Visual and visuospatial short-term memory in mild cognitive impairment and Alzheimer disease: role of attention.

It has been proposed that visual recognition memory and certain attentional mechanisms are impaired early in Alzheimer disease (AD). Little is known about visuospatial recognition memory in AD. The crucial role of the hippocampus on spatial memory and its damage in AD suggest that visuospatial recognition memory may also be impaired early. The aim of the present study was to evaluate which modality, i.e. visual or visuospatial, is more implicated in the early memory impairment in AD. First, to determine onset of memory impairment, we compared the performances of patients with AD to those with amnestic mild cognitive impairment (MCI). Second, to determine the relative contribution of attentional impairment on the performance of MCI and AD patients, we tested the influence of a distractor in the interval between the memory image and recognition tests. Results showed that visuospatial short-term deficits appear earlier than visual short-term ones. In addition to mnemonic deficits, results showed attentional deficiency in both MCI and AD patients. Deficits of performances in visual modality seemed of attentional origin whereas those of visuospatial modality seemed of memory origin. The combination of attentional and mnemonic evaluation is likely to be a promising approach to finding predictive markers that distinguish MCI patients that convert to AD.

Behavioral and immunohistological effects of cholinergic damage in immunolesioned rats: alteration of c-Fos and polysialylated neural cell adhesion molecule expression.

The aim of this study was to determine the brain structures as well as the plasticity events associated with the behavioral effects of cholinergic damage. Rats were submitted to injection of 192 IgG-saporin in the medial septum/diagonal band of Broca complex and the nucleus basalis magnocellularis. The immunohistochemical expression of c-Fos protein and PSA-NCAM (polysialylated neural cell adhesion molecule) and the behavioral performances in the nonmatching-to-position task were assessed at various post-lesion times. Thus, 3 days after injection of the immunotoxin, increased c-Fos labeling was observed in the areas of infusion, indicating these cells were undergoing some plastic changes and/or apoptotic processes. A drastic increase was observed in the number of PSA-NCAM positive cells and in their dendritic arborization in the dentate gyrus. At 7 days post-lesion, no behavioral deficit was observed in immunolesioned rats despite the drastic loss of cholinergic neurons. These neurons showed decreased c-Fos protein expression in the piriform and entorhinal cortex and in the dentate gyrus. In the latter, PSA-NCAM induction was high, suggesting that remodeling occurred, which in turn might contribute to sustaining some mnemonic function in immunolesioned rats. At 1 month, cholinergic neurons totally disappeared and behavioral deficits were drastic. c-Fos expression showed no change. In contrast, the increased PSA-NCAM-labeling observed at short post-lesion times was maintained but the plastic changes due to this molecule could not compensate the behavioral deficit caused by the immunotoxin. Thus, as the post-lesion time increases, a gradual degeneration process should occur that may contribute to mnemonic impairments. This neuronal loss leads to molecular and cellular alterations, which in turn may aggravate cognitive deficits.

Time course of behavioral changes following basal forebrain cholinergic damage in rats: Environmental enrichment as a therapeutic intervention.

The present experiment was designed to study changes in behavior following immunolesioning of the basal forebrain cholinergic system. Rats were lesioned at 3 months of age by injection of the 192 IgG-saporin immunotoxin into the medial septum area and the nucleus basalis magnocellularis, and then tested at different times after surgery (from days 7-500) on a range of behavioral tests, administered in the following order: a nonmatching-to-position task in a T-maze, an object-recognition task, an object-location task, and an open-field activity test. The results revealed a two-way interaction between post-lesion behavioral testing time and memory demands. In the nonmatching-to-position task, memory deficits appeared quite rapidly after surgery, i.e. at a post-lesion time as short as 1 month. In the object-recognition test, memory impairments appeared only when rats were tested at late post-lesion times (starting at 15 months), whereas in the object-location task deficits were apparent at early post-lesion times (starting from 2 months). Taking the post-operative time into account, one can hypothesize that at the shortest post-lesion times, behavioral deficits are due to pure cholinergic depletion, while as the post-lesion time increases, one can speculate the occurrence of a non-cholinergic system decompensation process and/or a gradual degeneration process affecting other neuronal systems that may contribute to mnemonic impairments. Interestingly, when middle-aged rats were housed in an enriched environment, 192 IgG-saporin-lesioned rats performed better than standard-lesioned rats on both the nonmatching-to-position and the object-recognition tests. Environment enrichment had significant beneficial effects in 192 IgG-saporin-lesioned rats, suggesting that lesioned rats at late post-lesion times (over 1 year) still have appreciable cognitive plasticity.

