Effects of L-arginine and Nω-nitro-L-arginine methylester on learning and memory and α7 nAChR expression in the prefrontal cortex and hippocampus of rats

Nitric oxide (NO) is a novel type of neurotransmitter that is closely associated with synaptic plasticity, learning and memory. In the present study, we assessed the effects of L-arginine and N^ω-nitro-L-arginine methylester (L-NAME, a nitric oxide synthase inhibitor) on learning and memory. Rats were assigned to three groups receiving intracerebroventricular injections of L-Arg (the NO precursor), L-NAME, or 0.9% NaCl (control), once daily for seven consecutive days. Twelve hours after the last injection, they underwent an electric shock-paired Y maze test. Twenty-four hours later, the rats’ memory of the safe illuminated arm was tested. After that, the levels of NO and α7 nicotinic acetylcholine receptor (α7 nAChR) in the prefrontal cortex and hippocampus were assessed using an NO assay kit, and immunohistochemistry and Western blots, respectively. We found that, compared to controls, L-Arg-treated rats received fewer foot shocks and made fewer errors to reach the learning criterion, and made fewer errors during the memory-testing session. In contrast, L-NAME-treated rats received more foot shocks and made more errors than controls to reach the learning criterion, and made more errors during the memory-testing session. In parallel, NO content in the prefrontal cortex and hippocampus was higher in L-Arg-treated rats and lower in L-NAME rats, compared to controls. Similarly, α7 nAChR immunoreactivity and protein expression in the prefrontal cortex and hippocampus were higher in L-Arg-treated rats and lower in L-NAME rats, compared to controls. These results suggest that the modulation of NO content in the brain correlates with α7 nAChR distribution and expression in the prefrontal cortex and hippocampus, as well as with learning and memory performance in the Y-maze.     

Serotonin depletion in rat hippocampus attenuates L-NAME-induced spatial learning deficits

Inhibition of nitric oxide (NO) synthesis has been found to produce learning deficits in spatial tasks. Recent studies also suggest a regulatory effect of endogenous NO on hippocampal serotonin (5-HT) release and have shown that NO-synthase (NOS) inhibitors increased extracellular levels of serotonin (5-HT) in the rat hippocampus. To clarify possible interactions between NO and 5-HT in the hippocampus on learning processes, the effect of selective hippocampal 5-HT depletion on NOS inhibition-induced spatial learning deficits was investigated. Rats received bilateral injections of 5,7-dihydroxytryptamine (5,7-DHT), a 5-HT neurotoxin, or its vehicle in the CA1 region of hippocampus following pretreatment with desipramine. Rats were subjected to 5 days of training in the Morris water maze (MWM); 4 days with the invisible platform to test spatial learning and the 5th day with the visible platform to test motivation and sensorimotor coordination. Nomega-nitro-L-arginine methyl ester (L-NAME), a NOS inhibitor, was administered to either sham-operated or 5,7-DHT-lesioned groups 30 min before training each day. Results showed that L-NAME significantly impaired the ability of rats to locate the hidden platform. This impairment was reversed by co-administration of mole equivalent dose of L-arginine, the NO precursor. Although the 5,7-DHT-induced lesion had no effect by itself on rat performance in the MWM, it attenuated the memory impairment caused by L-NAME. The observed effect suggests an interaction between NO and 5-HT in the hippocampus on spatial memory formation; however, the mechanism of interaction is still unclear and requires further investigation.     

Systemic Administration of N-Nitro-l-Arginine Methyl Ester and Indomethacin Reduces the Elevation of Brain PGE2Content and Prevents Seizures and Hippocampal Damage Evoked by LiCl and Tacrine in Rat

Administration of tacrine (5 mg/kg i.p.), an anticholinesterase agent, in rats pretreated (24 h beforehand) with lithium chloride (LiCl; 12 mEq/kg i.p.) enhances the expression of neuronal nitric oxide (NO) synthase (NOS), increases NO, and causes seizures and hippocampal damage. Here we report immunohistochemistry evidence showing that in rat LiCl and tacrine enhance the expression of cyclooxygenase type 2 (COX-2) enzyme protein in the dorsal hippocampus and elevate brain PGE₂content during the preconvulsive period. The latter effect, but not enhanced COX-2 expression, is inhibited by previous (30 min before tacrine) administration ofN^ω-nitro-l-arginine-methyl ester (L-NAME; 10 mg/kg i.p.), an inhibitor of NO synthesis, thus implicating NO in the mechanism of stimulation of COX activity leading to elevation of brain PGE₂content. Indomethacin (10 mg/kg given i.p. 30 min before tacrine), an inhibitor of COX activity, prevented brain PGE₂elevation and abolished the expression of seizures and hippocampal damage thus supporting a role for this metabolite of the arachidonic acid cascade in the mechanisms of LiCl and tacrine-evoked neurotoxicity in rat.     

