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.     

Scopolamine does not disrupt spatial working memory in rats

The importance of cholinergic systems for spatial working memory was examined by injecting scopolamine at varying times during a 5 hr-long retention interval imposed between the rat's fourth and fifth choices in an 8 arm maze. Regardless of whether or not the testing procedure required the rats to adopt a spatial solution for the task, scopolamine (1.0–5.0 mg/kg) did not impair retention in a manner that was suggestive of an effect on working memory. Modest deficits observed in some conditions appeared to result from drug effects on performance. Previous findings of impaired acquisition of accurate spatial behavior by scopolamine-treated rats evidently reflect an influence of the drug on physiological systems other than those necessary to maintain working memory for spatial information.     

Neuropeptide substance P improves water maze performance in aged rats

The effects of the peripherally administered neuropeptide substance P (SP) on spatial learning capacities were investigated in 27-month-old rats using a water-maze task. Old rats were injected intraperitoneally once daily for 6 days with 50 or 250 µg/kg SP or vehicle 30 min prior to acquisition trials. Improvement in maze performance was observed following injections of 250 µg/kg SP only. Furthermore, vehicle-treated old rats showed significantly poorer acquisition rates than vehicle-treated 12-week-old rats. Thus, the improvement in performance after the 250 µg/kg dose of SP can be interpreted in terms of a compensation of performance deficit in the old rats.     

Physostigmine improves water maze performance following nucleus basalis magnocellularis lesions in rats

Bilateral excitotoxic lesions of the nucleus basalis magnocellularis in rats were used along with testing in the water maze task to assess whether inhibition of acetylcholinesterase with physostigmine would reverse the lesion-induced impairment. Rats were lesioned bilaterally in stages using ibotenic acid and then behaviorally tested 3 weeks after surgery. Lesioned animals were administered one of three doses of physostigmine (0.06, 0.19, or 0.32 mg/kg) or vehicle solution 15 min prior to water maze testing. Sham lesioned animals injected with vehicle solution served as an untreated control group. Animals were tested for 5 consecutive days followed by 2 days off and then tested for 5 additional days. The rats were then sacrificed and their frontal cortex was assayed for choline acetyltransferase. The nucleus basalis magnocellularis lesion caused approximately a 27% depletion of choline acetyltransferase in the frontal cortex of these animals. The lesion also impaired the performance of the rats given vehicle solution as compared to untreated controls. Two doses (0.06 and 0.19 mg/kg) of physostigmine improved performance relative to lesioned controls. The lower dose, 0.06 mg/kg, improved performance more than the 0.19 mg/kg dose of physostigmine. The highest dose of physostigmine impaired water maze performance relative to lesioned controls. These data are discussed in relation to the cholinergic hypothesis of Alzheimer's disease and the potential therapeutic use of physostigmine.     

Hippocampal endocannabinoids inhibit spatial learning and limit spatial memory in rats

Rationale

As exogenous cannabinoid agonists impair memory formation, could it be that antagonists have opposing effects and act as memory-enhancing drugs?

Objectives

Here, we studied the effects of the cannabinoid antagonist SR141716A (SR; Rimonabant) on spatial learning and memory formation and assessed the possible involvement of hippocampal CB₁ receptor in these actions.

Materials and methods

In the water maze, spatial reference memory was probed using different training protocols followed by assessment of behavioral flexibility. The CB₁ receptor antagonist SR (3 mg/kg) was intraperitoneally administered before or immediately after training in experiment 1, or via minipumps intrahippocampally (0.89 ng and 0.089 ng/day) either during or after spatial learning, or subcutaneously in experiment 2.

Results

In experiment 1, systemic SR impaired spatial learning when given intraperitoneally (ip) before training coincident with increasing swim speed and thigmotaxis. Pretraining before drug treatment eliminated these effects while post-training injections had no effect. In experiment 2, intrahippocampal infusion of 0.089 ng SR during training enhanced acquisition learning, but did not affect long-term consolidation of spatial memory. In contrast, subcutaneous infusion of SR via minipumps had no effect. Post-training infusion of SR did not affect reversal learning, but short-term memory (1 h post-training) was weaker, and long-term memory for the reversal platform location was enhanced.