Age-related learning and memory deficits in odor-reward association in rats.

In these experiments, potential cognitive deficits in aged rats were studied using an odor-reward association task. Aged Fischer 344 rats first performed to an odor-reward association task. After five daily sessions of 60 trials, the aged rats were globally impaired in comparison to the control rats. However, considering individual performance, 40% of the aged population performed as well as the control animals. These aged rats were then tested for retention at various times. They demonstrated an increased rate of forgetting which was confirmed by a final reversal experiment. The other group of aged rats remained severely impaired and unable to make the odor-reward association correctly until the inter-trial interval was decreased from 15 to 5 s. When they were submitted to a task requiring the learning and retention of 7 new odor pairs, these aged rats again performed poorly. A subsequent reversal session confirmed the rapid forgetting phenomenon for this aged group, even when the odor-reward associations were in fact made.

Lithostathine and pancreatitis-associated protein are involved in the very early stages of Alzheimer's disease.

According to one of the theories formulated to explain the etiology of Alzheimer's disease (AD), amylosis may reflect a specific inflammatory response. Two inflammatory proteins, lithostathine and PAP, were evidenced by immunohistochemistry in senile plaques and neurofibrillary tangles of patients with AD. In addition, lithostathine and PAP were significantly increased in the cerebrospinal fluid of patients with AD when compared to patients with multiple sclerosis, another inflammatory disease, and to normal control subjects. However, no correlation was observed with age of occurrence. Furthermore, lithostathine and PAP were increased even at the very early stages of AD, and their level remained elevated during the course of the AD unlike TNFalpha whose level, very high at very early stages, regularly decreased. Finally, if part of lithostathine and PAP are synthesized in the brain, a large part comes from serum by passage over the blood-brain barrier. These results indicate (i) the existence of an acute phase response followed by a chronic inflammation in AD, and (ii) that lithostathine and PAP are involved even at the first pre-clinical biochemical events of AD. In addition, because lithostathine undergoes an autolytic cleavage leading to its precipitation and the formation of fibrils, we believe that it may be involved in amyloidosis and tangles by allowing heterogeneous precipitation of other proteins.

Role of vasopressin in learning and memory in the hippocampus.

The involvement of arginine8-vasopressin (VP) in learning and memory in the hippocampus is examined in mice using a discriminative learning task. Bilateral dorsal hippocampal lesion blocks the enhancing effect of intracerebroventricular (i.c.v.) injection of VP on retrieval and relearning processes. An additional study showed that immunoneutralization of dorsal hippocampal endogenous VP inhibited the facilitating effect of i.c.v. injection of VP, suggesting that hippocampus is essential for the expression of VP's behavioral effects. Using in situ microinjection, a greater sensitivity of the ventral part of the hippocampus to the memory enhancing effects of VP has been reported. This effect is mediated by vasopressin V1 type receptors and oxytocin receptors. Then, we examined the effects on behavior of VP applied to the ventral hippocampus, in relation to the time of treatment during learning. When the animals have no previous information about the task to learn, a deleterious effect of VP appears (pre-first session treatment). Regarding memory consolidation, the effects of VP may depend upon the previous level of performance acquired by the animals since, when injected after the first learning session, the peptide slightly delayed performance, whereas when the injection took place after the second learning session, it enhanced learning. Concerning memory retrieval, the effects of VP depend on the quality of the previously stored information. The fact that VP did not generate the same behavioral effects when the treatment was performed at the beginning or in the middle of the learning processes, suggests that mnemonic context is an important factor in understanding the effect of VP on memory in the ventral hippocampus. Finally, the role of hippocampal adrenergic receptors in the enhancing VP effects on memory retrieval has been examined. The facilitatory effects of VP seem to depend upon the functional state of both alpha- and beta-adrenergic receptors, but further studies will be necessary to clarify the role played by each receptor type in retrieval processes, and to determine the relationships that might exist between them.

Effects of peripherally administered arginine-vasopressin on learning, retention and forgetting in mice.

