Some antiepileptic compounds impair learning by rats in a Morris water maze

In the present experiments, we investigated the effects of several commonly employed antiepileptic drugs on the performance of adult rats in a Morris water maze task. We found that phenytoin treatment produced the most deleterious performance impairments across all days of training, and that these performance deficits are not likely due to any general sensorimotor impairments. Carbamazepine had milder, but detectable negative effects, as carbamazepine-treated animals exhibited initial acquisition deficits, but rapidly achieved escape levels comparable to controls. In marked contrast, valproate and ethosuximide had no detectable effects on learning in the water maze. These results parallel previous findings in rats treated with these compounds and tested in an instrumental learning task, and are in general agreement with the human clinical literature. To the extent that one might wish to minimize learning deficits associated with maintenance on antiepileptic drugs, phenytoin is definitely not the treatment of choice, while valproate or ethosuximide are apparently much less disruptive.     

Effects of Unilateral Entorhinal Cortex Lesion and Ganglioside GM1 Treatment on Performance in a Novel Water Maze Task

Transient deficits have been reported after unilateral entorhinal cortex (EC) lesion. To determine whether there is a more persistent deficit, adult male Sprague–Dawley rats with electrolytic or sham lesions of the left entorhinal cortex were examined on acquisition of a modified working memory task in the Morris water maze. This delayed matching-to-sample task, with a 1-h intertrial interval, reveals a significant deficit in total distance to platform in both presentation (Trial 1) and matching (Trial 2) in the rats with entorhinal lesions. We have also found that this test can be used to assess significant deficits in perseveration (repeated nonproductive movement) in rats with entorhinal lesions. The deficits can be seen up to 16 days postinjury. Administration of ganglioside GM1 resulted in a moderate improvement in performance in both water maze measures analyzed. All groups (sham operated, lesion with saline treatment, and lesion with ganglioside GM1 treatment) were given three other tests, which were used to evaluate possible contributing factors to deficient water maze performance. A one-trial test for exploration of novel objects revealed no significant, simple working memory deficit in any group. Plus maze testing, to assess possible differences in levels of anxiety or increased activity as a component of water maze performance, also revealed no differences in the three groups. All groups were also similar in motor activity, shown by monitoring of activity levels. The worsened water maze performance observed in rats with EC lesion may be related to deficits in working memory ability within the framework of acquisition of a more complex spatial learning task.     

Discrete and Contextual Cue Alterations Eliminate the Instrumental Appetitive-to-Aversive Transfer Impairment in Phenytoin-Treated Rats

We have shown previously that the antiepileptic phenytoin impairs transfer in an instrumental learning task (Banks et al., 1999). The present study examined the effects of contextual alterations on appetitive-to-aversive transfer performance of rats treated with either phenytoin or tang. Adult rats were tested in tone-signaled appetitive and aversive instrumental tasks, where the animal bar-pressed to obtain a food reward (sugar pellet) or to avoid shock. Rats were trained on the appetitive task for 31 days. Beginning on the twenty-first day, rats were gavaged with either phenytoin or tang twice daily. Animals were then transferred to aversive training, with the phenytoin or tang treatment continuing throughout the 25 testing days. For some animals, contextual changes were introduced as they shifted from appetitive to aversive training, while for other animals these changes were not made. Phenytoin-treated rats that were presented with changes in context as they transferred from the appetitive to the aversive task learned the avoidance response to levels substantially higher than drug-treated rats not presented with the contextual changes. These results indicate that phenytoin impairs avoidance learning following transfer from the appetitive task, and that this impairment can be eliminated by introducing changes in context at the point of transfer. In the tang-treated control subjects, on the other hand, there was no improvement in transfer learning performance associated with the changes in contextual cues. This pattern of results suggests that contextual encoding processes in rats being trained in an instrumental appetitive-to-aversive paradigm are dramatically affected by phenytoin.     