Conclusions

Systemic Rimonabant-induced deficits are due to anxiogenic properties of the drug. The difference between administration regimes is discussed in terms of CB₁ receptor blockade in multiple non-memory and memory-related brain regions and the possibility that selective inactivation of hippocampal CB₁ receptors may be memory enhancing.

     

Repeated methamphetamine treatment impairs spatial working memory in rats: reversal by clozapine but not haloperidol

Rationale Although chronic use of methamphetamine (METH) leads to long-lasting cognitive dysfunction in humans, there are few reports about an animal model that reflects METH-induced impairment of working memory. Objectives In this study, we investigated the effect of repeated METH treatment on spatial working memory in rats. Materials and methods Rats were repeatedly administered METH (2 mg/kg) once a day for 7 days, and their memory function was assessed with a delayed spatial win-shift task in a radial arm maze. The task consisted of two phases, a training phase and a test phase, separated by a delay. Results METH-treated animals showed an impairment of performance in the test phase when the delay time was increased from 5 to 30 min or longer. The effect of METH persisted for at least 14 days after the drug withdrawal. METH-induced impairment of working memory was reversed by clozapine (3 and 10 mg/kg, for 7 days), but not haloperidol (1 and 2 mg/kg, for 7 days). The improving effect of clozapine diminished 7 days after the withdrawal. Phosphorylated extracellular signal-regulated kinase1/2 (ERK1/2) levels were significantly increased in the hippocampus of saline-treated control rats from 5 to 60 min after the training phase. In contrast, hyperphosphorylation of ERK1/2 was abolished in the hippocampus of rats treated with METH. Conclusions These findings suggest that repeated METH treatment induces impairment of working memory, which is associated with a dysfunctional ERK1/2 pathway in the hippocampus. Furthermore, clozapine may be effective for the treatment of METH-induced cognitive dysfunction. Taku Nagai and Kazuhiro Takuma contributed equally to the work.     

Propranolol blocks chronic risperidone treatment-induced enhancement of spatial working memory performance of rats in a delayed matching-to-place water maze task

Rationale Atypical antipsychotics improve cognitive function, including working memory, in schizophrenia. Some atypical antipsychotics have been reported to activate the locus coeruleus and induce beta-adrenoceptor antagonist sensitive c-Fos-like immunoreactivity in the prefrontal cortex. Materials and methods The present study investigated the effects of chronic treatment of rats with risperidone (1 mg kg⁻¹ day⁻¹ s.c.), clozapine (10 mg kg⁻¹ day⁻¹ s.c.), or acidified saline vehicle control for 2, 4, or 8 weeks on spatial working memory performance in a delayed matching-to-place water maze task with a 60-s inter-trial retention interval with and without acute challenge with propranolol (10 mg/kg i.p.). Results Treatment with risperidone for 8 weeks, but not 2 or 4 weeks, significantly improved working memory performance. In contrast, treatment with clozapine for up to 8 weeks did not improve working memory. Acute challenge with propranolol blocked the improvement in working memory produced by chronic treatment with risperidone, but had no significant effect on performance in saline- or clozapine-treated animals. Conclusions The delayed matching-to-place water maze task may prove valuable in the investigation of the behavioural pharmacology of the cognitive effects of antipsychotic drugs. These data suggest that beta adrenoceptors may contribute to the cognitive effects of chronic treatment with atypical antipsychotics.     

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.     

Long-term neurotoxicity of chlorpyrifos: spatial learning impairment on repeated acquisition in a water maze.

