Differential effect of antipsychotics on place navigation of rats in the Morris water maze. A comparative study between novel and reference antipsychotics

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.     

A comparison of four corvid species in a working and reference memory task using a radial maze.

Birds were tested in an open-room radial maze with learned spatial locations that varied from trial to trial (working memory) and locations that remained spatially stable (reference memory). Three of the species, the Clark's nutcracker (Nucifraga columbiana), pinyon jay (Gymnorhinus cyanocephalus), and Western scrub jay (Aphelocoma coerulescens) store food to varying degrees. The other species, the Eurasian jackdaw (Corvus monedula) does not. Pinyon jays and scrub jays performed better than the nutcrackers and jackdaws in both working and reference memory components of the maze. The pinyon jay and jackdaw performed as would be expected on the basis of their natural history and previous research, but the scrub jay and nutcracker did not. Results are consistent with phylogenetic relationships among the 4 species, but could also be explained by differences in response strategies or interference in processing both types of memory components of the maze. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Differential ontogeny of working memory and reference memory in the rat.

Examined the ability of 15-, 21-, and 27-day-old rats to perform 2 spatial working memory problems (delayed alternation and discrete-trials delayed alternation) and a reference memory problem (position habit) in a T-maze. In the delayed alternation problem, each S was presented with a series of free-choice trials and was rewarded for regularly alternating responses to the left and right arms of the T-maze. In the discrete-trials delayed alternation problem, each S was forced to one maze arm and rewarded (forced run) and was then placed back into the start box and given a choice of arms (choice run). The direction of forced runs followed an irregular, counterbalanced series, and Ss were rewarded for choosing the alternate maze arm on choice runs. In the position habit problem, Ss were rewarded for consistently choosing 1 of the 2 arms of the T-maze. At all ages, rat pups learned to perform the delayed alternation and position habit problems. Only 21- and 27-day-old rats were able to learn the discrete-trials delayed alternation problem. Results of these experiments show that reference memory capacity is present by at least 15 days of age in the rat and does not develop further at later ages. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Entorhinal-perirhinal lesions impair performance of rats on two versions of place learning in the Morris water maze.

The effects of entorhinal–perirhinal lesions in rats were studied with 2 versions of a place learning task in the Morris water maze. These lesions impaired performance on a multiple-trial task (3 days of 6 trials and a probe trial). This assessment was followed by a task in which rats were repeatedly trained to find novel locations with a variable delay (30 sec or 5 min) imposed between each sample trial and retention test. Entorhinal–perirhinal damage produced a delay-dependent deficit in spatial memory: Rats with lesions were impaired at the 5-min delay relative to the control group and to their own performance at 30 sec. These findings are discussed in relationship to memory impairment after entorhinal damage and spatial learning deficits observed after hippocampal damage. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Fractionating the nonspatial pretraining effect in the water maze task.

Nonspatial pretraining (NSP) enables rats to learn the general strategies of the water maze task (WMIs; e.g., learning to swim away from the wall and to climb onto the hidden platform), reduces sensorimotor disturbances, and eliminates acquisition impairments caused by scopolamine hydrobromide, a muscarinic antagonist. To evaluate the contributions of the components of NSP to these effects, NSP was fractionated so that different groups of male rats swam, were placed onto the hidden platform, climbed onto the hidden platform, or were placed into an empty maze before spatial training under scopolamine. No single component of the NSP procedure was sufficient to produce its full effects on sensorimotor disturbances and WMT acquisition. Experience with most or perhaps all of the specific behaviors required in the WMT appears to be important for NSP to produce its full effects. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Modafinil and memory: Effects of modafinil on Morris water maze learning and Pavlovian fear conditioning.

