东莨菪碱和毒扁豆碱对吗啡处理大鼠Morris水迷宫空间学习能力的影响

目的:研究吗啡及胆碱能系统的药物对大鼠空间学习能力的影响 方法:应用Morris水迷宫学习程序研究吗啡处理大鼠的空间学习能力及其在东莨菪碱和毒扁豆碱作用下的变化.结果:高剂量吗啡(10mg/kg)和低剂量吗啡(3mg/kg)对大鼠学习能力的影响差异有显著性;东莨菪碱(3mg/kg)和吗啡(10mg/kg)联合给药,可以使吗啡时学习能力的损害进一步加重;毒扁豆碱(0.1mg/kg)可以改善吗啡所致的学习能力损害,但不能完全逆转.结论:吗啡损害大鼠空间学习能力,已存在量-效关系;胆碱能系统与吗啡处理大鼠空间学习能力关系密切,有可能影响成瘾的发生及治疗.     

Diazepam impairs place learning in naive but not in maze-experienced rats in the Morris water maze

Anxiolytic benzodiazepines have been shown to impair place learning in the Morris water maze. However, a clear-cut demonstration of a direct and specific effect on mnemonic processes has not yet been offered. In the present study, the effects of diazepam on place navigation in the Morris water maze were studied in rats. Three conditions were examined: learning, reversal learning and learning after familiarisation of animals with the maze. In view of the anxiolytic and sedative properties of diazepam, appropriate doses of the drug, i.e. those that produced an anxiolytic effect but no major motor impairment, were initially selected in the water-lick conflict and rotarod tests, respectively. Doses of 2.5 and 5 mg/kg PO increased punished drinking in the water-lick conflict test without significantly decreasing rotarod performance. These doses were then used to assess the effects of diazepam on spatial behaviour. Diazepam, at both doses, impaired place learning in behaviourally naive rats. Such an effect appeared to be transient: diazepam-treated rats eventually reached control performance. Moreover, analysis of the probe trial at the end of training revealed adoption of a spatial strategy to locate the submerged platform. Neither reversal learning nor learning after familiarisation was affected. These results do not replicate previous findings in the Morris water maze and provide some evidence that the diazepam-induced place learning deficit may be primarily anxiolytic in nature.     

Beneficial effects of resveratrol on scopolamine but not mecamylamine induced memory impairment in the passive avoidance and Morris water maze tests in rats

Resveratrol (3,5,4-trihydroxy-trans-stilbene), which is found in grapes and red wine has been shown to protect neuronal cells with its antioxidant activity, improve memory function in dementia and reverse acetylcholine esterase (AChE) activity. The aim of this study was to investigate the effect of resveratrol on emotional and spatial memory in naive rats, as well as on scopolamine- and mecamylamine-induced memory impairment in the passive avoidance and Morris water maze (MWM) tests. Resveratrol (12.5, 25 and 50 mg/kg), scopolamine (0.6 mg/kg) and mecamylamine (10 mg/kg) were administered to male Wistar rats. In the passive avoidance test, there was no significant difference in the first day latency between all groups, whereas scopolamine and mecamylamine significantly shortened the second day latency compared to the control group. Resveratrol reversed the effect of scopolamine at all doses used, but it had no effect on mecamylamine-induced memory impairment in the passive avoidance test. Both scopolamine and mecamylamine significantly decreased the time spent in the escape platform quadrant during the probe trial of the MWM test compared to the control group. Resveratrol reversed the effect of scopolamine at all doses, but did not change the effect of mecamylamine in the MWM test. There were no significant differences in the locomotor activities of any of the groups. In conclusion, we suggested that resveratrol had improving effects on learning and memory by acting on muscarinic cholinergic receptors and at least in part, may reverse AChE activity.     

