Vasopressin antagonizes retrograde amnesia in rats following electroconvulsive shock

Rats given an electroconvulsive shock immediately following training in a passive avoidance task showed amnesia when tested 24 hr after training. This amnesia was prevented if lysine vasopressin was injected either one hr before the training trial or one hr before the first test trial. The results indicate that it is unlikely that either electroconvulsive shock or lysine vasopressin affect memory storage.     

Lysine vasopressin attenuation of diethyldithiocarbamate-induced amnesia

The effect of lysine vasopressin on diethyldithiocarbamate-induced amnesia for a step-through passive avoidance task was studied in rats. It was determined that although the hormone attenuates the amnesia when it is administered prior to retrieval testing, it fails to do so when it is injected prior to training. These results are consistent with the reports of others which demonstrate the reversal of diethyldithiocarbamate-induced amnesia by catecholamine agonists.     

Effects of 4-hydroxy, 4-phenyl,caproamide on pentylenetetrazol-induced amnesia

Early reports suggest a relationship between pentylenetetrazol-induced convulsions (PTZ) and amnesia. 4,-Hydroxy, 4-phenyl caproamide (YPCA) is potently anticonvulsant againts PTZ-induced convulsions. The purpose of these experiments is to show the possible role of PTZ in these amnestic effects. Experiment 1 proves YPCA antagonism of PTZ-induced convulsions in mice. Experiment 2 shows how YPCA, injected before PTZ and after animal training, protects against convulsions, leaving memory storage un-affected. However, when YPCA is injected before training (10 and 5 min) and PTZ 15 min afterwards (5 and 10 min after training), a retention impairment was observed. The results are discussed in terms that emphasize the need of convulsions in retrogarde amnesia. Experiment 3 shows that foot shock is necessary for passive avoidance acquisition. Experiment 4 shows that subconvulsive doses of PTZ (5, 10, 20, and 40 mg/kg^-1) have no effect on memory.     

Phencyclidine-induced retrograde amnesia in mice

The amnesic action of phencyclidine (PCP) was investigated in mice using a passive avoidance- and escape-learning method. PCP (10–30 mg/kg) administered immediately after the training test dose-dependently shortened and prolonged the step-down latency and escape latency, respectively in the retention test. There was a significant inverse relationship between the step-down and escape latencies, indicating that PCP had induced amnesia. The amnesic actions of PCP were retrograde, being observed when mice were given PCP within 10 min but not more than 30 min after the training test. The amnesic effects of PCP on both variables were antagonized significantly by physostigmine and naloxone, whereas cyproheptadine and haloperidol had no effect. None of these drugs by themselves affected passive avoidance- or escape-learning performance. These results suggest that the retrograde amnesic actions of PCP were produced via either the cholinergic or the opioidergic systems or both, but not through the serotonergic and the dopaminergic systems. Offprint requests to: T. Nabeshima     

Prevention of retrograde amnesia by injection of magnesium pemoline in dimethylsulfoxide

Summary It was demonstrated that magnesium pemoline in DMSO attenuates ECS-produced retrograde amnesia when administered prior to training in a passive avoidance task. We also observed that although there is RA for the specific step-off response that led to painful footshock, Ss receiving ECS showed an increase in emotionality similar to footshock controls suggesting RA for the specific response but not the general test situation. High doses of pemoline (24 mg/kg) not followed by ECS disrupted performance of the response but not retention. Magnesium hydroxide Mg (OH)₂ 8 mg/kg administered in DMSO proved to be severely disrupting when followed by ECS indicating an interaction with pemoline since pemoline without magnesium + ECS and Mg (OH)₂ + FS had no effect on performance in this type of situation.This research was supported by NSF grant No. GB 7041 to both authors.     

Reversal of ECS-induced amnesia by post-ECS injections of amphetamine.

Water deprived rats were trained to drink from a water spout within an apparatus on each of 2 days. On the third day, passive avoidance of the spout was induced by giving the animal a 0.3 sec, 5 mA footshock after 1 lick at the spout. A test for retention of the avoidance learning was given 48 hr following training. ECS administered through cortical electrodes at 15 sec following the footshcok impaired retention. The amnesia was attenuated when amphetamine (1 mg/kg) was injected immediately but not at 6 hr following the ECS. In a second experiment, attentuation of amnesia by amphetamine was not found when the ECS occured at 4 sec instead of 15 sec following the footshock. The results are interpreted in terms of reactivation by amphetamine of a consolidation process that was interrupted by ECS.     

Pentylenetetrazol-induced retrograde amnesia and brain seizures in mice

These experiments examined in three strains of mice (Ha/ICR, Swiss Webster and C57BL/6J) the influence of pentylenetetrazol injections on: 1) brain seizure activity recorded from cortical electrodes, and 2) retrograde amnesia in an inhibitory avoidance task. In Ha/ICR mice, pentylenetetrazol administered after training impaired retention in doses that elicited brain seizures as well as in doses just below those which elicit brain seizures. The degree of retention impairment decreased with increasing training-treatment intervals. In Swiss Webster and C57BL/6J mice, doses of pentylenetetrazol which produced brain seizures did not affect retention. The results indicate that elicitation of brain seizures is not a sufficient condition for producing retrograde amnesia with pentylenetetrazol.Supported by Research Grant MH 12526 and Predoctoral Training Grant MH 11095-05 from the National Institute of Mental Health, United States Public Health Service.     