Modafinil has been shown to promote wakefulness and some studies suggest the drug can improve cognitive function. Because of many similarities, the mechanism of action may be comparable to classical psychostimulants, although the exact mechanisms of modafinil's actions in wakefulness and cognitive enhancement are unknown. The current study aims to further examine the effects of modafinil as a cognitive enhancer on hippocampus-dependent memory in mice. A high dose of modafinil (75 mg/kg ip) given before training improved acquisition on a Morris water maze. When given only before testing, modafinil did not affect water maze performance. We also examined modafinil (0.075 to 75 mg/kg) on Pavlovian fear conditioning. A low dose of pretraining modafinil (0.75 mg/kg) enhanced memory of contextual fear conditioning (tested off-drug 1 week later) whereas a high dose (75 mg/kg) disrupted memory. Pretraining modafinil did not affect cued conditioning at any dose tested, and immediate posttraining modafinil had no effect on either cued or contextual fear. These results suggest that modafinil's effects of memory are more selective than amphetamine or cocaine and specific to hippocampus-dependent memory. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Hippocampal lesions cause learning deficits in inbred mice in the Morris water maze and conditioned-fear task.

This study examined the effect of hippocampal lesions on acquisition of the Morris water maze and conditioned-fear task in inbred mice. C57BL/6J, DBA/2J, and B6D2F1 hybrid mice were given hippocampal lesions or sham surgery and then tested. The lesioned C57BL/6J and B6D2F1 mice failed to learn the Morris task relative to sham-operated controls, and no DBA group learned the task. In the contextual component of conditioned fear, lesions decreased freezing in all strains. But the lesions only affected freezing to the conditioned stimulus in the DBA/2J and B6D2F1 strains. These data demonstrate that C57BL/6J and B6D2F1 mice use the hippocampus to solve the Morris water maze and conditioned-fear task, and the DBA mice use the hippocampus, to some degree, in the conditioned-fear task. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The effect of excitotoxic lesions centered on the perirhinal cortex in two versions of the radial arm maze task.

Rats with bilateral ibotenic acid lesions centered on the perirhinal cortex and sham-operated controls were tested in 2 versions of a spatially guided radial arm maze task. Lesioned rats made significantly more errors and required more sessions to reach criterion relative to controls in the standard radial maze task. When they were tested in a delayed nonmatch to sample version of this task, lesioned rats made more errors during the predelay phase and at both the 30-s and 10-min delays of the postdelay phase. These findings provide further support for the hypothesis that the role of the perirhinal cortex in object recognition memory may include reference to some spatial aspect of the environment. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Nitric oxide is involved in the formation of learning and memory in rats: studies using passive avoidance response and Morris water maze task

Blood leukocytes of 16 patients with alcoholic liver cirrhosis and 18 healthy controls were induced for interferon (IFN) production by phytohemagglutinin (PHA) and concanavalin A (ConA) in the presence or absence of isoprinosine and levamisole at concentrations of 10 micrograms/ml and 1 ng/ml. This interferon was neutralized in 87-95% by anti-HuIFN-gamma monoclonal antibodies. In the presence of the drugs the IFN-gamma production was enhanced, however, IFN-gamma titers yielded from leukocytes of cirrhotic patients were still below the titers observed in stimulated and unstimulated blood leukocytes of healthy controls. For example, IFN titers induced by PHA in the presence of levamisole (1 ng/ml) in cirrhotic patients were 2.5 times lower (20.2 +/- 11.1 U/ml) in comparison to healthy subjects (50.6 +/- 27.3 U/ml).     

Age-related deficits in mice performing working memory tasks in a water maze.

This study determined whether mice exhibit spatial working memory deficits with increased age. C57BL/6JNia mice of 3 different ages were tested in the Morris water maze with 2 protocols designed to assess immediate and delayed working memory abilities. Young mice required multiple trials in order to show improvements in the working memory task. Deficits in immediate working memory were detected in both 10- and 24- to 26-month-old mice. Reference memory deficits and declines in performance in the delayed working memory task were only seen in 24- to 26-month-olds. This increased susceptibility of immediate working memory processes to the aging process in mice may be related to their need for more rehearsal in the water maze than other species. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Differential effects of cholinergic blockade on performance of rats in the water tank navigation task and in a radial water maze.