Organophosphate compounds are cholinesterase inhibitors widely used in agriculture, industry, household products, and even as chemical weapons. Their major mechanism of acute toxic action is the inhibition of acetylcholinesterase, which is responsible for the degradation of the neurotransmitter acetylcholine. An organophosphorus ester-induced chronic neurotoxicity (OPICN) syndrome has been proposed. The OPICN syndrome could result from both long-term exposure to subclinical doses of OPs and after acute poisoning. Development of animal models for the cognitive decline are required and could later help to elucidate the mechanisms involved in this long-term effect on the central nervous system. Previously, we have found performance decrements in a four-trial repeated acquisition spatial task in a water maze. The present study includes two experiments to extend the long-term behavioral effects observed. Rats were injected either once or twice with chlorpyrifos (CPF) and then tested months after in a two-trial repeated acquisition task in a water maze. Our results confirm and extend the long-term behavioral effects of subcutaneous administration of CPF. The two treatments used produced performance decrements that suggest functional central nervous system alterations.     

A high fructose diet does not affect amphetamine self-administration or spatial water maze learning and memory in female rats

High energy diets can have a detrimental effect on brain plasticity. For example, a high fructose diet impairs spatial memory in male rats. The aim of the present study was to determine whether a high fructose diet impairs another form of learning and memory: drug reinforcement learning. Female Sprague-Dawley rats were fed a high fructose diet (60%) from weaning at postnatal day (PND) 21, then allowed to acquire lever-pressing maintained by intravenous (i.v.) amphetamine at PND 68, 109, or 165. Acquisition was tested on a fixed ratio one (FR1) schedule of reinforcement (0.025 mg/kg/infusion, 1 h daily sessions, 10 sessions over 14 days), followed by testing for reinforcing efficacy on a progressive ratio (PR) schedule (0.025, 0.01, and 0.1 mg/kg/infusion), 14 days of abstinence, and within-session extinction and reinstatement tests. Subsequently, water maze acquisition and retention were tested in these subjects as well as a separate cohort tested in the water maze only. The diet had no effect on acquisition, reinforcing efficacy, extinction, or reinstatement of amphetamine seeking. Nor did the diet alter any measures of spatial memory. The high fructose diet did decrease body mass and increase relative liver and spleen mass, but did not affect plasma triglyceride concentrations consistently. Together with prior research on males, these results suggest that the metabolism of fructose and the effects of a high fructose diet on learning and memory may be sex-dependent.     

Phencyclidine injections into the dorsal hippocampus disrupt long- but not short-term memory within a spatial learning task

Since the hippocampus is likely to be a major site of phencyclidine (PCP) action, the effects of various doses of PCP (1.8, 18 or 36 nM) as well as 3.6 nM MK-801 or saline injected directly into the dentate gyrus of the hippocampus was tested for acquisition of a spatial navigation task (dry land version of a water maze) using a paradigm that assesses short term memory based on learning within a day and long term memory based on learning between days. Results indicated that relative to saline or 1.8 nM PCP injected rats, rats with 18 or 36 nM PCP or 3.6 nM MK-801 injections were impaired in acquisition of the task as measured by increased distances traveled to find the food location between days but not within days. In additional experiments 36 nM PCP or 3.6 nM MK-801 did not produce any deficits in the acquisition of an object discrimination task. It is suggested that PCP through its blocking action of the NMDA receptor in the dentate gyrus or CA1 region of the dorsal hippocampus mediates the consolidation of new spatial location information.     

Stimulation of 5-HT1A receptors in the dorsal raphe ameliorates the impairment of spatial learning caused by intrahippocampal 7-chloro-kynurenic acid in naive and pretrained rats