Hippocampal lesioned rats are able to learn a spatial position using non-spatial strategies

In the last two decades, many experiments have demonstrated that the hippocampus plays a role in the learning and processing of spatial and contextual information. Despite these demonstrations, some recent publications have indicated that the hippocampus is not the only structure involved in spatial learning and that even after hippocampal lesions, rats can perform spatial tasks. However, it is not well established whether animals with hippocampal dysfunction still have some spatial learning capacities or develop non-spatial solutions; these may require lengthier acquisition training. We now report the effects of conventional, dorsal hippocampal ablation on rats' performance on the water maze. We tested rats using a short (4 days) versus a long (16 days) acquisition period. We demonstrated that animals with dorsal hippocampal lesions have some residual capacity for learning the localization of a hidden escape platform in a pool during both a reference memory task and a working memory task. The animals with dorsal hippocampal lesions learned to escape at a fixed location, but only with extended training. It is suggested that these animals used non-spatial strategies to compensate for a spatial memory impairment. The results are discussed with respect to the experimental procedure and the strategy applied by the lesioned rats.     

Perseveration on place reversals in spatial swimming pool tasks: Further evidence for place learning in hippocampal rats

Animals with damage to the fimbria–fornix (FF) or cells of the hippocampus (HIP) can learn a place problem but cannot learn matching-to-place problems, which feature a series of place “reversals.” The two experiments described in the present report were designed to examine the causes of impairment on reversal learning. In experiment 1, control, HIP, and FF groups were trained to asymptote on a place problem, and then the location of the platform was moved. Control rats learned the reversal response more quickly than the initial response; the HIP rats learned both problems at the same rate. Swim analysis showed that the impairment in the lesion group on the reversal response was aggravated by perseverative returns to the first learned place. In experiment 2, control and FF groups were trained on a task in which the platform was visible on three daily trials and hidden on one daily trial. After 10 days, the platforms were moved. In the reversal response, the FF group showed enhanced performance on the cue trials and severely impaired performance on the place trials relative to initial learning and control performance. Swim analysis showed that FF rats perseverated on the initial place response in place trials. These experiments provide further evidence for place learning in hippocampal rats and show that perseverative responses contribute to impairments in new learning. The results are discussed in relation to the idea that the hippocampus mediates spatial mapping and/or uses self-movement cues to solve spatial problems. Hippocampus 7:361–370, 1997. © 1997 Wiley-Liss, Inc.     

Lack of Involvement of Nitric Oxide in the Mechanisms of Seizures and Hippocampal Damage Produced by Kainate and Ouabain in Rats

The gross behavioural, electrocortical and neuropathological effects of kainate (10mg/kg i.p,) and ouabain (1μg, given into one dorsal hippocampus) were studied in rats. The effects of these treatments on nitric oxide synthase (NOS) activity in homogenates of hippocampus and cortex were also studied. Administration of kainate or ouabain produced motor and electrocortical seizures similar for latency to onset (approximately 15min) and intensity (in all instances 80–100% of the treated rats showed behavioural and electrographic seizures). These effects were accompanied at 24 h by severe damage to all subsectors of the hippocampal formation and this concerned a similar proportion of the treated rats (n=4–8 per treatment). No significant changes in nitric oxide synthase (NOS) activity were noted in the cerebral cortex and hippocampus of rats receiving injections of kainate and ouabain. In addition, pretreatment with N^ω-Nitro-L-arginine methyl ester (300μg, given into one lateral cerebral ventricle 15 min previously) was ineffective in preventing the effects of kainate and ouabain. In conclusion, present data suggest that excessive production of NO is not involved in the mechanisms triggering seizures and neurodegeneration produced by kainate or ouabain.     