Discrete and contextual cue alterations eliminate the instrumental appetitive-to-aversive transfer impairment in phenytoin-treated rats

We have shown previously that the antiepileptic phenytoin impairs transfer in an instrumental learning task (Banks et al., 1999). The present study examined the effects of contextual alterations on appetitive-to-aversive transfer performance of rats treated with either phenytoin or tang. Adult rats were tested in tone-signaled appetitive and aversive instrumental tasks, where the animal bar-pressed to obtain a food reward (sugar pellet) or to avoid shock. Rats were trained on the appetitive task for 31 days. Beginning on the twenty-first day, rats were gavaged with either phenytoin or tang twice daily. Animals were then transferred to aversive training, with the phenytoin or tang treatment continuing throughout the 25 testing days. For some animals, contextual changes were introduced as they shifted from appetitive to aversive training, while for other animals these changes were not made. Phenytoin-treated rats that were presented with changes in context as they transferred from the appetitive to the aversive task learned the avoidance response to levels substantially higher than drug-treated rats not presented with the contextual changes. These results indicate that phenytoin impairs avoidance learning following transfer from the appetitive task, and that this impairment can be eliminated by introducing changes in context at the point of transfer. In the tang-treated control subjects, on the other hand, there was no improvement in transfer learning performance associated with the changes in contextual cues. This pattern of results suggests that contextual encoding processes in rats being trained in an instrumental appetitive-to-aversive paradigm are dramatically affected by phenytoin.     

Vitamins E and C pretreatment prevents ovariectomy-induced memory deficits in water maze

We investigated whether the pretreatment with vitamins E (alpha-tocopherol) and C (ascorbic acid) would act on ovariectomy-induced memory deficits in Morris water maze tasks. Adult female Wistar rats were divided into three groups: (1) naive (control), (2) sham (submitted to surgery without removal of ovaries) and (3) ovariectomized. Thirty days after surgery, they were trained in the Morris water maze in order to verify ovariectomy effects both on reference and working memory tasks. Results show that ovariectomized rats presented impairment in spatial navigation in the acquisition phase, as well as in the time spent in target quadrant and in the latency to cross over the location of the platform in test session, when compared to naive and sham groups (controls), in the reference memory task. Ovariectomy did not affect performance in the working memory task. Confirming our hypothesis, ovariectomized rats pretreated for 30 days with vitamins E and C had those impairments prevented. We conclude that ovariectomy significantly impairs spatial reference learning/memory and that pretreatment with vitamins E and C prevents such effect. Assuming this experimental memory impairment might mimic, at least in part, the cognitive deficit sometimes present in the human condition of lack of reproductive hormones, our findings lend support to a novel therapeutic strategy, based on vitamins E and C, to cognitive impairments in post-menopausal women.     

Longitudinal attentional engagement rescues mice from age-related cognitive declines and cognitive inflexibility

Learning, attentional, and perseverative deficits are characteristic of cognitive aging. In this study, genetically diverse CD-1 mice underwent longitudinal training in a task asserted to tax working memory capacity and its dependence on selective attention. Beginning at 3 mo of age, animals were trained for 12 d to perform in a dual radial-arm maze task that required the mice to remember and operate on two sets of overlapping guidance (spatial) cues. As previously reported, this training resulted in an immediate (at 4 mo of age) improvement in the animals' aggregate performance across a battery of five learning tasks. Subsequently, these animals received an additional 3 d of working memory training at 3-wk intervals for 15 mo (totaling 66 training sessions), and at 18 mo of age were assessed on a selective attention task, a second set of learning tasks, and variations of those tasks that required the animals to modify the previously learned response. Both attentional and learning abilities (on passive avoidance, active avoidance, and reinforced alternation tasks) were impaired in aged animals that had not received working memory training. Likewise, these aged animals exhibited consistent deficits when required to modify a previously instantiated learned response (in reinforced alternation, active avoidance, and spatial water maze). In contrast, these attentional, learning, and perseverative deficits were attenuated in aged animals that had undergone lifelong working memory exercise. These results suggest that general impairments of learning, attention, and cognitive flexibility may be mitigated by a cognitive exercise regimen that requires chronic attentional engagement.     

Undernutrition during suckling and latent learning ability of rehabilitated adult male rats

The present report investigates the effects of early undernutrition on the latent learning ability of rehabilitated adult male rats in a simple maze task. Rats were undernourished during suckling by feeding their dams an 8% casein diet. Well-nourished dams received a 25% casein diet during the same period. Rats were weaned at 21 days of age and nutritionally rehabilitated until they became adults, when behavioral task was conducted. Under a nonappetitive condition, rats were exposed either to an open field or to a maze apparatus. They were thereafter deprived of water and tested in the maze apparatus. Both well-nourished and undernourished rats that had been previously exposed to the maze performed better than those exposed to the open field. Nutritional treatment had no effect on performance of either the latent learning or of the open-field groups. These results suggest that rehabilitated adult rats are able to learn about the environment when no immediate reinforcement is involved. The discrepancy between our findings and results reported by others may be due to differences in task complexity and/or perhaps to the fact that nutritional rehabilitation also plays a role in reversing some of the deleterious effects of early undernutrition on learning ability of rats.     