Tested the disruptive effect of cholinergic blockade under conditions in which either the working memory or the spatial mapping requirements of the behavioral task were emphasized. In Exp I, 13 male hooded rats were trained in an 8-arm radial water maze to asymptotic performance. When delays of 5, 10, 20, and 40 min were inserted between Choice 4 and Choice 5, incidence of errors in Choices 5–8 increased after pretrial (20 min) intraperitoneal scopolamine (0.2 mg/kg) faster than under control conditions and approached chance level with the 40-min delay. Scopolamine after Choice 4 or pretrial methylscopolamine was ineffective. In Exp II, 30 Ss were trained in a Morris water tank. Acquisition was impaired by pretrial injection (20 min) of 0.1 and 0.2 mg/kg scopolamine, but a higher dose (1.0 mg/kg) was required to impair overtrained performance. In a working memory version of the navigation task, scopolamine administered 20 min before the 1st trial deteriorated retention tested 40 min later at a dose of 1.0 but not at 0.4 and 0.2 mg/kg. It is concluded that the disruptive effect of scopolamine is proportional to the demands on the working memory component of the task, whereas the use of an overtrained mapping strategy is relatively resistant to cholinergic blockade. (35 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Spatial working memory and reference memory of Brown Norway and WAG rats in a holeboard discrimination task

PURPOSE: To investigate the effects of bradykinin (BK) on the outflow facility (C) of human and bovine perfused anterior segments, the [Ca2+]i of cultured bovine trabecular meshwork (BTM) cells, and the area and major axis of BTM cells. METHODS: Cellular studies were performed using first- through third-passage cultures of BTM cells. For [Ca2+]i and shape change assessment, BTM cells were loaded with fura-2 acetoxymethyl ester, and individual fluorescence images were analyzed after the different experimental manipulations. C studies were performed in vitro using human and bovine anterior segments perfused at constant pressure. RESULTS: Bradykinin at 10(-6) M elicited a [Ca2+]i increase of 8 to 10 times the basal levels in 90% of the studied cells. From the responder cells, 60% elicited a 15%+/-1% reduction of the initial cell area, and 37% showed a 13%+/-2% reduction of their major axis. Bradykinin failed to induce any effect in the presence of the BK-B2 receptor antagonist HOE-140. Zero [Ca2+]o the depletion of intracellular stores with thapsigargin, or the presence of the calmodulin antagonist W13, decreased the BK response significantly (P < 0.001; P < 0.001; and P < 0.05). A second application of BK elicited a significantly lower (P < 0.001) response than the previous one. Perfusion with 10(-6) M BK decreased CD, calculated as the area under the curve, by 13%+/-4% (P < 0.05) in human anterior segments and 12%+/-4% (P < 0.05) in bovine anterior segments. The presence of 10(-6) M HOE-140, a BK-B2 receptor antagonist, completely blocked the decrease in C after perfusion with BK. CONCLUSIONS: The C of human and bovine trabecular meshwork (perfused anterior segments) is decreased by BK, acting through BK-B2 receptors. Primary cultured BTM cells respond to BK stimulation by increasing their [Ca2+]i by mobilization of extracellular and intracellular Ca2+. Moreover, these cells are reduced in area and their major axis shortened after the [Ca2+]i peak elicited by BK through BK-B2 receptors. The [Ca2+]i mobilization and shape changes are calmodulin dependent. Taking into account the [Ca2+]i mobilization, the BTM shape changes, the decrease of C, and the temporal sequence of these parameters, a contraction of trabecular meshwork cells related to the functional role of trabecular meshwork is discussed.     

Aging and atropine effects on spatial navigation in the Morris water task.