An investigation on the role of nitric oxide in the modulation of the binding characteristics of various radioligands of GABAA receptors by 5α-pregnan-3α-ol-20-one in the rat brain regions

Chronic administration of N^ω-nitro- -arginine methyl ester ( -NAME), an inhibitor of nitric oxide synthase, diminished the ability of 5α-pregnan-3α-ol-20-one, a neurosteroid, to potentiate the [³H]muscimol (5 nM) binding in the rat hippocampus but not in the cerebellum or cerebral cortex. This effect of NAME was stereospecific and susceptible to reversal by the pre-treatment of rats with -arginine. However, chronic administration of -NAME did not affect the modulation of the [³H]flunitrazepam (2 nM) or [³⁵S]TBPS (4 nM) binding by the neurosteroid in any of the brain regions investigated in this study. These results suggest that nitric oxide may be involved in some of the effects of neurosteroids in hippocampus.     

Local nitric oxide synthase activity in a model of neuropathic pain

A local inflammatory reaction may play an important role in the development of neuropathic pain following peripheral nerve injury. One important participant in the inflammatory response of injured peripheral nerve may be nitric oxide (NO). In this work, we examined physiological and morphological evidence for nitric oxide synthase (NOS) activation in the chronic constriction injury model of neuropathic pain in rats. Physiological evidence of local NO action was provided by studying NO-mediated changes in local blood flow associated with the injury site. Immunohistochemistry was used to localize isoforms of NOS that might generate NO. Sciatic nerve injury associated with behavioural evidence of neuropathic pain had substantial rises in local blood flow. The NOS inhibitor N^G-nitro-l -arginine methyl ester (L-NAME), but not N^G-nitro-d -arginine methyl ester (D-NAME), reversed the hyperaemia in a dose-dependent fashion proximal to the constriction at 48 h and distally at 14 days post-operation when applied systemically or topically. Aminoguanidine, a NOS inhibitor with relatively greater selectivity for the inducible NOS (iNOS) isoform, reversed nerve hyperaemia distal to the constriction only at 14 days. NOS-like immunoreactivity of the neuronal and endothelial isoforms was identified just proximal to the constriction at 48 h. iNOS-like immunoreactivity was observed at 7 and 14 days at the constriction and distal sites, respectively. This work provides evidence for local NOS expression and NO action in the chronic constriction injury model of neuropathic pain. NO has local physiological actions that include vasodilatation of microvessels and that may be important in the development of pain sensitivity.     

Conditional associative learning and the hippocampal system

Rats with lesions of the fornix, the dorsal hippocampus, or a control operation were trained on a spatial-visual conditional associative learning task in which they had to learn to associate particular locations with specific visual stimuli. Animals with damage of the fornix were able to learn the task at a rate comparable to that of the control animals, but the performance of the hippocampal rats was significantly impaired in comparison with that of both the control and the fornix groups. In a second experiment, lesions to the fornix or the dorsal hippocampus significantly impaired performance on a spatial working memory task, the eight-arm radial maze. These findings suggest that the interaction between the hippocampus and subcortical structures via the fornix may be critical only for certain types of spatial learning and memory. Hippocampus 1998;8:131–137. © 1998 Wiley-Liss, Inc.     

Nitric oxide content measured by ESR-spectroscopy in the rat brain is increased during pentylenetetrazole-induced seizures

Nitric oxide (NO) content in rat cerebral cortex was measured using Electron Spin Resonance (ESR) spectroscopy. A nearly fivefold elevation in NO content was found at the peak time of pentylenetetrazole (PTZ)-induced seizures. The administration of N-nitro-l-arginine (L-NNA), a competitive inhibitor of NO-synthase, at the dose of 250 mg/kg, completely prevented the NO increase induced by PTZ, although clonic convulsions in the animals have been observed. L-NNA (10 mg/kg) was shown to delay the onset of clonic seizures as well as to shorten the latency of the first convulsive twitch. The level of lipid peroxidation secondary products measured as the content of thiobarbituric acid reactive species (TBARS) was increased in the cerebral cortex of PTZ-treated rats. L-NNA (250 mg/kg) failed to prevent the increased TBARS level produced by PTZ. The results support the notion that NO may play a trigger role in the pathophysiology of convulsive seizures.     

Effects of a nitric oxide synthase inhibitor on NMDA receptor function in organotypic hippocampal cultures

Nitric oxide (NO) has been proposed to trigger long-term potentiation (LTP) at CA3 to CA1 synapses. We previously reported that NO synthesis inhibitors and blockers reduce an electrophysiological index of NMDA receptor activation in acute hippocampal slices. We now show that the NOS inhibitor, N^G-methyl-

Full-size image

-arginine (MLA), also reversibly prevents LTP induction in organotypic hippocampal slices and significantly reduces a biochemical index of NMDA receptor function. These results further indicate that MLA inhibits LTP induction by interfering with NMDA receptor functions.     