Phthalic acid amygdalopetal lesion of the nucleus basalis magnocellularis induces reversible memory deficits in rats

The basolateral amygdala (BLA) is extensively implicated in emotional learning and memory. The current study investigated the contribution of cholinergic afferents to the BLA from the nucleus basalis magnocellularis in influencing aversive learning and memory. Sprague-Dawley rats were given permanent unilateral phthalic acid (300 ng) lesions of the nucleus basalis magnocellularis and were chronically implanted with cannulas aimed at the ipsilateral BLA. Lesioned rats showed a pronounced inhibitory avoidance task retention deficit that was attenuated by acute posttraining infusions of the muscarinic cholinergic agonist oxotremorine (4 ng) or the indirect agonist physostigmine (1 microg) into the BLA. Continuous multiple-trial inhibitory avoidance training and testing revealed that lesioned rats have a mild acquisition deficit, requiring approximately 1 additional shock to reach the criterion, and a pronounced consolidation deficit as indicated by a shorter latency to enter the shock compartment on the retention test. Because lesioned rats did not differ from sham-operated controls in performance on a spatial water maze task or in shock sensitivity, it is not likely that the memory impairments produced by the phthalic acid lesions are due to any general sensory or motor deficits. These findings suggest that the dense cholinergic projection from the nucleus basalis magnocellularis to the BLA is involved in both the acquisition and the consolidation of the aversive inhibitory avoidance task.     

Long-term effects of prior cocaine exposure on Morris water maze performance

Cocaine addiction is associated with long-term cognitive alterations including deficits on tests of declarative/spatial learning and memory. To determine the extent to which cocaine exposure plays a causative role in these deficits, adult male Long-Evans rats were given daily injections of cocaine (30 mg/kg/day x 14 days) or saline vehicle. Three months later, rats were trained for 6 sessions on a Morris water maze protocol adapted from Gallagher, Burwell, and Burchinal [Gallagher, M., Burwell, R., & Burchinal, M. (1993). Severity of spatial learning impairment in aging: development of a learning index for performance in the Morris water maze. Behavioral Neuroscience, 107, 618-626]. Rats given prior cocaine exposure performed similarly to controls on training trials, but searched farther from the platform location on probe trials interpolated throughout the training sessions and showed increased thigmotaxis. The results demonstrate that a regimen of cocaine exposure can impair Morris water maze performance as long as 3 months after exposure. Although the impairments were not consistent with major deficits in spatial learning and memory, they may have resulted from cocaine-induced increases in stress responsiveness and/or anxiety. Increased stress and anxiety would be expected to increase thigmotaxis as well as cause impairments in searching for the platform location, possibly through actions on ventral striatal dopamine signaling.     

Fischer 344 and wistar rats differ in anxiety and habituation but not in water maze performance

The fact that various neuropharmacological substances have anxiolytic as well as amnesic effects suggests that neuronal mechanisms of anxiety and learning/memory closely interact. Hence, we hypothesized that differences in anxiety-related behavior could be accompanied with differences in cognition or habituation. Two rat strains with different levels of anxiety, more anxious Fischer 344 rats by Charles River (FC) and less anxious Wistar rats by Winkelmann (WW), were tested in the Morris water maze task and an open field test for habituation learning. Additionally, we investigated the effect of different light intensities on the performance in the Morris water maze and the elevated plus maze. The results of the water maze task indicate that differences in anxiety-related behavior do not go along with differences in this performance of learning/memory. Moreover, the test was not affected by different light intensities. In contrast, illumination did affect performance in the elevated plus maze test, wherein dim light provoked an anxiolytic effect in both rat strains. The findings that neither different baseline levels of anxiety nor fear modulating light conditions were accompanied by changes in the performance of rats in the Morris water maze led us to the suggestion that there is no connection between anxiety and learning/memory in this task. Contrarily, anxiety might be associated with habituation learning in the open field test, shown by the superior habituation of the anxious FC rats in comparison to the less anxious WW rats. In sum, these results indicate that anxiety and learning/memory seem to be independently regulated behaviors, whereas habituation might be more closely correlated with anxiety. Nevertheless, a general statement about the relation between emotionality and learning/memory mechanisms would be premature and the link between behaviors remains to be clarified.     