OBJECTIVE: The present study investigated the effect of stimulating 5-HT(1A) receptors in the dorsal raphe on the impairment of spatial learning caused by intrahippocampal 7-chloro-kynurenic acid (7-Cl-Kyn) in naive rats and in rats familiar with the general requirements of the task. METHODS: A week after implantation of cannulae to give access to the dorsal raphe (DR) and the CA1 region of the dorsal hippocampus, rats started their 5 days acquisition training on a two-platform spatial discrimination task in a water maze. On each acquisition day, WAY 100635 and 8-OH-DPAT alone or in combination were injected into the dorsal raphe (DR) 5 min before intrahippocampal injections of 7-Cl-Kyn which was given 10 min before the training session. Similar experiments were conducted in rats that had been familiarized with the general requirements of the task by pretraining them in the water maze in the absence of distal cues. RESULTS: 7-Cl-Kyn (3 microg/microl), injected bilaterally in the CA1 region of the dorsal hippocampus, impaired choice accuracy with no significant effect on choice latency. Rats treated with 7-Cl-Kyn tended to spend more time swimming close to the pool walls and made more errors of omission than controls in the first two sessions. Administered into the DR, the 5-HT1A receptor agonist 8-OH-DPAT (1 microg/0.5 microl) had no effect on any parameter of rats' performance but antagonized the impairment of choice accuracy caused by intrahippocampal 7-Cl-Kyn. Injected into the DR, 1 microg/0.5 microl WAY 100635, a 5-HT(1A) receptor antagonist, had no effect on rats' performance or on the impairment caused by intrahippocampal 7-Cl-Kyn, but antagonized the effect of 8-OH-DPAT on the 7-Cl-Kyn-induced deficit. The non-mnemonic behavioral disturbances shown by naive rats treated with 7-Cl-Kyn were greatly reduced in pretrained rats which, nevertheless, showed a marked impairment of choice accuracy similar to that of naive rats. As in previous experiments, administration of 1 microg/0.5 microl 8-OH-DPAT in the dorsal raphe antagonized the impairment of choice accuracy caused by intrahippocampal 7-Cl-Kyn without any effect on other parameters of rats' performance. CONCLUSIONS: The results show that stimulation of presynaptic 5-HT(1A) receptors in the dorsal raphe counteracts the deficit in spatial learning caused by a reduced NMDA-mediated excitatory input on pyramidal cells in the hippocampus. The possible mechanisms and the importance of these findings for the symptomatic treatment of memory disorders in man are discussed.     

Paternal alcohol consumption in the rat impairs spatial learning performance in male offspring

Pubescent (30 day old) male rats were maintained on an alcohol liquid diet containing 35% ethanol-derived calories (ALC) for 39 days or were pairfed an isocaloric control diet (PF). The concentration of alcohol in the diet was gradually increased to permit adaptation, then stabilized and then gradually tapered to prevent an alcohol withdrawal syndrome. Following a drug-free period (2 weeks), the males were mated with nontreated females. Offspring were evaluated on several developmental indices and on various learning/memory tasks to assess functional deficits in adulthood. Offspring sired by ALC-treated males did not differ from the offspring of PF males on several developmental parameters including body weights, when developmental landmarks appeared, or on tests of sensorimotor development. As adults, male offspring groups did not differ on tests of activity or on an object exploration/recognition task. However, male offspring of ALC-treated males demonstrated impaired acquisition performance (days and errors to criterion) on a win-shift spatial discrimination in an eight-arm radial maze and on a win-stay discrimination (days to criterion) conducted in a T-maze at a later age. The radial maze results were replicated in a subsequent experiment using different groups of rats.     

Gestational-lactational exposure to Aroclor 1254 impairs radial-arm maze performance in male rats.

Developmental exposure to polychlorinated biphenyls (PCBs) has been associated with cognitive deficits in children. The current study assessed effects of gestational and lactational exposure to a commercial PCB mixture, Aroclor 1254 (A1254), on spatial learning and memory in rats, using the radial-arm maze (RAM). Pregnant Long-Evans females (10/dose group) were exposed to 0 or 6-mg/kg/day A1254 (po in corn oil) from gestation day (GD) 6 to weaning at postnatal day (PND) 21. After they reached adulthood, 1 male and 1 female from each litter were tested on a working/reference memory task using a 12-arm RAM. Eight of the 12 arms were baited, with the pattern of baited arms remaining the same on every trial for each rat. Compared to control males, the A1254-exposed males made significantly more working memory errors (2.15 +/- 0.13 and 3.20 +/- 0.18 errors +/- SEM for control and A1254 males, respectively) and reference memory errors (3.17 +/- 0.10 and 4.13+/-0.14 errors +/- SEM for control and A1254 males, respectively) on the RAM. In contrast, A1254-exposed females were not impaired relative to control females on the RAM. Drug challenges with dizocilpine (MK-801) and scopolamine did not differentially affect working or reference memory of control and exposed rats. These data suggest that perinatal exposure to A1254 may cause sex-specific deficits in spatial learning and memory, and that NMDA-mediated and muscarinic neurotransmission, as assessed with the drug challenges, were not markedly impaired in the A1254-exposed animals.     