Refining the critical period for methamphetamine-induced spatial deficits in the Morris water maze

Rationale Neonatal administration of methamphetamine (MA) to rats from postnatal day (P) 11 to 20, but not from P1 to P10, produces lasting deficits in spatial learning and memory. The preweaning period of development in the rat corresponds to human third trimester hippocampal development and because of the increased use of MA in women of childbearing age, there is a greater likelihood that fetuses will be exposed to this drug. Development of the hippocampus is dependent upon many factors, including an optimal level of corticosterone (CORT). We have demonstrated that the CORT response of animals on P11 to MA is protracted relative to administration on P15 or P20. Interestingly, the P11 animals are still in the stress hyporesponsive period. Objectives We postulated that because of the prolonged CORT response on P11, the effects of MA on spatial learning and memory may be confined to a shorter period of exposure. Methods Neonatal rats were administered MA (10 mg/kg) 4 times daily from either P11 to P15 or from P16 to P20, raised to adulthood and tested against animals only administered saline (SAL) from P11 to P20 for anxiety, swimming ability, and spatial learning and memory. Results Animals exposed to MA, regardless of exposure period, tended to be less anxious in the Zero maze relative to SAL animals. No differences were noted for swimming ability. Only animals exposed to MA from P11 to P15 demonstrated deficits in spatial learning and memory during acquisition as well as during a shifted platform phase where learning a new position was required. Conclusions The results demonstrate that spatial learning and memory deficits produced by MA administration are dependent upon when the exposure of the animal occurs and appears to be during the period of development in the rat when the response to threatening environments, stressors, is greatly reduced.     

The immobility produced by intermittent swim stress is not mediated by serotonin

Exposure to uncontrollable stressors such as intermittent swim stress (ISS) produces a behavioral syndrome that resembles behavioral depression including immobility in a Forced Swim Test (FST) and escape learning deficits. The results of previous studies suggest that stress causes a temporary sensitization of the brain serotonin (5-HT) system that is necessary and sufficient for producing behavioral depression. If this hypothesis is true in the ISS paradigm, then enhancing or inhibiting 5-HT transmission during stress should exacerbate or block the development of behavioral depression, respectively. The selective 5-HT uptake inhibitor fluoxetine (FLX) was administered prior to ISS or confinement; 24 h later the FST was used to detect behavioral immobility. ISS, but not FLX, significantly increased immobility in the FST. The purported 5-HT uptake enhancer tianeptine (TPT) was administered in place of FLX. Again ISS increased immobility in the FST, but TPT had no effect. These results suggested that 5-HT is not a critical mediator of ISS induced behavioral depression. However, some authors have raised concern that TPT does not act directly on 5-HT. Therefore, the 5-HT synthesis inhibitor, para-chlorophenylaline (PCPA) was administered to deplete central 5-HT before stress. PCPA did not alter immobility in the FST. Finally, a sub-chronic regimen of FLX given after ISS, but before the FST, was without effect on reversing the ISS-induced immobility. Taken together, these experiments indicate that ISS produces a significant behavioral depression manifested as increased immobility but offer no support of the hypothesis that 5-HT is a critical mediator of these effects.     

Ondansetron improves cognitive performance in the Morris water maze spatial navigation task

In the present studies we investigated the actions of ondansetron, a prototypic 5-hydroxytryptamine₃ (5-HT₃) receptor antagonist, on performance in a complex spatial navigation/memory task in rats. Specifically, we compared the activity of ondansetron to that of the cholinesterase inhibitor physostigmine in attenuating two distinct cognitive deficits in the Morris water maze. In the first model, rats treated with the muscarinic receptor antagonist atropine (30 mg/kg) had significantly longer latencies to find the submerged platform across two days of testing. Physostigmine (0.03, 0.1 and 0.3 mg/kg) and ondansetron (0.03–1 mg/kg) significantly reduced the latencies to find the submerged platform in atropine-treated animals, suggesting an increase in cognitive performance. There was little evidence of a dose-response relationship for either compound, and a loss of efficacy for ondansetron was seen at 3 mg/kg. In the second model, pre-screened, aged (23 months), cognition-impaired and nonimpaired rats were tested. Ondansetron (0.1 mg/kg), but not physostigmine (0.1 mg/kg), decreased the latencies to find the submerged platform in the aged-impaired rats, while neither compound improved performance of aged-nonimpaired rats. These data suggest that ondansetron may have cognition enhancing properties in animal models of aging and cholinergic hypofunction.     