Combined uridine and choline administration improves cognitive deficits in spontaneously hypertensive rats

Rationale. Hypertension is considered a risk factor for the development of cognitive disorders, because of its negative effects on cerebral vasculature and blood flow. Genetically induced hypertension in rats has been associated with a range of cognitive impairments. Therefore, spontaneously hypertensive rats (SHR) can potentially be used as a model for cognitive deficits in human subjects. Consecutively, it can be determined whether certain food components can improve cognition in these rats. Objective. The present study aimed to determine whether SHR display specific deficits in attention, learning, and memory function. Additionally, effects of chronic uridine and choline administration were studied. Methods. 5-7 months old SHR were compared with normotensive Wistar-Kyoto (WKY) and Sprague-Dawley (SD) rats. (a) The operant delayed non-matching-to-position (DNMTP) test was used to study short-term memory function. (b) The five-choice serial reaction time (5-CSRT) task was used to assess selective visual attention processes. (c) Finally, the Morris water maze (MWM) acquisition was used as a measure for spatial learning and mnemonic capabilities. Results. (1) SHR exhibited significantly impaired performance in the 5-CSRT test in comparison with the two other rat strains. Both the SHR and WKY showed deficits in spatial learning when compared with the SD rats. (2) Uridine and choline supplementation normalized performance of SHR in the 5-CSRT test. (3) In addition, uridine and choline treatment improved MWM acquisition in both WKY and SHR rats. Conclusion. The present results show that the SHR have a deficiency in visual selective attention and spatial learning. Therefore, the SHR may provide an interesting model in the screening of substances with therapeutic potential for treatment of cognitive disorders. A combination of uridine and choline administration improved selective attention and spatial learning in SHR.     

The effects of aging and dorsal hippocampal lesions: performance on spatial and nonspatial comparable versions of the water maze

Aged intact and young hippocampal-lesioned rats show similar deficits on the spatial water maze. However, this does not necessitate that the source of these deficits in the aged animals is due to hippocampal damage. These water maze deficits may arise from other aging factors such as changes in thermoregulation, muscle fatigue, swim ability, and response to stress. Consequently, it is imperative to examine the performance of aged rats on a comparable nonhippocampal version of this task. Past attempts to develop a hippocampus-independent version of the water maze were confounded because these tasks were easier (i.e., the rats spent much less time swimming in the water) than the spatial versions of the task. The current study examined performance on a hippocampus-independent task comparable in difficulty to the spatial water one. Middle-aged (16-m) and old (25-m) male F344 rats were given sham or dorsal hippocampus lesions and tested on both a spatial and a nonspatial water maze. The middle-aged rats with hippocampal lesions were impaired on the spatial task but not on the nonspatial task. Conversely, aged animals showed a similar impairment on both types of water maze tasks. Additionally, hippocampal lesions exacerbated the age-related impairment on both tasks. These findings indicate that caution must be used when interpreting the results of water maze tasks for aged animals.     

Differential Effects of Global Ischemia on Delayed Matching- and Non-Matching-to-Position Tasks in the Water Maze and Skinner Box

In order to assess effects of global ischemia in tasks of spatial learning and working memory, male Wistar rats were subjected to four vessel occlusion (4 VO) for periods of 5, 10, and 20 min and compared with sham-operated controls over four test phases, from 6 to 54 weeks after surgery. Rats were assessed on acquisition in the water maze, a task that is sensitive to ischemic impairments, before testing in Skinner box and water maze working memory tasks, which both require the short-term storage of information, but make different demands on spatial information processing. Phases 1 and 3 assessed spatial learning in a standard water maze procedure (12 and 10 training days, 2 trials/day with a 10-min intertrial interval: ITI). Phase 2 involved training and testing in delayed non-matching-to-position task in the Skinner box, with delays of 2–10 s between the information and choice stages. Phase 4 examined working memory in a water maze delayed matching-to-position task with 4 trials/day, an ITI of 30 s, and a novel platform position on each day. Ischemic rats showed duration-related impairments in water maze acquisition and working memory, but not in the less spatially demanding Skinner box task. Since water maze acquisition deficits were seen both before and after testing in the Skinner box the lack of effect cannot be attributed to time or to prior training. Ischemic deficits were more marked in Phase 3 than in Phase 1 of acquisition, suggesting that impairment may be progressive. Histological assessment showed that cell loss was largely confined to the hippocampal CA1 field and was linearly related to duration of occlusion. At the maximal level of loss (5.7 mm before the interaural line) the 20-min group showed 90% loss, the 10-min group 60% loss, and the 5-min group, which did not differ from controls, less than 10% loss. Only the 20-min group showed significant damage beyond the CA1 field, ranging from 30–40% loss in the CA3 field to 5% loss in one striatal area. No cortical damage was seen. The extent of CA1 cell loss correlated modestly with water maze acquisition (Phase 3) and working memory scores, but not with trials to criterion in the Skinner box task. There were significant correlations between different measures both within and between water maze tasks, but not Skinner box tasks, suggesting that the two types of procedure engaged different cognitive processes. The results indicate that the intrahippocampal damage induced by 4 VO impaired tasks which required processing of allocentric spatial information, but did not impair the storage of limited spatial information in working memory.     