A recent animal model that has been particularly useful in the neurobiology of aging has been the age-related decline of spatial information processing capacity in Sprague-Dawley rats measured in the place-learning water task developed by Morris (1981). In the first experiment of the present study, place behavior was examined in young (6 months), old (23–24 months), and very old (28 months) rats of another strain, Long-Evans. As an analogue of aging-related cholinergic dysfunction the effects of atropine sulfate (5–50 mg/kg), an anticholinergic drug that is known to disrupt behavior in this task, also was determined. Place navigation was not impaired in undrugged rats, even those in the oldest age group. Rats treated with atropine showed dose-dependent deficits. In a second experiment, young (4–5 months), old (18–20 months), and very old (28 months) Fischer-344 rats were examined. Place navigation was impaired in the old rats. The very old (28 months) rats could not swim well enough to be tested adequately. Although nonspatial deficits associated with aging may be found across most strains tested, there appear to be very large strain-related differences in spatial processing ability as a function of age. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Preweanling rats solve the Morris water task via directional navigation.

Adult rats show a preference for directional navigation over place navigation in the Morris water task. Here, the authors investigated whether preweanling rats with a newly developed ability to perform the water task also solve the task via directional navigation. After 24-day-old rats were trained to find a hidden platform in a fixed spatial location, a no-platform probe trial was conducted with the pool either in the same position as that used during training (no shift group) or shifted to a new position in the room (shift group). The authors found that rats in the shift group did not search for the platform at its absolute spatial location but rather navigated in the same direction that the platform was located during training and searched at the correct distance from the pool wall, resulting in a search at a location that was never trained. This pattern of results suggests that young rats learn to solve the water task by navigating in a particular direction rather than navigating to a precise place--a finding that may have implications for understanding hippocampal development. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Differential effects of selective immunotoxic lesions of medial septal cholinergic cells on spatial working and reference memory.

The effect of injection into the medial septum of a toxin selective for cholinergic neurons, 192 IgG-saporin, was examined in rats trained to perform 2 versions of the radial 8-arm maze task. Rats were first trained to perform a task with varying delays (0, 1, 2 min) imposed between the 4th correct arm choice and access to all 8 arms. Lesioned rats made significantly more errors in the first 4 choices compared with controls and significantly more errors after delays; however, this effect was not delay dependent. Rats were then trained on a different version of this 8-arm maze task in which they learned to avoid 2 arms that were never baited. There was no treatment effect on acquisition of this task. These data are consistent with the hypothesis that the cholinergic projection to the hippocampus facilitates the acquisition of information into the system responsible for short-term memory for locations visited (spatial working memory) but is not involved in retention of this information. It also appears to play no role in either the acquisition or retention of place-nonreward associations (spatial reference memory). (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of haloperidol and d-amphetamine on working and reference memory performance in a spatial cone field task

The present study was designed to examine the effects of haloperidol (0.03, 0.1 mg/kg, intraperitoneal (i.p.)) and d-amphetamine (0.3, 1.0 mg/kg, i.p.) in a cone field task in which spatial working and reference memory (WM and RM, respectively) were assessed simultaneously. The apparatus is a large open field in which 16 cones are placed with four cones baited by placing a food reward in the top. After food-deprived rats had acquired this task they showed a high level of performance, that is avoided visits to non-baited cones (RM) and made few revisits to baited cones (WM). Haloperidol had a greater negative effect on RM than on WM performance, but also decreased the number of food rewards collected. On the other hand, the high dose of d-amphetamine induced a clear WM performance deficit, whereas RM performance was only marginally affected. The present study suggests that spatial discrimination performance can be dissociated using the measures RM and WM in the present task. Further, the deficits induced by haloperidol and d-amphetamine may not be specifically related with impaired mnemonic functions.     

The relative influence of place and direction in the Morris water task.