Differential effect of antipsychotics on place navigation of rats in the Morris water maze

A group of novel neuroleptics (e.g. olanzapine, seroquel, sertindole and ziprasidone) and already marketed compounds (e.g. clozapine, haloperidol and risperidone) were tested for acute effect on spatial learning and memory in Morris' water maze task. Young rats were trained for 4 consecutive days (three trials/day) to find a platform situated beneath the water surface. Two compounds, sertindole and seroquel, were without effect on spatial performance, whereas clozapine impaired performance on the first 2 test days but showed no effect compared to the controls on the last 2 test days. Ziprasidone and olanzapine markedly impaired spatial memory without affecting motor function (measured by the swimming speed). Risperidone and haloperidol also impaired performance but in addition both compounds significantly lowered the swimming speed. The present study indicates that several of the compounds impair spatial learning in Morris water maze. This might be of clinical importance in the treatment of schizophrenics, as many of these patients already show severe cognitive deficits. Therefore, certain antipsychotics could worsen the preexisting memory deficits in schizophrenic patients and this aspect should be considered before antipsychotic treatment.     

Cocaine self-administration improves performance in a highly demanding water maze task

Rationale Long-term potentiation (LTP) is considered to be a cellular substrate of learning and memory. Indeed, the involvement of LTP-like mechanisms in spatial learning has consistently been demonstrated in the Morris water maze test. We have previously shown that hippocampal LTP in Lewis rats was modulated by cocaine self-administration, although the performance of cocaine-self-administered rats in the Morris water maze was not altered. Objective Given that the ease of the task previously used could have masked any possible effects of the cocaine-induced LTP enhancement on spatial learning, a new and more difficult water maze task was devised to address this issue. Materials and methods Animals self-administered cocaine (1 mg/kg) or saline under a fixed ratio 1 schedule of reinforcement for 22 days. Spatial learning was assessed in a difficult water maze task (four sessions, two trials per session with a 90-min intertrial interval), and spatial memory was also evaluated 48 h after training (a 90-s test). Additionally, reversal learning and perseverance were also studied. Results There was a reduced latency in finding the hidden platform during training, as well as improved memory of the platform location in cocaine-self-administered rats with respect to animals that self-administered saline. No differences were observed in reversal learning or perseverance between groups. Conclusions Our data suggest that cocaine self-administration facilitates learning and memory in the water maze test only when animals are submitted to highly demanding tasks, involving working memory or consolidation-like processes during the intertrial interval. Del Olmo and Higuera-Matas contributed equally to this work.     

Activation of hippocampal nitric oxide and calcium/calmodulin-dependent protein kinase II in response to Morris water maze learning in rats

This study investigates the interactive roles of nitric oxide (NO) and CaM-kinase II (calcium/calmodulin-dependent protein kinase II) in Morris water maze learning. In Experiment I, experimental rats received 5 days of training on a Morris water maze, where the controls were trained in the water maze with no spatial cue condition or were trained via a visually guided landmark condition. The experimental rats showed improvement in their rate of spatial learning in the water maze. The escape latencies were significantly correlated with the Ca2+-independent activity of the hippocampal CaM-kinase II. Moreover, there was a significant increase in the endogenous phosphorylation of neuronal NOS and CaM-kinase II in the experimental group when compared to the controls. The intra-hippocampal infusion of 7-NI, KN-93, or AP5 did disrupt water maze learning. SDS-PAGE analysis showed that these drugs significantly depressed phosphorylation of hippocampal NOS. The Ca2+-independent activity of hippocampal CaM-kinase II was significantly lower in the KN-93 or the AP5 infused group when compared to the controls. Although these depressed activities were not reversed by the infusion of NO donor (sodium nitroprusside, SNP), the rats' water maze learning behavior were ameliorated significantly. These results, taken together, indicate that the NOS activation is essential for water maze learning, which may be triggered via the CaM-kinase II activation in hippocampus.     