Neurotoxic dorsal CA1 lesions versus 4 VO ischaemic lesions: behavioural comparisons

Anterograde amnesia, a common consequence of transient cerebral ischaemia, has been attributed to cell loss in the hippocampal CA1 subfield. However, variable, widespread damage outside hippocampal CA1 can also occur following ischaemia. We compared the functional consequences of ischaemia and ibotenate acid CA1 lesions on 2 spatial memory tasks (water maze 'place' and 'matching-to-position') to address the possibility that extra-CA1 loss contributes to ischaemia-induced memory deficits in the rat. During place task acquisition, ischaemic rats showed deficits on more measures than ibotenic rats, and during a 1 min probe trial, only ischaemic rats were impaired. On the matching-to-position task, ibotenic rats showed greater impairment than ischaemic rats in terms of one-trial learning, whereas ischaemic rats were more impaired after Trial 2. Ischaemia and ibotenic acid lesions resulted in equivalent CA1 loss, but silver impregnation revealed additional extra-CA1 cell loss in ischaemic rats. Together with the greater behavioural deficits of ischaemic rats, these data indicate a role for extra-CA1 cell loss in ischaemia-induced memory impairments in both animals and humans.     

Accelerated cognitive aging in diabetic rats is prevented by lowering corticosterone levels

Diabetes and normal aging are both characterized by increases in levels of glucocorticoids. Because long-term exposure to elevated glucocorticoids can be detrimental to hippocampal function, we evaluated the performance of young diabetic rats in the 14-unit T-maze, a task that is sensitive to hippocampal deficits. To assess the contribution of diabetes-induced elevations in corticosterone levels, we examined maze learning in diabetic rats that had levels of corticosterone 'clamped' through adrenalectomy and low-dose corticosterone replacement. For comparison, we also tested a separate group of young and aged rats in the maze. Adrenally intact diabetic rats learned poorly in the 14-unit T-maze. Preventing the increases in corticosterone levels that accompanies the onset of experimental diabetes also prevented deficits in complex maze learning. The pattern of errors made by adrenally intact diabetic rats was similar to the pattern of errors made by aged rats, suggesting that the cognitive profiles of diabetic and aged rats share common features.     

Fetal Alcohol-Exposed Rats Exhibit Differential Response to Cholinergic Drugs on a Delay-Dependent Memory Task

Fetal alcohol exposure in human and rodents produces a number of cognitive deficits including impairments in learning and memory. Recent evidence in our laboratory has shown that fetal alcohol-exposed (FAE) rats respond differently to systemic administration of cholinergic drugs when tested for vigilance and locomotor activity. The present study examined the effects of muscarinic and nicotinic agonists and antagonists on memory performance in a delayed alternation task. Subjects were male offspring of Sprague-Dawley rats fed a 35% ethanol-derived caloric diet, pair-fed with sucrose, or chow-fed with lab chow during the last 2 weeks of gestation. Rats (3 months old) were food-deprived prior to training in the T-maze. Rats were first trained in the alternation task at no delay for five sessions. Rats were then trained at longer delays (20, 60, 180 s) until all groups showed similar performance for two consecutive sessions. Each animal was then tested following systemic injections of the cholinergic antagonists scopolamine and mecamylamine (60-s delay) and the cholinergic agonists pilocarpine and nicotine (180-s delay). Rats received saline injections on alternate days of testing. The results revealed that FAE rats exhibited no impairments in alternation performance at the no delay and 20-s delay, but showed impairments on both the 60- and 180-s delays during the initial sessions. However, with additional training, FAE rats showed performance similar to that of control groups at these delays. Following both pilocarpine and nicotine injections, control groups, but not the FAE group, showed significant memory enhancement in the alternation task. Following scopolamine injections, the FAE rats showed a significant impairment, while control groups showed a nonsignificant decrease in performance. All three groups showed impairments in the alternation task following administration of mecamylamine compared to saline treatment. These findings suggest that alterations in the cholinergic system in FAE rats may underlie some of the cognitive deficits observed with prenatal alcohol exposure.     

