Pharmacological effects and behavioral interventions on memory consolidation and reconsolidation

In this article, we will review some behavioral, pharmacological and neurochemical studies from our laboratory on mice, which might contribute to our understanding of the complex processes of memory consolidation and reconsolidation. We discuss the post-training (memory consolidation) and post-reactivation (memory reconsolidation) effects of icv infusions of hemicholinium, a central inhibitor of acetylcholine synthesis, of intraperitoneal administration of L-NAME, a non-specific inhibitor of nitric oxide synthase, of intrahippocampal injections of an inhibitor of the transcription factor NF-κB, and the exposure of mice to a new learning situation on retention performance of an inhibitory avoidance response. All treatments impair long-term memory consolidation and retrieval-induced memory processes different from extinction, probably in accordance with the "reconsolidation hypothesis".

Differential role of entorhinal and hippocampal nerve growth factor in short- and long-term memory modulation

We studied the effects of infusion of nerve growth factor (NGF) into the hippocampus and entorhinal cortex of male Wistar rats (250-300 g, N = 11-13 per group) on inhibitory avoidance retention. In order to evaluate the modulation of entorhinal and hippocampal NGF in short- and long-term memory, animals were implanted with cannulae in the CA1 area of the dorsal hippocampus or entorhinal cortex and trained in one-trial step-down inhibitory avoidance (foot shock, 0.4 mA). Retention tests were carried out 1.5 h or 24 h after training to measure short- and long-term memory, respectively. Immediately after training, rats received 5 æl NGF (0.05, 0.5 or 5.0 ng) or saline per side into the CA1 area and entorhinal cortex. The correct position of the cannulae was confirmed by histological analysis. The highest dose of NGF (5.0 ng) into the hippocampus blocked short-term memory (P < 0.05), whereas the doses of 0.5 (P < 0.05) and 5.0 ng (P < 0.01) NGF enhanced long-term memory. NGF administration into the entorhinal cortex improved long-term memory at the dose of 5.0 ng (P < 0.05) and did not alter short-term memory. Taken as a whole, our results suggest a differential modulation by entorhinal and hippocampal NGF of short- and long-term memory.

Differential effects of lead and zinc on inhibitory avoidance learning in mice

We studied the effects of chronic intoxication with the heavy metals lead (Pb2+) and zinc (Zn2+) on memory formation in mice. Animals were intoxicated through drinking water during the pre- and postnatal periods and then tested in the step-through inhibitory avoidance memory task. Chronic postnatal intoxication with Pb2+ did not change the step-through latency values recorded during the 4 weeks of the test (ANOVA, P>0.05). In contrast, mice intoxicated during the prenatal period showed significantly reduced latency values when compared to the control group (day 1: q = 4.62, P<0.05; day 7: q = 4.42, P<0.05; day 14: q = 5.65, P<0.05; day 21: q = 3.96, P<0.05, and day 28: q = 6.09, P<0.05). Although chronic postnatal intoxication with Zn2+ did not alter a memory retention test performed 24 h after training, we noticed a gradual decrease in latency at subsequent 4-week intervals (F = 3.07, P<0.05), an effect that was not observed in the control or in the Pb2+-treated groups. These results suggest an impairment of memory formation by Pb2+ when the animals are exposed during the critical period of neurogenesis, while Zn2+ appears to facilitate learning extinction

Effects of oxytocin and an oxytocin receptor antagonist on retention of a nose-poke habituation response in mice

