rats in a Morris water maze: differential effects of fimbria fornix and medial prefrontal cortex lesions

The question examined in this study is concerned with a possible functional dissociation between the hippocampal formation and the prefrontal cortex in spatial navigation. Wistar rats with hippocampal damage (inflicted by a bilateral lesion of the fimbria fornix), rats with damage to the medial prefrontal cortex, and control-operated rats were examined for their performance in either one of two different spatial tasks in a Morris water maze, a place learning task (requiring a locale system), or a response learning task (requiring a taxon system). Performance of the classical place learning (allocentric) task was found to be impaired in rats with lesions of the fimbria fornix, but not in rats with damage of the medial prefrontal cortex, while the opposite effect was found in the response learning (egocentric) task. These findings are indicative of a double functional dissociation of these two brain regions with respect to the two different forms of spatial navigation. When the place learning task was modified by relocating the platform, the impairment in animals with fimbria fornix lesions was even more pronounced than before, while the performance of animals with medial prefrontal cortex lesions was similar to that of their controls. When the task was again modified by changing the hidden platform for a clearly visible one (visual cue task), the animals with fimbria fornix lesions had, at least initially, shorter latencies than their controls. By contrast, in the animals with medial prefrontal cortex damage this change led to a slight increase in escape latency.     

The NMDA receptor antagonist MK-801 blocks acquisition and extinction of conditioned hypoalgesic responses in the rat

The role of the N-methyl-D-aspartate (NMDA) receptor in Pavlovian conditioning of hypoalgesic responses in the hotplate apparatus was examined using the non-competitive NMDA antagonist MK-801. Either MK-801 or saline were administered before the training phase, test phase, or both, and MK-801 disrupted the acquisition and extinction but not the expression of conditioned hypoalgesic responses. All rats received counterbalanced injections of both MK-801 and saline after the training phase, therefore the learning decrements could not be attributed to a delayed, non-specific action of the drug. MK-801 did not augment paw-lick latencies on either the training or test days, indicating that its behavioural effects are not due to alterations in nociceptive sensitivity or motor performance. Similarly, MK-801's effects upon acquisition and extinction could not be attributed to state-dependent generalization decrement or impairments in processing of the hot-plate apparatus cues during training, as rats displayed normal hypoalgesic responses when tested with MK-801, and MK-801-treated animals displayed normal habituation of novelty-induced hypoalgesia in the hot-plate apparatus. These data suggest that the NMDA receptor system is involved in the acquisition and extinction, but not the expression of conditioned hypoalgesia and parallels the effects of NMDA receptor antagonists on the acquisition and expression of long-term potentiation (LTP) both in vitro and in vivo. It is plausible that an endogenous NMDA-mediated form of LTP plays a vital role in the acquisition and storage of aversive representations mediating conditioned hypoalgesic responses.     

Differential interaction of platelet-activating factor and NMDA receptor function in hippocampal and dorsal striatal memory processes

The interaction between platelet activating factor (PAF) and NMDA receptor function in hippocampal and dorsal striatal memory processes was examined. In both a hidden and a visible platform water maze task, peripheral post-training injection of MK-801 (0.05 mg/kg) impaired memory. Post-training intrahippocampal infusions of PAF (1.0 microg/0.5 microl) enhanced memory in the hidden platform task, while intradorsal striatal infusion of PAF (1.0 microg/0.5 microl) enhanced memory in the visible platform task. The memory impairing effects of post-training injection of MK-801 was blocked by concurrent intrahippocampal infusion of PAF. In contrast, post-training injection of MK-801 blocked the memory enhancing effects of concurrent intradorsal striatal infusion of PAF. The results suggest that (1) the memory enhancing effects of intracerebral PAF infusion involve an interaction with NMDA receptor function, and (2) the nature of this interaction may represent a differential mechanism mediating the distinct roles of the hippocampus and dorsal striatum in cognitive memory and stimulus-response habit formation, respectively.     