The effects of peripheral injections of (Arg)-vasopressin were investigated on different stages of memory processes using an appetitive visual discrimination task and a one-trial passive avoidance conditioning in mice. The peptide was administered at one of two doses: 50 micrograms/kg or 25 micrograms/kg. The main effects of vasopressin were observed only for the higher dose. Concerning pre-session vasopressin administration in the visual discrimination task, the effect of the peptide seemed to depend on the level of learning reached at the time of treatment. Indeed, we observed a deleterious effect of vasopressin on learning capacities when the peptide was administered before the first learning session, a bimodal effect (either an improvement or an impairment) on performance when the peptide was administered before the second learning session and an important enhancement of retention performance when the peptide was administered before the retention session, performed 24 days after training. When post-session vasopressin administration was assessed, an improvement of performance was observed indicating a facilitatory effect of vasopressin on consolidation processes. When passive avoidance conditioning was used, an enhancement of retention performance was registered only when the peptide was injected before the retention session at the 50 micrograms/kg dose. No facilitation was observed for the 25 micrograms/kg dose whatever the experimental condition was, i.e. post-learning or pre-retention injection. In order to test eventual non-specific effects of vasopressin, the influence of the peptide on locomotor activity was assessed before the two doses. The results show an important reduction of locomotor activity with the 50 micrograms/kg dose, during 4 h following vasopressin injection. No effect was observed with the 25 micrograms/kg dose. The whole results suggest that vasopressin-induced hypoactivity can directly influence the subsequent learning performance when the treatment was performed in pre-session situations. However, when the level of information is sufficient and beyond the direct effect of the drug, a memory effect may be considered with the 50 micrograms/kg dose independently from the locomotor effect, when the treatment was delivered during consolidation period (post-session) or in long-term retrieval situation (pre-session).

Hippocampal lesions block behavioral effects of central but not of peripheral pre-test injection of arginine vasopressin in an appetitive learning task.

The effects of peripheral and central administration of arginine-vasopressin (AVP) were examined in intact or hippocampal-lesioned mice, when administered just before the retention session of an appetitive visual discrimination task. All the subjects underwent a partial learning of this task and were tested 24 days later when a partial forgetting occurred in controls. In Expt. 1, intact mice received AVP just before the test session either subcutaneously (s.c., 1 microgram) or intracerebroventricularly (i.c.v., 1 ng). Both routes of administration resulted in an enhancement of the retention performance. In Expt. 2, bilateral lesions of the dorsal hippocampus were carried out 2 days after the end of initial learning. The lesions did not modify retrieval performance on the 24th day. In additional groups, AVP was injected in pre-test situation in lesioned animals. An s.c. AVP injection induced the same improvement of retrieval as observed in intact mice. On the contrary, i.c.v. administration of AVP accentuated forgetting in lesioned animals. In other words, hippocampal lesions reversed the effects of i.c.v. pre-test administration of AVP. The results are analyzed in terms of different mechanisms for both routes of administration of AVP.

Effects of arginine8-vasopressin administered at different times in the learning of an appetitive visual discriminative task in mice.

A visual discrimination task was used to investigate the effect of the intra-hippocampal injection of arginine8-vasopressin (AVP) in male Balb/c mice at different stages of the learning processes. The peptide was bilaterally microinjected at a dose of 25 pg per animal, i.e. 833 pg/kg, into the ventral hippocampus, in a volume of 0.3 microliter 10 min before either the first or the second learning session, or immediately after the first or second learning session. Following pre-session administration of AVP, no effect of the peptide was observed on the session prior to which it was administered. On the other hand, 48 h after the pre-first session treatment, it seems that AVP animals had trouble learning the task. Following post-session injection of AVP, no effect was observed when the treatment was given after the first learning session and a tendency to improve performance was noted when the treatment was given after the second learning session. Thus, whatever time AVP was injected during learning, little or no effect was observed. These results and previous work on the same behavioral task showing a clear enhancing effect of the peptide on retrieval processes, suggest that prior experience or mnemonic context before AVP treatment is as important a factor in understanding the effects of AVP on memory processes as the administration route or the doses used.

Microinjection of anti-vasopressin serum into hippocampus in mice: effects on appetitively reinforced task after intraventricular administration of Arg-vasopressin.

Antiserum to [Arg8]vasopressin (anti-AVP) was bilaterally administered into dorsal hippocampus at 1:50 or 1:10 dilution 20 min before the 24-day retention session of a visual discrimination task. This treatment by itself did not affect the retention performance by comparison with the respective control group, whatever the dilution of anti-AVP, suggesting that hippocampal endogenous AVP is not involved in our behavioral paradigm. On the other hand, intracerebroventricular (i.c.v.) administration of AVP 10 min before the retention session improved retention performance of the visual discrimination task. When anti-AVP was injected at the 1:10 dilution into the dorsal hippocampus 10 min before the i.c.v. administration of AVP, the retention performance was not improved. These data suggest the involvement of the hippocampus in the behavioral expression of AVP following an i.c.v. treatment.