A double dissociation of dorsal and ventral hippocampal function on a learning and memory task mediated by the dorso-lateral striatum

The objectives of this research were to further delineate the neural circuits subserving proposed memory-based behavioural subsystems in the hippocampal formation. These studies were guided by anatomical evidence showing a topographical organization of the hippocampal formation. Briefly, perpendicular to the medial/lateral entorhinal cortex division there is a second system of parallel circuits that separates the dorsal and ventral hippocampus. Recent work from this laboratory has provided evidence that the hippocampus incidentally encodes a context-specific inhibitory association during acquisition of a visual discrimination task. One question that emerges from this dataset is whether the dorsal or ventral hippocampus makes a unique contribution to this newly described function. Rats with neurotoxic lesions of the dorsal or ventral hippocampus were assessed on the acquisition of the visual discrimination task. Following asymptotic performance they were given reversal training in either the same or a different context from the original training. The results showed that the context-specific inhibition effect is mediated by a circuit that includes the ventral but not the dorsal hippocampus. Results from a control procedure showed that rats with either dorso-lateral striatum damage or dorsal hippocampal lesions were impaired on a tactile/spatial discrimination. Taken together, the results represent a double dissociation of learning and memory function between the ventral and dorsal hippocampus. The formation of an incidental inhibitory association was dependent on ventral but not dorsal hippocampal circuitry, and the opposite dependence was found for the spatial component of a tactile/spatial discrimination.     

Neonatal hippocampal damage in rats: Long-term spatial memory deficits and associations with magnitude of hippocampal damage

This study investigated the effects of neonatal hippocampal ablation on the development of spatial learning and memory abilities in rats. Newborn rats sustained bilateral electrolytic lesions of the hippocampus or were sham-operated on postnatal day 1 (PN1). At PN20–25, PN50–55, or PN90–95, separate groups of rats were tested in a Morris water maze on a visible “cue” condition (visible platform in a fixed location of the maze), a spatial “place” condition (submerged platform in a fixed location), or a no-contingency “random” condition (submerged platform in a random location). Rats were tested for 6 consecutive days, with 12 acquisition trials and 1 retention (probe) trial per day. During acquisition trials, the rat's latency to escape the maze was recorded. During retention trials (last trial for each day, no escape platform available), the total time the rat spent in the probe quadrant was recorded. Data from rats with hippocampal lesions tested as infants (PN20–25) or as adults (PN50–55 and PN90–95) converged across measures to reveal that 1) spatial (place) memory deficits were evident throughout developmental testing, suggesting that the deficits in spatial memory were long-lasting, if not permanent, and 2) behavioral performance measures under the spatial (place) condition were significantly correlated with total volume of hippocampal tissue damage, and with volume of damage to the right and anterior hippocampal regions. These results support the hypothesis that hippocampal integrity is important for the normal development of spatial learning and memory functions, and show that other brain structures do not assume hippocampal-spatial memory functions when the hippocampus is damaged during the neonatal period (even when testing is not begun until adulthood). Thus, neonatal hippocampal damage in rats may serve as a rodent model for assessing treatment strategies (e.g., pharmacological) relevant to human perinatal brain injury and developmental disabilities within the learning and memory realm. Hippocampus 7:403–415, 1997. © 1997 Wiley-Liss, Inc.     

Delayed behavioral response to antidepressant drugs following selective damage to the hippocampal noradrenergic innervation in rats

The present study was undertaken to investigate in rats the role of the noradrenergic innervation of the hippocampus in the reversal by antidepressant drugs of escape failures caused by previous exposure to insecapable shocks (learned helplessnes design). Rats were either sham-operated or given a bilateral infusion of 6-hydroxydopamine (6-OHDA, 8.1 μg of free base in 0.8 μl saline containing 0.02% ascorbic acid) into the dorsal hippocampus. Three weeks later, sham lesioned rats were exposed (experimental rats) or not exposed (control rats) to 60 randomized, inescapable footschocks (0.8 mA, 15 s duration) and 48, h later, experimental and control rats were subjected to daily consecutive shuttle-box sessions (30 trials/day; intertrial INTERVAL = 30 s). Separate groups of experimental animals were given twice daily injection (i.p.) of clomipramine (total daily dose: 16 or 32 mg/kg), desipramine (24 mg/kg), imipramine (32 mg/kg), nialamide (16 mg/kg) or saline. After behavioral testing, animals were sacrificed and [³H]noradrenaline uptake was assayed in synaptosomal preparations from the hippocampus, the cerebral cortex and the septum, [³H]serotonin uptake being assessed in hippocampal synaptosomes. We found that hippocampal 6-OHDA infusion resulted in a mean 70% reduction in local [³H]noradrenaline uptake and a marked delay in the response to antidepressants (reversal of escape failures over consecutive shuttle-box sessions). The 6-OHDA infusion was found not to alter hippocampal [³H]serotonin uptake but to decrease (30%) [³H]noradrenaline uptake in the cerebral cortex. These data clearly suggest that the noradrenergic innervation of the hippocampus and perhaps the cerebral cortex might be a crucial neuronal target in the ‘antidepressant’ action of imipramine-like drugs and monoamine oxidase inhibitors in animals.     