Functional interaction of mGlu5 and NMDA receptors in aversive learning in rats

Metabotropic glutamate receptor 5 (mGlu5) has been implicated in a variety of learning processes and is important for inhibitory avoidance and conditioned taste aversion learning. MGlu5 receptors are physically connected with NMDA receptors and they interact with, and modulate, the function of one another in several brain regions. The present studies used systemic co-administration of an mGlu5 receptor positive allosteric modulator, 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) and an NMDA receptor antagonist dizocilpine maleate (MK-801) to characterize the interactions of these receptors in two aversive learning tasks. Male Sprague-Dawley rats were trained in a single-trial step-down inhibitory avoidance or conditioned taste aversion task. CDPPB (3 or 10mg/kg, s.c.), delivered by itself prior to the conditioning trial, did not have any effect on performance in either task 48 h after training. However, CDPPB (at 3mg/kg) attenuated the MK-801 (0.2mg/kg, i.p.) induced learning deficit in both tasks. CDPPB also reduced MK-801-induced hyperactivity. These results underlie the importance of mGlu5 and NMDA receptor interactions in modulating memory processing, and are consistent with findings showing the efficacy of positive allosteric modulators of mGlu5 receptors in reversing the negative effects of NMDA receptor antagonists on other behaviors such as stereotypy, sensorimotor gating, or working, spatial and recognition memory.     

MK-801-Induced Disruptions of One-Trial Inhibitory Avoidance Are Potentiated by Stress and Reversed by Naltrexone

Five experiments were carried out to investigate opioid and NMDA receptor-mediated responses to one-trial inhibitory avoidance training in CD1 mice. In the first experiment immediate posttraining intraperitoneal administration of the noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 impaired the performance of mice. The effects of MK-801 were time-dependent (they were absent in mice injected with the drug starting 120 min after training). No effect was evident in no-foot-shock groups, showing lack of proactive influence of the treatment on performance. In the second experiment preexposure of the mice to the testing apparatus decreased the effects of MK-801. In the the third experiment naltrexone antagonized the effects of MK-801, suggesting an involvement of opioid neurons. In the fourth experiment immediate posttraining immobilization stress exerted a potentiating effect on the performance of MK-801-injected animals. In the fifth experiment the potentiation of the impairing effect of MK-801 induced by immobilization stress was antagonized by naltrexone.     

纳络酮、地卓西平(MK-801)对大鼠食物渴求的影响

实验以条件性位置偏爱（CPP）的表达为渴求模型观察纳络酮及MK-801对大鼠食物CPP表达,探讨摄食行为调控的心理机制。48只SD大鼠分成食物组（24）与对照组（24）,3轮食物匹配训练后,在CPP表达前分别注射生理盐水、纳络酮（1.0 mg˙kg -1）及MK-801(0.1 mg˙kg -1),观察各组动物在食物匹配训练侧停留时间的变化。结果发现,MK-801促进食物CPP的表达,但纳络酮对食物CPP的表达没有显著影响。以上结果表明MK-801（0.1mg˙kg -1）增强动物的食物渴求至少是其增加摄食量的原因之一,而1.0 mg˙kg -1的纳络酮降低动物的摄食量并不是由于食物渴求的下降导致的。MK-801与纳络酮调节动物摄食行为的心理机制可能不一致。     

Memory-Enhancing Treatments Do Not Reverse the Impairment of Inhibitory Avoidance Retention Induced by NMDA Receptor Blockade

The aim of the present research was to verify whether the impairment of retention induced by the N-methyl-d-aspartate (NMDA) receptor blocker (+)-10,11-dihydro-5-methyl-5H-dibenzo[a,d]cycloheptene-5,10 imine (MK-801) can be reversed by memory-enhancing treatments. Adult female Wistar rats were trained and tested in a step-down inhibitory avoidance task (0.3-mA foot shock, 24-h training-test interval). Animals were given an ip injection of saline (SAL) or MK-801 (0.0625 mg/kg) 30 minutes before training, and an ip injection of SAL, epinephrine (EPI) (25 microg/kg), the opioid receptor antagonist naloxone (NAL) (0.4 mg/kg), the glucocorticoid receptor agonist dexamethasone (DEX) (0.3 mg/kg), or glucose (GLU) (320 mg/kg) immediately after training. There was an impairment of inhibitory avoidance retention in the MK-801-SAL, MK-801-EPI, MK-801-NAL, MK-801-DEX, and MK-801-GLU groups. There was an enhancement of retention in the SAL-EPI, SAL-NAL, SAL-DEX, and SAL-GLU groups. A control experiment showed that the amnestic effects of MK-801 could not be attributed to decreased reactivity to the foot shock. The results suggest that memory-enhancing treatments directed at modulatory mechanisms do not reverse the memory impairment induced by NMDA receptor blockade.     