Fos protein expression induced by intracerebroventricular injection of vasopressin in unconditioned and conditioned mice.

Arginine8-vasopressin (AVP) has been shown to improve memory consolidation in various mnemonic tasks. Our previous studies have pointed out the involvement of the hippocampus in memory consolidation and retrieval processes during discriminative learning by mice. The present study attempts to determine what other brain areas besides the hippocampus might be involved in the enhancing effect of intracerebroventricularly (i.c.v.) injected AVP on memory consolidation in a visual discrimination task using a polyclonal antibody that acts against Fos and Fos-like proteins. For behavioral testing, AVP was i.c.v. injected at the behaviorally active dose of 2 ng after the last learning session and improvement in consolidation processes was assessed in a retention session. Changes in Fos and Fos-like protein expression were determined in non-conditioned and conditioned mice. In non-conditioned mice, AVP i. c.v. injected at a dose of 2 ng evoked a time-dependent increase in Fos and Fos-like protein expression in the dentate gyrus (DG), CA1 and CA3 hippocampal fields, lateral septum (LS), bed nucleus of the stria terminalis, and basolateral and central amygdaloid nuclei, with a peak 120 min after the injection in most of the these brain areas. In contrast, in conditioned mice, an increase in the level of Fos expression, assessed 120 min after the end of learning and the injection of AVP, was detected only in the DG, ventral CA3 hippocampal field, and LS. Thus, the pattern observed after post-training injection of AVP was not the same as that evoked by AVP alone, since among the limbic structures activated following AVP alone, only the DG, the CA3 hippocampal field, and the LS seem to be involved in the enhancing effect of AVP on memory consolidation in discriminative learning.

Neuromodulation of memory in the hippocampus by vasopressin.

The involvement of [Arg(8)]vasopressin in memory processes was analyzed in the hippocampal structure, since we have reported that this is one of the main central target structures of the vasopressin-enhancing effect on memory. This structure is functionally differentiated along its dorsoventral axis, and the expression of the vasopressinergic system is dependent upon whether the dorsal or ventral part of the hippocampus is involved. For this reason, the effect of vasopressin injected into hippocampus was evaluated on the basis of the site of injection. We have shown, using a Go-No Go visual discrimination task with mice that both parts of the hippocampus are involved in the effect of endogenous or exogenous vasopressin, but with higher sensitivity for the ventral part. Based on the expression of Fos protein following intracerebroventricular injection of vasopressin in unconditioned or conditioned mice, we confirmed the greater involvement of the ventral hippocampus in the enhancing effect of vasopressin on memory processes. The effect of the peptide seems specific, since only a few of the hippocampal cells that expressed Fos protein in the unconditioned mice did so in the conditioned mice (cells in the dentate gyrus and the CA3 hippocampal field). Moreover, we have shown that in the ventral hippocampus, vasopressin generates different behavioral effects whether treatment is performed at the beginning or in the middle of the learning process, suggesting that the mnemonic context is an important factor for understanding the effect of vasopressin on memory in the ventral hippocampus.

The behavioral effect of vasopressin in the ventral hippocampus is antagonized by an oxytocin receptor antagonist.

[Arg8]vasopressin improved long-term retrieval processes and relearning in a go-no go visual discrimination task when bilaterally microinjected at a dose of 25 pg/animal into the ventral hippocampus of mice, 10 min prior to the retention session. We had shown that this enhancing effect is antagonized by pretreatment with equal or lower doses (25 pg or 1 ng) of the vasopressin V1 receptor antagonist, (d(CH2)5Tyr(Me)-vasopressin). The present study was an attempt to determine whether the vasopressin V2 receptor antagonist or oxytocin receptor antagonist is as effective as the vasopressin V1 receptor antagonist to block the behavioral effect of vasopressin in the ventral hippocampus. We tested the effect of 25 pg of [d(CH2)5-D-Ile2,Ile4,Arg8]vasopressin, a vasopressin V2 receptor antagonist, and [d(CH2)5,Tyr(Me)2,Thr4,Tyr-NH9(2)]ornithine vasotocin, an oxytocin receptor antagonist, under the same experimental conditions as those used to test the effect of the vasopressin V1 receptor antagonist. The results showed that the vasopressin V2 receptor antagonist microinjected into the ventral hippocampus did not alter the enhancing effect of vasopressin on retrieval and relearning. In contrast, the oxytocin receptor antagonist blocked the vasopressin-enhancing effect on retention processes. We can conclude from the data that both vasopressin V1 receptors and oxytocin receptors seem to be involved in the enhancing effect of vasopressin on memory retention. In contrast, the vasopressin V2 receptors do not seem to be involved in the effect of the peptide.