Effects of hippocampal cholinergic deafferentation on learning strategy selection in a visible platform version of the water maze

Recent evidence has suggested that the relative levels of acetylcholine (ACh) between brain structures may be an important factor in the choice of behavioral strategy in settings in which either hippocampal or dorsal striatal brain systems can be employed both effectively and independently (McIntyre and Gold. 1999. Soc Neurosci Abs 25:1388). The current investigation used the neurotoxin 192 IgG-saporin to deplete the hippocampus of ACh selectively, while leaving ACh in other brain regions, including dorsal striatum, intact. Rats were then trained on a version of the Morris water maze, in which behavioral strategies attributed to the hippocampus and dorsal striatum are placed in direct competition. It was predicted that rats with hippocampal ACh depletion would display a cue bias. Contrary to this prediction, depleting hippocampal ACh did not bias against and, in fact, promoted use of a hippocampal place strategy in this task, as indicated by choice in competition tests and performance on hidden platform training trials. These data add to a growing literature demonstrating that the septohippocampal cholinergic system is not required for accurate spatial learning and suggest a complex role for basal forebrain projections in processing information about the spatial environment.     

Re-evaluation of the spatial memory deficits induced by hippocampal short lasting inactivation reveals the need for cortical co-operation.

Evidence has accumulated that the rat hippocampus plays a central role in spatial memory. In complement to lesion studies, reversible lidoca?ne-induced inactivations have been used to investigate the time-course of the memory processes mediated by the hippocampus. A number of studies suggest that, in some conditions, the hippocampus is not necessary for online acquisition of spatial information. To test this hypothesis, we examined the effects of bilateral lidoca?ne-induced inactivations of the dorsal hippocampus in the acquisition of new spatial information. After initial learning of a place navigation task in the water maze, rats were tested for acquisition of a new platform location and received injections of lidoca?ne in the hippocampus prior to each daily four-trial block. The training blocks were separated by a 24-h period allowing the hippocampus to recover from inactivation. The results show that lidoca?ne-injected rats were able to learn the new platform location like controls. Inactivations, however, was found to induce a within-block learning impairment. This suggests that the hippocampus can perform off-line processing and that another structure is able to handle spatial information during hippocampal inactivations. Parietal-lesioned rats that received an injection of lidoca?ne were still able to learn the new platform location suggesting that the parietal cortex does not sustain this role. Overall, our results suggest that the hippocampus is not necessary for all stages of memory formation and co-operates with other brain, possibly cortical, structures which remain to be determined.     

Place navigation in the Morris water task results in greater nuclear Arc mRNA expression in dorsal compared to ventral CA1

Previous work has shown that the dorsal hippocampus has greater activity than ventral regions during place navigation. Exposure to a novel context has also been found to increase hippocampal activation, possibly due to increased spatial demands. However, activation patterns in dorsal and ventral regions have not been investigated in the Morris water task (MWT), which remains the most popular assay of place memory in rodents. We measured activity in a large population of neurons across the CA1 dorsal–ventral axis by estimating nuclear Arc mRNA with stereologic systematic‐random sampling procedures following changes to goal location or spatial context in the MWT in rats. Following changes to goal location or spatial context in the MWT, we did not find an effect on Arc mRNA expression in CA1. However, Arc expression was greater in the dorsal compared to the ventral aspect of CA1 during task performance. Several views might account for these observed differences in dorsal–ventral Arc mRNA expression, including task parameters or the granularity of representation that differs along the dorsal–ventral hippocampal axis. Future work should determine the effects of task differences and required memory precision in relation to dorsal–ventral hippocampal neuronal activity.     