The present study describes the use of nose-poke habituation as a memory task in mice and demonstrates that it is sensitive to oxytocin (OT) and an oxytocin receptor antagonist (AOT) administered after the learning trial. Habituation of nose-poke behavior of mice was defined as a reduction in number of nose-pokes compared to baseline, and was measured in a hole-board apparatus to which male Swiss mice were exposed on two consecutive days for 5 min, respectively. Immediate post-training subcutaneous administration of OT (2.00 mug/kg) impaired retention performance, whereas AOT (0.20 mug/kg) enhanced it. Neither the impairing effects of OT (2.00 mug/kg) nor the enhancing effects of AOT (0.20 mug/kg) were seen when the training treatment interval was 180 min, suggesting that both treatments influenced the storage of recently acquired information. The effects of OT (2.00 mug/kg) on retention were prevented by AOT (0.02 mug/kg) administered immediately after training but 10 min prior OT treatment. This dose of antagonist did not affect retention by itself which suggest that impairing effects of OT on retention are probably due to an interaction of the neuropeptide with specific receptors. The actions of OT and AOT on retention were not due to enduring proactive effects of the compounds on performance during the retention test, since when given to untrained mice did not modify their spontaneous activities in the hole-board when recorded 24 h later. We suggest that nose-poke habituation learning can be a suitable method to investigate the mnestic effects of drugs, and that oxytocin negatively modulates memory storage of this form of learning elicited by stimuli repeatedly presented without reinforcement.

Involvement of hippocampal NMDA receptors in retention of shuttle avoidance conditioning in rats

The purpose of this research was to evaluate the role of hippocampal N-methyl-D-aspartate (NMDA) receptors in acquisition and consolidation of memory during shuttle avoidance conditioning in rats. Adult male Wistar rats were surgically implanted with cannulae aimed at the CA1 area of the dorsal hippocampus. After recovery from surgery, animals were trained and tested in a shuttle avoidance apparatus (30 trials, 0.5-mA footshock, 24-h training-test interval). Immediately before or immediately after training, animals received a bilateral intrahippocampal 0.5-µl infusion containing 5.0 µg of the NMDA competitive receptor antagonist aminophosphonopentanoic acid (AP5) or vehicle (phosphate-buffered saline, pH 7.4). Infusion duration was 2 min per side. Pre-training infusion of AP5 impaired retention test performance (mean Ý SEM number of conditioned responses (CRs) during retention test session was 16.47 Ý 1.78 in the vehicle group and 9.93 Ý 1.59 in the AP5 group; P<0.05). Post-training infusion of AP5 did not affect retention (mean Ý SEM number of conditioned responses during retention test session was 18.46 Ý 1.94 in the vehicle group and 20.42 Ý 2.38 in the AP5 group; P>0.10). This impairment could not be attributed to an effect on acquisition, motor activity or footshock sensitivity since AP5 affected neither training session performance measured by the number of CRs nor the number of intertrial crossings during the training session. These data suggest that NMDA receptors in the hippocampus are critical for retention of shuttle avoidance conditioning, in agreement with previous evidence showing a role of NMDA receptors in fear memory

Age-related effects of diazepam on retention of inhibitory avoidance and shuttle avoidance tasks in rats

We investigated the effect of diazepam on memory of 30 days-old and 60-70 days-old female Wistar rats, using two behavioral tasks: step-down inhibitory avoidance (IA) and shuttle avoidance (SA). Diazepam (0.2,1.0 or 5.0 mg/kg) or its vehicle were given i.p., 60 min prior to the training session. Training-test interval was 24h. Diazepam impaired the retention of IA in 30 days-old rats at the three doses used, while retention of SA was not impaired by any dose. In the 60-70 days-old animals, diazepam at the dose of 0.2 mg/kg was facilitatory in IA and had no effect on SA, while doses of 1.0 mg/kg and 5.0 mg/kg impaired retention of both tasks. We suggest that these age-dependent effects of diazepam on memory of IA and SA could be related to developmental changes in brain GABA(A) receptors.

Effect of gestational undernutrition and chlordiazepoxide treatment on black/white discrimination learning and retention in young rats.