Effects of olanzapine, sertindole and clozapine on learning and memory in the Morris water maze test in naive and MK-801-treated mice

Cognitive dysfunction in schizophrenia is associated with functional disease symptoms. The beneficial effects of second generation antipsychotic drugs on cognitive function in schizophrenic patients are controversial. In this study, we investigated the effects of the second generation antipsychotics olanzapine, sertindole and clozapine on cognitive function in the Morris water maze task in naive or MK-801-treated animals. Male balb-c mice were treated subchronically with olanzapine (1.25, 2.5 and 5 mg/kg, i.p.), sertindole (0.63, 1.3, 2.5 mg/kg, s.c.) or clozapine (0.5 and 1 mg/kg, i.p.), and cognitive deficits were induced by MK-801 (0.2 mg/kg, i.p.) administration. Water maze performance was expressed as escape latency to find the hidden platform, the time spent in target quadrant, the mean distance to platform and the swim speed. In naive mice olanzapine impaired water maze performance, whereas sertindole and clozapine had no effect while the MK-801-induced cognitive impairment was reversed by the second generation antipsychotics — olanzapine, sertindole and clozapine at the doses used. These results revealed that while olanzapine had some disturbing effects on cognitive functions in naive animals; olanzapine, sertindole and clozapine might improve cognitive deficits in schizophrenic patients.     

Effects of oral BMY 21502 on Morris water task performance in 16–18 month old F-344 rats

In the present study we have examined the effects of oral administration of BMY 21502, a potential cognition enhancing drug, on the impaired Morris water task performance of 16–18 month old F-344 rats. BMY 21502 did not affect swim speeds or performance on the first trial of each day, but it did increase the rate of acquisition and initial retention, resulting in decreased swim distances on the second trial of each day. This increased rate of acquisition was dose-dependent, increasing to a peak at 5.0 mg/kg; the effect was decreased at 10 mg/kg, but still above control values. These results suggest that BMY 21502 is orally active over a broad range of doses, and lend further support for its potential as a therapeutic agent for the treatment of dementia.     

The effects of eticlopride on Morris water task performance in male and female rats neonatally treated with quinpirole

Rationale Previous studies have shown that neonatal quinpirole treatment which results in long-term dopamine D2 receptor supersensitization (D2 receptor priming) produces cognitive deficits in preweanling and adult rats behaviorally tested on the Morris water task (MWT).Objective This study was designed to analyze whether pretraining administration of the D2 antagonist eticlopride alleviates cognitive deficits produced by neonatal quinpirole treatment.Methods Both male and female Sprague–Dawley rats were treated with quinpirole HCl (1 mg/kg) or saline from postnatal days 1 to 21. From P22 to P24, rats were tested on the place version of the MWT in which a hidden platform remains stationary throughout training. From P25 to P28, rats were tested on the match-to-place version of the MWT, and rats are given a pair of daily training trials to locate the hidden platform that was moved to a new location each day. Fifteen minutes before each training session, rats were intraperitoneally administered with eticlopride (0.01 or 0.02 mg/kg) or saline.Results Pretraining eticlopride treatment alleviated cognitive deficits produced by neonatal quinpirole treatment in both male and female rats on the place version of the MWT, as well as in males tested on the match-to-place version of the MWT. However, there were no significant deficits produced by neonatal quinpirole treatment in females tested on the match-to-place version of the MWT, and control males demonstrated superiority over control females on this version of the task.Conclusions Pretraining administration of the dopamine D2 antagonist eticlopride alleviated cognitive deficits produced by neonatal quinpirole treatment. However, it appears that the dopamine D2 receptor may have a more important influence on cognitive performance in males than in females, which may be related to increased sensitivity of the D2 receptor in males.     

Effects of CRF<Subscript>1</Subscript> receptor antagonists and benzodiazepines in the Morris water maze and delayed non-matching to position tests

Rationale Benzodiazepines continue to be widely used for the treatment of anxiety, but it is well known that benzodiazepines have undesirable side effects, including sedation, ataxia, cognitive deficits and the risk of addiction and abuse. CRF₁ receptor antagonists are being developed as potential novel anxiolytics, but while CRF₁ receptor antagonists seem to have a better side-effect profile than benzodiazepines with respect to sedation and ataxia, the effects of CRF₁ receptor antagonists on cognitive function have not been well characterized. It is somewhat surprising that the potential cognitive effects of CRF₁ receptor antagonists have not been more fully characterized since there is some evidence to suggest that these compounds may impair cognitive function.Objective The Morris water maze and the delayed non-matching to position test are sensitive tests of a range of cognitive functions, including spatial learning, attention and short-term memory, so the objective of the present experiments was to assess the effects of benzodiazepines and CRF₁ receptor antagonists in these tests.Results The benzodiazepines chlordiazepoxide and alprazolam disrupted performance in the Morris water maze and delayed non-matching to position at doses close to their therapeutic, anxiolytic doses. In contrast, the CRF₁ receptor antagonists DMP-904 and DMP-696 produced little or no impairment in the Morris water maze or delayed non-matching to position test even at doses 10-fold higher than were necessary to produce anxiolytic effects.Conclusions The results of the present experiments suggest that, with respect to their effects on cognitive functions, CRF₁ receptor antagonists seem to have a wider therapeutic index than benzodiazepines.     