Upstairs/downstairs revisited: spatial pretraining‐induced rescue of normal spatial learning during selective blockade of hippocampal N‐methyl‐d‐aspartate receptors

Spatial pretraining can enable spatial learning in another environment that ordinarily requires hippocampal N‐methyl‐d ‐aspartate (NMDA) receptor activity to become independent of that activity. This study explored further the circumstances in which this training‐induced ‘rescue’ of later learning in the presence of the NMDA receptor antagonist 2‐amino‐5‐phosphonovaleric acid (D‐AP5) can occur. D‐AP5 (0, 10, 20 and 30 mm in artificial cerebrospinal fluid) was infused continuously (0.5 μL/h, from a minipump) and bilaterally into the dorsal hippocampus during spatial‐reference‐memory training in a watermaze (4 trials/day, 8 days). This was preceded either by handling only or by identical spatial training in another watermaze in a separate laboratory with different extramaze cues. In naïve rats, D‐AP5 caused a dose‐related impairment in spatial reference memory acquisition that was significant at the lowest 5 nm /h infusion concentration. In pretrained rats, the dose–response function was shifted such that, in watermaze 2, spatial learning was normal at this low concentration, with a deficit at higher infusion concentrations. The induction of long‐term potentiation in the dentate gyrus in vivo was blocked at all D‐AP5 concentrations. Sensorimotor abnormalities sometimes seen with NMDA receptor antagonists were only apparent at the highest concentration. The implication of this paradoxical dissociation between hippocampal NMDA receptor‐dependent plasticity and spatial learning is discussed with reference to two rival hypotheses of the impact of pretraining.     

Hippocampal damage produces retrograde but not anterograde amnesia for a cued location in a spontaneous exploratory task in rats

Performance in several memory tasks is known to be unaffected by hippocampal damage sustained before learning, but is severely disrupted if the same damage occurs after learning. Memories for preferred locations, or home bases, in exploratory tasks can be formed by rats with hippocampal damage, but it is unknown if the memory for a home base survives hippocampal damage. To examine this question, for 30 min each day for five consecutive days, rats explored a circular open field containing one local cue. By Day 5 the rats preferentially went directly to that location, spent the majority of their time at that location, made rapid direct trips to that location when returning from an excursion and so demonstrated that the location was a home base. Memory for the cued location was examined after a 24 h or 14‐day interval with the cue removed. In Experiments 1 and 2, control rats and rats with prior N‐methyl‐D ‐aspartic acid hippocampal lesions demonstrated memory of the home base location by making direct trips to that location. In Experiment 3, rats that had first explored the open field and cue and then received hippocampal lesions showed no memory for the cued location. The absence of anterograde impairment vs. the presence of retrograde impairment for memory of a spatial home base confirms a role for the hippocampus in the retention of spatial memory acquired during exploration. © 2009 Wiley‐Liss, Inc.     

A study of hippocampal structure-function relations along the septo-temporal axis

This study examined structural-functional differences along the septo-temporal axis of hippocampus using radial-maze tasks that involved two different memory processes [reference memory (RM) and working memory (WM)], and the use of two kinds of information (spatial vs. nonspatial cue learning). In addition, retention of the nonspatial cue task was tested nine weeks following completion of acquisition, and the rats then underwent discrimination reversal training. Ibotenic acid lesions limited to either the dorsal pole, intermediate area, or ventral pole had minimal effects on acquisition of the complex place and cue discrimination tasks. The one exception was that rats with lesions confined to the dorsal third of hippocampus made more WM errors on the spatial task (but not the cue task) early in training. Selective lesions of the three hippocampal regions had no effects on either long-term retention or reversal of the nonspatial cue discrimination task. In contrast, rats that had all of the hippocampus removed were severely impaired in learning the spatial task, making many RM and WM errors, whereas on the nonspatial cue task, the impairment was limited to WM errors. Further analysis of the WM errors made in acquisition showed that rats with complete lesions were significantly more likely on both the spatial and nonspatial cue tasks to reenter arms that had been baited and visited on that trial compared to arms that had not been baited. A similar pattern of errors emerged for complete hippocampal lesioned rats during reversal discrimination. This pattern of errors suggests that in addition to an impairment in handling spatial information, complete removal of hippocampus also interferes with the ability to inhibit responding to cues that signal reward under some conditions but not under others. The finding that selective lesions limited to the intermediate zone of the hippocampus produce no impairment in either WM ("rapid place learning") or RM in our radial maze tasks serve to limit the generality of the conclusion of Bast et al. (Bast et al. (2009) PLos Biol 7:730-746) that the intermediate area is needed for behavioral performance based on rapid learning about spatial cues.