Spatial learning and goldfish telencephalon NMDA receptors

Recent results have demonstrated that the mammalian hippocampus and the dorso-lateral telencephalon of ray-finned fishes share functional similarities in relation to spatial memory systems. In the present study, we investigated whether the physiological mechanisms of this hippocampus-dependent spatial memory system were also similar in mammals and ray-finned fishes, and therefore possibly conserved through evolution in vertebrates. In Experiment 1, we studied the effects of the intracranial administration of the noncompetitive NMDA receptor antagonist MK-801 during the acquisition of a spatial task. The results indicated dose-dependent drug-induced impairment of spatial memory. Experiment 2 evaluated if the MK-801 produced disruption of retrieval of a learned spatial response. Data showed that the administration of MK-801 did not impair the retrieval of the information previously stored. The last experiment analyzed the involvement of the telencephalic NMDA receptors in a spatial and in a cue task. Results showed a clear impairment in spatial learning but not in cue learning when NMDA receptors were blocked. As a whole, these results indicate that physiological mechanisms of this hippocampus-dependent system could be a general feature in vertebrate, and therefore phylogenetically conserved.     

Impaired, spared, and enhanced ACh efflux across the hippocampus and striatum in diencephalic amnesia is dependent on task demands

Diencephalic amnesia manifests itself through a host of neurological and memory impairments. A commonly employed animal model of diencephalic amnesia, pyrithiamine-induced thiamine deficiency (PTD), results in brain lesions and impairments similar in nature and distribution to those observed in humans with Wernicke–Korsakoff syndrome (WKS). In the current investigation, 2 separate experiments were conducted in which acetylcholine (ACh) efflux was assessed in the hippocampus and striatum of PTD-treated and pair-fed (PF) control male Sprague–Dawley rats. The goal was to determine under what behavioral conditions and in which brain structures ACh efflux was spared, impaired, or adaptively enhanced. In Experiment 1, rats were assessed on a spontaneous alternation task; in Experiment 2, rats were tested on a T-maze discrimination task that could be learned via a hippocampal- or striatal-based strategy. In Experiment 1, PTD-treated rats were impaired on the spontaneous alternation task and ACh efflux in the hippocampus during testing was significantly reduced, but spared in the striatum. In Experiment 2, PTD- and PF-treated rats did not differ in the number of trials to criterion, but PTD-treated rats demonstrated greater reliance upon egocentric cues to solve the task. Furthermore, ACh efflux in the striatum was greater during maze learning in the PTD-treated animals when compared to the PF animals. These results suggest that there is behavioral and systems level plasticity that can facilitate the use of alternative strategies to solve a task following diencephalic damage and WKS.     

A comparison of the effects of fimbria-fornix, hippocampal, or entorhinal cortex lesions on spatial reference and working memory in rats: short versus long postsurgical recovery period.

Using a radial maze task and different postoperative recovery periods, this experiment assessed and compared the reference and working memory performances of adult Long-Evans male rats subjected to entorhinal cortex, fimbria-fornix, and hippocampus lesions. Sham-operated rats were used as controls. In order to see whether the duration of the postsurgical recovery period would influence acquisition of the complex radial maze task, training began 1 month following surgery (Delay 1) for half the rats in each group, while for the other half training was started 6.5 months following surgery (Delay 2). The results indicated that at both recovery periods the entorhinal cortex lesions failed to affect either working or reference memory in the spatial task. Conversely, both fimbria-fornix and hippocampus lesions impaired both reference and working memory. While the reference memory deficit was generally similar in both fimbria-fornix and hippocampal lesion groups, analysis of the results for working memory indicated that at the longer delay rats with fimbria-fornix lesions were still impaired but in animals that had the hippocampus removed, working memory did not differ from that of controls. These results suggest that there was some recovery in those rats with hippocampal lesions (e.g., on the working memory task) but both hippocampal and fimbria-fornix animals were still impaired compared to controls when training was delayed 6.5 months following the operations.     