Inhibition of the vasopressin-enhancing effect on memory retrieval and relearning by a vasopressin V1 receptor antagonist in mice.

We have previously shown that [Arg8]vasopressin bilaterally administered into the ventral hippocampus of mice at a dose of 0.025 ng/animal 10 min prior to the retention session, improved long-term retrieval processes and relearning of a Go-No-Go visual discrimination task. The purpose of the present study was to determine whether the vasopressin V1 receptor antagonist, -beta-mercapto-beta,beta-cyclopentamethylenepropionyl1, O-Me-Tyr2,Arg8]vasopressin, d(CH2)5Tyr(Me)vasopressin), is able to block the behavioral effect of arginine-vasopressin in the ventral hippocampus. We first tested the effect of three doses of d(CH2)5Tyr(Me)vasopressin (0.025, 1, and 6.3 ng/animal) in the same experimental conditions as used for arginine-vasopressin. The results showed a dose-dependent deleterious effect of the vasopressin V1 receptor antagonist on retrieval and relearning, suggesting the involvement of endogenous arginine-vasopressin in the ventral hippocampus for these memory processes. Second, we tested the ability of d(CH2)5Tyr(Me)vasopressin to block the enhancing effect of experimentally administered arginine-vasopressin. The antagonist was injected at a dose of 0.025 ng, which had no intrinsic effect on behavior, or at a dose of 1 ng, which had a weak deleterious effect on behavior, followed by administration of 0.025 ng of arginine-vasopressin. The results showed that even at the weakest dose (0.025 ng), d(CH2)5Tyr(Me)vasopressin blocked the enhancing effect of arginine-vasopressin on retrieval and relearning. Thus, as for other behaviors and structures, the antagonist microinjected into the ventral hippocampus prevents the enhancing effect of arginine-vasopressin on long-term retrieval and relearning. However, the exclusive involvement of the vasopressin V1 receptors remain to demonstrate vis-a-vis oxytocin receptors.

Facilitation of retention performance in mice by pretest microinjection of AVP into dorsal or ventral hippocampus: differential influence of the peptide on appetitive task.

Pre-test local microinjection of arginine-vasopressin (AVP) into dorsal or ventral hippocampus resulted in an improvement of retention performance in an appetitively motivated task. Nevertheless, a better improvement appeared when AVP treatment was performed into ventral hippocampus suggesting a higher sensitivity of this part of hippocampus to the action of AVP. To examine a non-specific behavioral action of the peptide, the effect of AVP treatment on locomotor activity was assessed. When the treatment was given into ventral hippocampus, a reduction of locomotor activity was recorded, whereas after AVP injection into dorsal hippocampus, the peptide failed to alter locomotor activity.

Posture and cognition in the elderly: interaction and contribution to the rehabilitation strategies.

In this paper we review the effects of aging on sensory systems and their impact on posture, balance and gait. We also address cognitive aging and attempt to specify which altered cognitive functions negatively impact balance and walking. The role of cognition in postural control is tested with dual-task experiments. This situation results in deleterious effects due to an attentional overload. Given the human cognitive system has limited capacities, we propose that simultaneously performing two tasks depends on the capacity of each individual to perform these tasks on a continuum between automatic execution to highly controlled performance. A level of maximum control exceeds the subject's attentional capacity, which makes it impossible to perform both tasks simultaneously. The subject therefore prioritizes one of the tasks. We use representative dual-task studies from the literature to illustrate the relationship between the different cognitive components and their impact on the control of posture and gait in elderly subjects with altered cognitive capacities and with elderly subjects who are fallers or who have altered sensory-motor capacities. Recently this postural-cognitive relationship was addressed with a new approach. We report how cognitive training can improve dual-task management and we attempt to define the cognitive mechanisms that may be responsible for better postural balance.

Therapeutic and preventive effects of methylene blue on Alzheimer's disease pathology in a transgenic mouse model.