Previous work from our laboratory has demonstrated that rats display a preference for directional responding over true place navigation in the Morris water task. The present study evaluated the range of situations in which this preference is observed and attempted to identify methods that favor navigation to the precise location of the escape platform in the room. A preference for directional responding over place navigation was observed in a wide range of procedures that included providing extensive training (Experiment 1), providing only platform placement experience in the absence of active swim training (Experiment 2), training navigation to multiple platform locations in a moving platform variant of the task (Experiment 3), and explicitly training navigation to a precise location in the room, versus navigation in a particular direction, regardless of the pool's position in the room (Experiments 4-5). A modest preference for navigation to the precise spatial location of the platform was observed when the pool wall was virtually eliminated as a source of control by filling it to the top with water (Experiment 6). (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Relation of spatial learning of rats in the Morris water maze task to the number of viable CA1 neurons following four-vessel occlusion.

Male Wistar rats were tested in the Morris water maze task 1 wk after 6, 9, or 12 min of transient global ischemia. The 9-min and 12-min ischemia groups were significantly impaired in the acquisition and the reversal experiment. A systematic counting of CA1 neurons in the whole hippocampal formation revealed a unilateral number of CA1 neurons of 286,000 in the sham group, of which two-thirds were located in the dorsal hippocampus. The ischemia groups showed a significant decline in the number of dorsal CA1 neurons, whereas only the 12-min ischemia group showed a significant but minor decline (10–25%) in the number of ventral CA1 neurons. A correlation analysis showed that the escape distance declined with increasing number of viable CA1 neurons, but poor correlation coefficients were obtained. Thus, some of the ischemic rats with even very few viable CA1 neurons in the dorsal hippocampus were capable of performing this spatial learning task at sham-group level. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of prenatal exposure to cocaine on Morris water maze performance in adult rats.

The spatial memory of adult rats prenatally exposed to cocaine and that of control offspring was assessed using the Morris water maze. Offspring were derived from Sprague Dawley dams that received subcutaneous injection of 40 mg/kg/3 cc cocaine hydrochloride (C40) daily on gestational Days 8-20, pair-fed dams injected with saline, or nontreated control dams. After acquisition, the platform was moved to a new location (reversal phase). Probe trials were conducted at the end of acquisition and reversal training. On the 1st acquisition day, adult male and female offspring prenatally exposed to cocaine required significantly more time and traversed a greater distance to find the hidden platform than did control offspring. Despite these initial differences observed in C40 offspring performance, all of the rats were performing at equivalent levels at the time probe trials were conducted. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cerebellar contribution to spatial event processing: Morris water maze and T-maze

Recently, a cognitive function of cerebellar networks has been challenging the traditional view of the cerebellum as a motor control centre. Among the cognitive abilities reported to be affected by cerebellar deficits is the capacity to solve a spatial problem. We investigated the influence of a cerebellar lesion on spatial abilities by behavioural analysis of rats that had undergone surgical hemicerebellectomy (HCb; HCbed rats). Experiments were performed with a Morris water maze (MWM) and a water T-maze in both cue and place versions (visible or hidden platform respectively). Results indicate a severe impairment in coping with spatial information in all phases of MWM testing as well as in the T-maze paradigm. However, if the MWM cue phase was prolonged, HCbed rats displayed some ability to learn platform position, although at a level significantly different from controls. They succeeded in finding the platform, even in a pure place paradigm, such as finding a hidden platform with the starting points sequentially changed. Retention testing was also performed, demonstrating that HCb affects acquisition but not retention of spatial information. HCbed animals exhibit such disrupted exploration behaviour that they can display only peripheral circling, and they can acquire spatial relations only when proximal cues are available. Furthermore, in all phases of testing, platform finding for HCbed animals is essentially based on place strategies. Thus, a specific pattern of spatial behaviour, markedly different from that displayed following hippocampal or cortical lesions, characterizes cerebellar lesioned rats. These results are discussed taking into account the role in procedural learning recently assigned to cerebellar networks, demonstrating that the cerebellar circuits represent the keystone of the procedural components of spatial event processing.