Strain-dependent interactions between MK-801 and cocaine on retention of C57BL/6 and DBA/2 mice tested in a one-trial inhibitory avoidance task: involvement of dopaminergic mechanisms

Two sets of experiments were carried out with C57BL/6 (C57) and DBA/2 (DBA) mice tested in a one-trial inhibitory avoidance task. In the first set C57 and DBA mice were injected posttraining with saline or with the D1 DA receptor antagonist SCH 23390 and then with saline, cocaine (5 mg/kg), MK-801 (0.1 mg/kg), or with a combination of these two drugs. Cocaine enhanced retention in the C57 strain and impaired it in the DBA strain, and MK-801 potentiated the effects of cocaine in both strains. Furthermore, pretreatment with SCH 23390 completely antagonized the potentiation of the effects of cocaine exerted by MK-801. In the second set of experiments mice belonging to these same two strains were injected posttraining with vehicle or with the D2 DA receptor antagonist (-)-sulpiride and then with saline, cocaine (5 mg/kg), MK-801 (0.1 mg/kg), or with a combination of these two drugs. Pretreatment with the D2 DA receptor antagonist completely antagonized in both strains the potentiation of the effect of cocaine exerted by MK-801. The results of the present research show that the noncompetitive NMDA receptor antagonist MK-801 enhances the effect of cocaine on retention performance in C57 and DBA mice and that dopaminergic mechanisms are involved in this potentiation.     

Establishment of a schizophrenic animal model through chronic administration of MK-801 in infancy and social isolation in childhood

BackgroundAlthough an increasing amount of evidence supports a “two-hit” hypothesis for the neurodevelopmental model of schizophrenia, there has been no development in animal models to test this hypothesis.MethodsAn animal model was established by chronic administration of 0.1, 0.3, and 0.5 mg/kg MK-801 in P7-P21 rats followed by four weeks of social isolation in childhood and then five days of social housing. Animal behaviors were measured by the open field (OF) test, the novel object recognition (NOR) test, the prepulse inhibition (PPI) test, and the elevated plus maze (EPM) test.ResultsWe found a significant decrease in the NOR index in adolescent rats compared to saline control rats when administering 0.5 mg/kg of MK-801 (P = 0.02). We found that social isolation had no significant effect on NOR index, though social isolation significantly increased the total distance traveled and significantly decreased the resting time in adolescent rats in the OF test (P < 0.001 and P = 0.003, respectively). In contrast, we observed that MK-801 administration showed no significant effects on either total distance traveled or resting time. Both MK-801 administration and social isolation had no significant effect on the percent of PPI and startle amplitudes in adolescent rats. Social isolation significantly reduced the open arm entries in adolescent rats in the EPM test (P = 0.023), but it did not reduce the ratio to enter the open arms and the stay time in open arm. Administration of MK-801 showed no significant effect on the indexes of entering the open arms in the EPM test on adolescent rats.ConclusionMK-801 intervention in infancy is associated with the damage of long-term visual memory, whereas social isolation in childhood is associated with the increased spontaneous activity and anxiety levels. Administration of MK-801 in infancy and social isolation in childhood are two independent factors on the neurodevelopmental defects.     

Fetal brain tissue transplants reduce visual deficits in adult rats with bilateral lesions of the occipital cortex

Fetal brain tissue from the occipital or the frontal cortex was implanted into the damaged occipital cortex of adult rats. The animals receiving grafts of embryonic frontal cortex showed partial restoration of brightness discrimination while recipients given homologous implants of occipital cortex were as impaired as those animals with lesions alone. Neither frontal nor occipital grafts aided in the performance of a pattern discrimination problem; both groups of brain-damaged animals were unable to learn the task. Nonetheless, both groups of animals had viable and enlarged grafts with similar neuronal and glial profiles.     