Methylene blue (MB) belongs to the phenothiazinium family. It has been used to treat a variety of human conditions and has beneficial effects on the central nervous system in rodents with and without brain alteration. The present study was designed to test whether chronic MB treatment taken after (therapeutic effect) or before (preventive effect) the onset of beta-amyloid pathology influences cognition in a transgenic mouse model (APP/PS1). In addition, the present study aims at revealing whether these behavioral effects might be related to brain alteration in beta-amyloid deposition. To this end, we conducted an in vivo study and compared two routes of drug administration, drinking water versus intraperitoneal injection. Results showed that transgenic mice treated with MB orally or following intraperitoneal injection were protected from cognitive impairments in a variety of social, learning, and exploratory tasks. Immunoreactive beta-amyloid deposition was significantly reduced in the hippocampus and adjacent cortex in MB-treated transgenic mice. Interestingly, these beneficial effects were observed independently of beta-amyloid load at the time of MB treatment. This suggests that MB treatment is beneficial at both therapeutic and preventive levels. Using solid-state High Resolution Magic Angle Spinning Nuclear Magnetic Resonance (HRMAS-NMR), we showed that MB administration after the onset of amyloid pathology significantly restored the concentration of two metabolites related to mitochondrial metabolism, namely alanine and lactate. We conclude that MB might be useful for the therapy and prevention of Alzheimer's disease. This article is part of the Special Issue entitled 'The Synaptic Basis of Neurodegenerative Disorders'.

Positive effects of computer-based cognitive training in adults with mild cognitive impairment.

Considering the high risk for individuals with amnestic Mild Cognitive Impairment (A-MCI) to progress towards Alzheimer's disease (AD), we investigated the efficacy of a non-pharmacological intervention, that is, cognitive training that could reduce cognitive difficulties and delay the cognitive decline. For this, we evaluated the efficacy of a 12-week computer-based memory-attention training program based on recognition in subjects with A-MCI and compared their performances with those of A-MCI controls trained in cognitively stimulating activities. The effect of training was assessed by comparing outcome measures in pre- and post-tests 15 days before and after training. To evaluate the duration of training benefits, a follow-up test session was performed 6 months after memory and attention training or cognitively stimulating activities. Outcome measures showed that the trained group, compared to control group, improved episodic recall and recognition. Six months after training, scores remained at the level of the post-test. Since the training program was exclusively based on recognition, our results showed a generalization from recognition to recall processes, which are memory components that represent part of the core cognitive impairments in individuals at risk of converting to AD. Thus, cognitive training based on recognition holds promise as a preventive therapeutic method and could be proposed as a non-pharmacological early-intervention strategy. Future investigations need to focus on methodological constraints and delineating possible neuroplastic mechanisms of action.

Involvement of alpha- and beta-noradrenergic receptors in the effects of hippocampal vasopressinergic treatment on retrieval and relearning.

Biochemical investigations show that vasopressin interacts with noradrenalin to potentiate noradrenalin-induced accumulation of cyclic-AMP in the hippocampus, via the beta-adrenergic receptors. We previously showed in BALB/c mice that the effects of vasopressin (bilaterally injected at a 25-pg dose) in the ventral hippocampus were more effective than in the dorsal hippocampus on the retrieval and relearning of a Go-No Go visual discrimination task. Considering our results and those reported by biochemical investigations, we evaluated possible noradrenergic-vasopressinergic interaction in the ventral hippocampus under our behavioral conditions. To do so, we first explored the effects of propranolol and phentolamine, antagonists of beta- and alpha-adrenergic receptors, respectively. Second, we assessed the modifications in the vasopressin-induced improvement of retrieval and relearning by pretreating the subjects with either propranolol or phentolamine. Third, we tested the treatments in a locomotor activity task to determine whether the effects demonstrated in the two preceding experiments could be partially due to locomotor alterations by the drug. The results indicated that bilateral injection of propranolol (1 microgram on each side), which did not appear to affect the retention performance itself, completely blocked the enhancement of retrieval and relearning resulting from the vasopressin treatment. In contrast, bilateral injection of phentolamine (1 microgram on each side), which moderately improved retrieval, enhanced the vasopressin effect. The present results lend further support to the view that both noradrenalin and vasopressin play important roles in retrieval and relearning processes. More importantly, they provide additional support for the functional interaction of the noradrenergic and vasopressinergic hippocampal systems.