Intraseptal administration of muscimol produces dose-dependent memory impairments in the rat

The present study examined the effects of intraseptal administration of the GABAergic agonist muscimol on performance of a radial-arm maze (RAM) task. Male Long-Evans rats were trained to perform a RAM task in which a 1-h delay was imposed between the sample and the test session. In this task rats have access to four out of eight maze arms during a predelay session. Following a 1-h delay, rats are returned to the maze and allowed to freely choose among all eight arms. Arms not blocked during the predelay session are baited, and entry into an arm chosen during the predelay session or a repeated entry into a postdelay chosen arm constitutes an error. Following acquisition, animals were implanted with a single cannula aimed at the medial septum. A within-subjects design was utilized to examine the effects of intraseptal administration of muscimol (0.0, 0.75, 1.5 or 3.0 nmol) on performance in this task. All drugs or artificial cerebrospinal fluid were administered immediately following the predelay session. Muscimol, a GABA-A agonist, produced a dose-dependent impairment in maze performance as evidenced by fewer correct choices in the first four postdelay choices and an increase in the number of errors. Intraseptal administration of muscimol did not significantly alter latency per choice on the RAM task nor did it affect locomotor activity levels. Muscimol-induced impairments were also observed when a 4-h delay was imposed between the fourth and the fifth maze selection, suggesting that the behavioral deficit represents an inability to store or retain spatial working memories rather than a general performance deficit. These data indicated that pharmacological manipulation of GABA-A receptors within the medial septum modifies working memory processes. The potential interaction of GABAergic and cholinergic mechanisms in the modulation of working memory processes is discussed.     

Persistent impairments in hippocampal function following a brief series of photoperiod shifts in rats

The impact of an acute circadian disruption on learning and memory in male and female rats was examined. Circadian disruption was elicited using a brief series of photoperiod shifts. Previous research using male rats showed that acute circadian disruption during acquisition of a spatial navigation task impaired long-term retention and that chronic circadian disruption impaired acquisition of the same task. However, the long-term effects of acute circadian disruption following circadian re-entrainment and whether sex differences in response to circadian disruption exist are still unknown. For the present study, rats were trained on the standard, spatial version of the Morris water task (MWT) and a visual discrimination task developed for the eight-arm radial maze. After reaching asymptotic performance, behavioural training was terminated and the experimental group experienced a series of photoperiod shifts followed by circadian re-entrainment. Following circadian re-entrainment, the subjects were given retention tests on the MWT and visual discrimination task. Following retention testing, an extra-dimensional shift using the eight-arm radial maze was also performed. An acute episode of circadian disruption elicited via photoperiod shifts negatively impacted retention of spatial memory in male and female rats. Retention of the visual discrimination task and the ability to detect extra-dimensional shifts were not impaired. The observed impairments on the MWT indicate that hippocampal representations are susceptible to a small number of photoperiod shifts even if the association is acquired prior to rhythm manipulation and retention is assessed following rhythm stabilization. Effects were limited to a hippocampus-dependent task, indicating that impairments are specific, not global.     

Reversible disconnection of the hippocampal-prelimbic cortical circuit impairs spatial learning but not passive avoidance learning in rats

Wistar rats, treated with the GABA(A) receptor agonist muscimol, were used to investigate the role of the hippocampal-prelimbic cortical (Hip-PLC) circuit in spatial learning in the Morris water maze task, and in passive avoidance learning in the step-through task. In the water maze task, animals were trained for three consecutive days and tested 24 h after the end of training. In the step-through task, the animals were trained once and tested 24h after training. On the training days, daily infusion of muscimol (0.5 microg/0.25 microl) was given (1) bilaterally to the ventral hippocampus (vHip), (2) bilaterally to the prelimbic cortex (PLC), (3) to the unilateral vHip and the ipsilateral PLC, or (4) for disconnecting the Hip-PLC circuit, to both the unilateral vHip and the contralateral PLC 30 min before training. The results showed that inhibition of the vHip resulted in disruption of performance in both tasks. Inhibition of the PLC produced impaired water maze performance, but had no effect on the step-through task. Disconnection of the Hip-PLC circuit produced similar effects to PLC inhibition. However, simultaneous inhibition of the unilateral vHip and the ipsilateral PLC had little effect on performance of the water maze task. The results suggested that spatial learning depends on the Hip-PLC circuit, whereas passive avoidance learning is independent of this circuit.