The effects of clozapine on delayed spatial alternation deficits in rats with hippocampal damage

Clozapine is an atypical antipsychotic drug that has been shown to improve spatial memory in some animal models; however its efficacy in reversing spatial memory impairment in rats with hippocampal lesions is unknown. To address this issue, we tested the effects of clozapine on delayed spatial alternation deficits in rats with hippocampal damage in three separate experiments. In each experiment, adult male rats received sham surgery or direct stereotaxic infusions of the excitotoxin, NMDA, into the hippocampus. In the first study, seven days after surgery, the sham control animals received daily saline injections while the lesioned animals were split into two groups that received daily saline or clozapine (2.0 mg/kg, sc) injections. During the fifth week of injections, all animals were tested in a food-motivated delayed spatial alternation task. Saline-treated rats with excitotoxic hippocampal damage displayed significant deficits in delayed spatial alternation. Daily clozapine injections completely reversed this deficit. In a second experiment, it was found that clozapine treatment limited to the testing days only did not improve alternation performance in lesioned rats. Finally, in a third experiment, chronic clozapine treatment did not improve alternation performance in lesioned rats that were pre-trained in the alternation task prior to surgery. These results suggest that chronic, but not acute, clozapine treatment enables rats with hippocampal damage to develop new spatial learning, but can not rescue old spatial learning established prior to damage. These results may have implications for the treatment of cognitive deficits caused by hippocampal dysfunction in disorders such as schizophrenia, Alzheimer's disease, and others.     

Latent inhibition disruption by MK-801 in a conditioned taste-aversion paradigm

N-Methyl-D-aspartate (NMDA) receptors appear to be involved in CS processing and memory consolidation. The present paper analyzed the effect of the non-competitive NMDA receptor antagonist Dizocilpine maleate (MK-801) on Latent Inhibition (LI)-retarded learning of a CS-US association after to-be-CS preexposures at time of testing, using Wistar rats as experimental subjects. If NMDA receptors are involved in CS processing, MK-801 administration should affect LI. In fact, previous experiments revealed that a 2.0mg/kg MK-801 dose, administered 20 h before preexposure and conditioning, abolished LI in a conditioned taste-aversion paradigm. In the present paper, MK-801 (0.2 mg/kg) was either injected after preexposure, after conditioning, or after both preexposure and conditioning stages. LI was abolished when MK-801 was injected after preexposure, but not when it was injected after conditioning. These results support the role of NMDA receptors in CS processing and memory consolidation.     

The Behavioral and Pharmacological Actions of NMDA Receptor Antagonism are Conserved in Zebrafish Larvae

Dizocilpine maleate (MK-801) is one of several NMDA receptor antagonists that is widely used to pharmacologically model the symptoms of psychosis and schizophrenia in animals. MK-801 elicits behaviors in adult zebrafish (Danio rerio) that are phenotypically consistent with behaviors observed in humans and rodents exposed to tbhe drug. However, the molecular and cellular processes that mediate the psychotomimetic, cognitive and locomotive behaviors of MK-801 are unclear. We exposed zebrafish larvae to MK-801 to assess their merit as a model organism to elucidate the behavioral effects of NMDA receptor blockade. Zebrafish larvae were acutely immersed in MK-801 to assess the effect on spontaneous swimming. MK-801 caused a time- and dose-dependent increase in larval swim speed, and the peak response (a five-fold increase in swim speed) was evoked by a three h exposure to a 20 uM dose. Zebrafish larvae did not exhibit sensitivity to the locomotor effects of MK-801 until 5 dpf, suggesting a critical role for developmental in sensitivity to the drug. Exposure to the low potency NMDA antagonist, memantine, did not alter the swim speed of zebrafish larvae. Co-immersion in D(1) or D(2) dopamine receptor antagonists did not disrupt the time course or magnitude of the increase in swim speed, suggesting dopaminergic signaling is not required for the locomotor actions of MK-801. Our findings of the behavioral actions of MK-801 in zebrafish larvae are consistent with previous observations in mammals and imply that the physiological, cellular and molecular processes disrupted by MK-801 are conserved in zebrafish larvae. These data suggest that the zebrafish larvae is a valid and useful model to elucidate neurobehavioral aspects of NMDA receptor antagonism and may provide insight to the neurobiology of psychosis and schizophrenia.     