Effects of prenatal undernutrition and chlordiazepoxide treatment on learning acquisition, and subsequent retention, of a black/white discrimination task, was assessed in the offspring. Undernutrition of the dams was induced by restricting food intake to half, throughout the period of gestation, whereas chlordiazepoxide (2.5 mg/kg, ip) treatment was given from day 13 to 20 of gestation, this being the critical period for neural development in this species. The pups born were subjected to brightness discrimination learning, and retention of the learning acquisition after an interval of one week, in a single unit black/white T-maze, at 8-9 weeks of age. The results indicate that prenatal undernutrition induces significant learning and retention deficits in the offspring. Prenatally administered chlordiazepoxide induced significant deficits in learning acquisition and subsequent retention of the discrimination problem. Chlordiazepoxide induced similar learning and retention deficits in the normal and undernourished rats, and exaggerated the learning and retention deficits induced by undernutrition. The results indicated that the prenatal insults in the form of undernourishment and anxiolytic benzodiazepine compounds, leave a lasting imprint on cognitive behaviour of the offspring.

Effect of post-training injections of flumazenil into the amygdala, hippocampus and septum on retention of habituation and of inhibitory avoidance in rats

Adult rats were submitted to two different behavioral tasks using the same apparantus: the habituation of exploration of the apparatus considered as a novel environment as measured by the decrease in number of reaings and of ambulation between training and testing, and step-down inhibitory avoidance as measured by the increase in the latency to step down from a start platform into an electrified grid between the training and the test session.The training-test interval for both tasks was 20 h.The immediate post-training injection of the benzodiazepine receptor antagonist flumazenil (10 nmol) bilateral into the hippocampus enhanced retention of the two tasks.Application of the same drug, at the same dose to the septum or amygdala had no effect on habituation but enhanced retention of the avoidance task. The data are consistent with previous findings showing that both tasks are accompanied by the release of benzodiazepine like immunoreactivity in the three structures and that this release is greater after the avoidance task. The present findings suggest a differential regional involvement of endogenous benzodiazepine-mediated mechanisms in memory modulation, according to the task undertaken

Effect of fencamfamine on avoidance performances of rats

The effects of fencamfamine (1.0 and 5.0 mg/kg, ip single dose) on an inhibitory task were studied in rats (N=15 per group).Post-training treatment with fencamfamine (1.0 mg/kg) significantly increased avoidance latency from 23 ñ 3 to 146 ñ 28 and 170 ñ 33 s for training day 1 and day 7, respectively, indicating an enhacement of retention.However, retention was significantly reduced with a high dose of fencamfamine (5.0 mg/kg). These results demonstrate that fencamfamine caused a reproducible dose-related increase and reduction in avoidance latency

Ethanol decreases choice accuracy in a radial maze delayed test

1. The effect of acute ethanol on memory was studied in an eight-arm radial maze by interposing a 15-s or 1-h delay between the rat's fourth and fifth arma choices. 2. Ethanol (1.0g/Kg) was injected intraperitoneally 5 min prior to the firsrt set of 4-arm choices, therefore being presrnt since the acquisition of the trial-unique event. 3. The results showed 1) a decrease in choice accuracu only in the final 4 arm choices after the 1-h delay, and 2) that errors consisted of re-entries into arms chosen before the delay was imposed. The data further support the contention that ethanol impairs retention of working memory

ß-endorphin and electroconvulsive shock alter the retrieval of two avoidance tasks when given after the first, but not the second, training session

1. Rats were submitted to three consecutive sessions, one sessions per day, of two-way active avoidance or of step-down inhibitory avoidance, and received 1 µg/Kgß-endorphin intraperitoneally or an electroconvulsive shock immediately aftere the first or after the second training session. 2. Administration of either treatment after the first session caused a reduction of performance in the second session in both tasks. There was no impairment of performance in the third session. 3. Administration of either treatment after the second session did not affect performance during the third session. 4. Therefore the effect of ß- endorphin and of electroconvulsive shock on active and inhibitory avoidance performance was expressed only when treatments were administered after the first, i.e., novel, training experience. We suggest this effect is on mechanisms acting on retrieval, since the retention performance of all groups for the third session were identical