Comparative studies using the Morris water maze to assess spatial memory deficits in two transgenic mouse models of Alzheimer's disease

Evaluation of the efficacy of novel therapeutics for potential treatment of Alzheimer's disease (AD) requires an animal model that develops age‐related cognitive deficits reproducibly between independent groups of investigators. Herein we assessed comparative temporal changes in spatial memory function in two commercially available transgenic mouse models of AD using the Morris water maze (MWM), incorporating both visible and hidden platform training. Individual cohorts of cDNA‐based ‘line 85’‐derived double‐transgenic mice coexpressing the ‘Swedish’ mutation of amyloid precursor protein (APPSwe) and the presenillin 1 (PS1) ‘dE9’ mutation were assessed in the MWM at mean ages of 3.6, 9.3 and 14.8 months. We found significant deficits in spatial memory retention in APPSwe/PS1dE9 mice aged 3.6 months and robust deficits in spatial memory acquisition and retention in APPSwe/PS1dE9 mice aged 9.3 months, with a further significant decline by age 14.8 months. β‐Amyloid deposits were present in brain sections by 7.25 months of age. In contrast, MWM studies with individual cohorts (aged 4–21 months) of single‐transgenic genomic‐based APPSwe mice expressing APPSwe on a yeast artificial chromosomal (YAC) construct showed no significant deficits in spatial memory acquisition until 21 months of age. There were no significant deficits in spatial memory retention up to 21 months of age and β‐amyloid deposits were not present in brain sections up to 24 months of age. These data, generated using comprehensive study designs, show that APPSwe/PS1dE9 but not APPSwe YAC mice appear to provide a suitably robust model of AD for efficacy assessment of novel AD treatments in development.     

Pharmacological dissociation between the spatial learning deficits produced by morphine and diazepam

This study sought to determine whether the place learning deficits produced by diazepam are a secondary result of opioid release. Rats pretreated with diazepam (3 mg/kg) or morphine (15 mg/kg) were trained in the Morris water maze. Diazepam impaired place learning-slowing acquisition and preventing the formation of a quadrant preference. Morphine also slowed acquisition, but did not prevent place learning, and impaired escape to a visible platform. Flumazenil blocked the deficits produced by diazepam, but not morphine. Naloxone (2 mg/kg) blocked the deficits produced by morphine, but not diazepam. A high dose of naloxone (10 mg/kg) slowed acquisition, and exacerbated the deficit produced by diazepam. These results demonstrate that diazepam interferes with mnemonic processes through endogenous benzodiazepine receptors, independently of opioidergic systems. Further, they suggest that morphine interferes with motivational processes through opioidergic systems, independently of endogenous benzodiazepine systems.     

Clonidine induced sedation is not altered by repeated stress in the RHA/iop and RLA/iop strains of rats

An hypothesis that repeated stress results in central changes in ₂-adrenoceptor sensitivity was investigated using a behavioural test. Stressed (immobilisation for 2 h/day for 7 days) and unstressed rats from the RHA/iop and RLA/iop strains were tested for the sedative effects of the ₂-adrenoceptor agonist clonidine on Y-maze behaviour. The measures used were number of lines crossed, arm entries and rearing. The stressed animals showed higher scores for line crossings and rearing; but the only significant difference between the strains was for rearing, which was higher for RHA/iop. Clonidine significantly depressed all the measures of activity. However, there was no evidence of an interaction of the drug with stress for any of the measures. It is concluded that neither repeated stress nor genetic differences in the ability to cope with stress influence the behavioural effects of clonidine. This suggests that stress responses are not related to the central ₂-adrenoceptor system.