Biphasic effect of citral, a flavoring and scenting agent, on spatial learning and memory in rats

Although some central effects of citral have been reported, cognitive effects on spatial memory have not been investigated. The evidence showed that citral can regulate the synthesis of retinoic acid (RA), which exerts a vital function in the development and maintenance of spatial memory. In this study, we applied Morris water maze to test the effect of citral on animals' spatial learning and memory. To elucidate the mechanism of this effect, we also measured the retinoic acid concentration in rats' hippocampus by high performance liquid chromatography (HPLC). Our data implied biphasic effects of citral. The low dose (0.1 mg/kg) of citral improved the spatial learning capability, and enhanced the spatial reference memory of rats, whereas the high dose (1.0 mg/kg) was like to produce the opposite effects. Meanwhile, the low dose of citral increased the hippocampal retinoic acid concentration, while the high dose decreased it. Due to the quick elimination and non-bioaccumulation in the body, effects of citral on spatial memory in this study seemed to be indirect actions. The change in hippocampal retinoic acid concentration induced by different doses of citral might be responsible for the biphasic effect of citral on spatial learning and memory.     

丙泊酚对大鼠空间学习记忆能力影响的实验研究

目的研究丙泊酚对于大鼠空间学习记忆能力的影响。方法给予大鼠丙泊酚(10、30和75mg·kg-1)腹腔注射,给予脂肪乳腹腔注射作为对照,然后应用Morris水迷宫评价其对于大鼠空间学习记忆的影响。结果30和75mg·kg-1的丙泊酚腹腔注射可以损害大鼠的空间学习记忆能力,而10mg·kg-1的丙泊酚腹腔注射不影响大鼠的空间学习记忆能力。结论多次给大鼠腹腔注射丙泊酚重复实施麻醉或镇静可以损害其空间学习记忆能力。     

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.     

Premature decline in morris water maze performance of aging micrencephalic rats

The rat with methylazoxymethanol-induced micrencephaly is a useful animal model of congenital brain defects and associated cognitive impairment. Born with profound morphological and neurochemical alterations in the forebrain, it shows impaired ability to learn mazes. In order to determine how an animal with such a developmentally damaged brain would function in old age, Long-Evans rats 6, 15, and 24 months of age were tested for their ability to learn to locate a hidden platform in the Morris water maze. The performance of micrencephalic rats of all ages was impaired on acquisition, retention, and transfer trials. Moreover, the magnitude of their acquisition deficit increased with age. It remains to be determined whether the premature decline of the micrencephalic rat in learning the task simply reflects a greater impact on an already compromised brain by neuron loss characteristic of aging brains or whether the prenatal insult alters some basic processes resulting in premature aging.     

5-HT6 receptor antagonists enhance retention of a water maze task in the rat

RATIONALE: 5-HT(6) receptors are predominantly located in the brain and may be involved in cognitive processes. The aim of this study was to assess the effects of two potent and selective 5-HT(6) receptor antagonists, SB-271046-A and SB-357134-A, on learning and memory in the rat. METHODS: Spatial learning and memory was assessed by testing the effects of SB-271046-A and SB-357134-A on acquisition and retention of a water maze task. RESULTS: In the water maze, administration of SB-271046-A or SB-357134-A (3 or 10 mg/kg) had no effect on learning per se. At 10 mg/kg, however, both compounds produced a significant improvement in retention of a previously learned platform position when tested 7 days after training. By contrast, the acetylcholinesterase inhibitor, Aricept (donepezil, 0.1, 0.3 mg/kg PO) had no effect in this task. CONCLUSIONS: This study demonstrates that systemic administration of SB-271046-A and SB-357134-A produces improvements in retention of a water maze task in the rat. These data indicate that 5-HT(6) receptor antagonism may be involved in cognitive function.     

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.