Phosphodiesterase type 5 (PDE5) inhibition improves object recognition memory: indications for central and peripheral mechanisms

A promising target for memory improvement is phosphodiesterase type 5 (PDE5), which selectively hydrolyzes cyclic guanosine monophosphate (cGMP). In rodents, PDE5 inhibitors (PDE5-Is) have been shown to improve memory performance in many behavioral paradigms. However, it is questioned whether the positive effects in animal studies result from PDE5 inhibition in the central nervous system or the periphery. Therefore, we studied the effects of PDE5 inhibition on memory and determined whether compound penetration of the blood-brain barrier (BBB) is required for this activity. Two selective PDE5-Is, vardenafil and UK-343,664, were tested in the object recognition task (ORT) in both a MK-801- and scopolamine-induced memory deficit model, and a time-delay model without pharmacological intervention. Compounds were dosed 30 min before the learning trial of the task. To determine if the PDE5-Is crossed the BBB, their concentrations were determined in plasma and brain tissue collected 30 min after oral administration. Vardenafil improved object recognition memory in all three variants of the ORT. UK-343,664 was ineffective at either preventing MK-801-induced memory disruption or time-dependent memory decay. However, UK-343,664 attenuated the memory impairment of scopolamine. Vardenafil crossed the BBB whereas UK-343,664 did not. Further, co-administration of UK-343,664 and scopolamine did not alter the brain partitioning of either molecule. This suggests that the positive effect of UK-343,664 on scopolamine-induced memory decay might arise from peripheral PDE5 inhibition. The results herein suggest that there may be multiple mechanisms that mediate the efficacy of PDE5 inhibition to improve memory performance in tasks such as the ORT and that these involve PDE5 located both within and outside of the brain. To further elucidate the underlying mechanisms, the cellular and subcellular localization of PDE5 needs to be determined.     

记忆过程中海马CA1区神经元的集群放电特征

观察空间工作记忆过程中海马CA1区神经元群的放电特征。应用多通道神经元集群放电记录技术, 同步观察和记录清醒大鼠在执行延迟选择任务时的行为轨迹以及海马CA1区神经元的放电活动。发现：海马CA1区位置细胞的位置野是在学习过程中逐渐形成并可消退; 部分位置细胞的放电对未来目标定向性行为具有预测作用; 在空间工作记忆过程中, 神经元放电之间的相关性加强, 神经元之间以及神经元与局部场电位之间存在相位编码方式。结果提示海马CA1区神经元参与对空间信息的初级编码和加工, 并为未来行为决策提供有效信息, 而且海马对信息的加工是通过局部神经网络进行, 时间编码可能是海马信息加工的重要方式之一。     

Knockdown of Nurr1 in the rat hippocampus: implications to spatial discrimination learning and memory

Nurr1 expression is up-regulated in the brain following associative learning experiences, but its relevance to cognitive processes remains unclear. In these studies, rats initially received bilateral hippocampal infusions of control or antisense oligodeoxynucleotides (ODNs) 1 h prior to training in a holeboard spatial discrimination task. Such pre-training infusions of nurr1 antisense ODNs caused a moderate effect in learning the task and also impaired LTM tested 7 d later. In a second experiment, ODN infusions were given immediately after the animals had received two sessions of training, during which all animals showed normal learning. Although antisense treated rats were significantly impaired during the post-infusion stages of acquisition of the task, no group differences were observed during the LTM test given 7 d later. These animals were subjected 3 d later to reversal training in the same maze in the absence of any additional treatments. Remarkably, rats previously treated with antisense ODNs displayed perseveration: The animals were fixated with the previously learned pattern of baited holes, causing them to be significantly impaired in the extinction of acquired spatial preferences and future learning. We postulate that Nurr1 function in the hippocampus is important for normal cognitive processes.