Electroshock-induced retrograde amnesia and brain serotonin metabolism: Effects of several antidepressant compounds

Summary Mice treated with either amitriptyline, nialamide, or pipradol showed a significant degree of antagonism toward the amnesic effect of electroconvulsive shock administered 10 sec following a single conditioning trial. Saline-treated control animals showed a high incidence of amnesia for the same response as a result of post-training electroshock. Under control conditions, where no posttraining ECS was given, a consistently high level of conditioned response retention was shown. Although the mechanism of action for each of the drugs with regard to serotonin metabolism was quite different, a common factor in each case was that brain serotonin levels were generally reduced following ECS, whereas for control animals one post-ECS effect was elevated brain serotonin. The present findings suggest that elevation of brain serotonin levels produced by ECS, and taking place during the post-training interval within which the memory trace is consolidated, may account, in part, for the resulting retrograde amnesia; antagonism of the amnesic effect of ECS is apparently accomplished by providing for conditions wherein this ECS-induced serotonin change is blocked.This study was supported, in part, by Grants MH 08698-03 and MH 13191-01 from the U.S.P.H.S. The author wishes to acknowledge the technical assistance of M. Steinberg and M. Golod.     

Emotion-induced retrograde amnesia varies as a function of noradrenergic-glucocorticoid activity

Rationale Privileged episodic encoding of an aversive event often comes at a cost of neutral events flanking the aversive event, resulting in decreased episodic memory for these neutral events. This peri-emotional amnesia is amygdala-dependent and varies as a function of norepinephrine activity. However, less is known about the amnesiogenic potential of cortisol. Objective We used a strategy of pharmacologically potentiating cortisol and norepinephrine activity to probe the putative neurochemical substrates of peri-emotional amnesia. Materials and methods Fifty-four healthy individuals participated in a randomized double-blind placebo-controlled study. Within the experimental context of an established peri-emotional amnesia paradigm, we tested the amnesiogenic potential of hydrocortisone (30 mg p.o.) in the presence or absence of the norepinephrine-reuptake inhibitor reboxetine (4 mg p.o.). Results Under dual challenge conditions, we observed a linear dose–response relationship in the magnitude and duration of emotion-induced retrograde amnesia. Conclusions Our results are consistent with a phenotypic expression of retrograde amnesia varying as a function of norepinephrine and cortisol coactivation during episodic encoding of aversive events. Our study demonstrates that the adverse cognitive and behavioral sequelae of aversive emotion can be experimentally modeled by a pharmacological manipulation of its putative neurochemical substrates. Electronic Supplementary Material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Glucocorticoid mechanisms may contribute to ECT-induced retrograde amnesia

Rationale Cortisol levels rise sharply immediately after electroconvulsive therapy (ECT); the resultant stimulation of steroid receptors in the hippocampus may be beneficial or harmful to cognition, depending on the magnitude of the stimulation. Steroid mechanisms may therefore modulate ECT-induced amnesia.Objectives Using mifepristone (a glucocorticoid receptor antagonist) as a chemical probe, we sought to examine steroid mechanisms in an animal model of ECT-induced retrograde amnesia.Materials and methods Adult, male Wistar rats (n = 68) trained in a step-through passive-avoidance task were randomized to receive mifepristone (20 or 40 mg kg⁻¹ day⁻¹) or vehicle (control). These treatments were administered 1 day before the electroconvulsive shock (ECS) course and, again, 1 h before each of five once-daily true (30 mC) or sham ECS. Recall of pre-ECS learning was tested 1 day after the last ECS.Results Relative to sham ECS, true ECS resulted in significant retrograde amnesia in the vehicle group but not in either of the mifepristone groups. In sham ECS-treated animals, mifepristone did not significantly influence recall. In ECS-treated rats, the higher but not the lower dose of mifepristone was associated with significant protection against the retrograde amnesia evident in the vehicle group.Conclusion Mifepristone administered before the ECT seizure may attenuate ECT-induced retrograde amnesia. This suggests that glucocorticoid mechanisms may contribute to ECT-induced retrograde amnesia.     

Time dependent changes in anterograde scopolamine-induced amnesia in rats

These experiments studied the effect of scopolamine on memory formation and subsequent memory recall. Different groups of rats were trained on a Y-maze brightness discrimination task 20 min after IP injection of 2 mg/kg scopolamine HBr, an anticholinergic. Retention tests were then conducted 1 day or 2, 4, or 6 weeks after training. Deficits in retention performance were observed at 1 day and 2 weeks after training but not at the longer intervals. In addition, other rats were trained in the same manner and after the same dose of scopolamine but were then retention tested 20 min after 0.5 mg/kg physostigmine salicylate, a cholinesterase inhibitor. These subjects also showed deficits at 1 day and 2 weeks but were not different from controls at the longer intervals. Amnesia was not, however, produced after treatment with scopolamine methyl nitrate or by injections of scopolamine HBr administered immediately after training. These results suggest that scopolamine, present in the central nervous system during training or within the first few moments thereafter, modifies the formation of the memory trace in such a way that memory is not available for recall for a period of weeks.     

Effects of pretraining on subsequent cycloheximide induced amnesia

In the first experiment, mice were trained on a passive avoidance (PA) task, given one extinction trial, and then were injected with cycloheximide or saline shortly before retraining on the PA task. On a subsequent test trial, the performance of the cycloheximide group was inferior to the saline group, but superior to a cycloheximide group not given the pretraining experience. In the second experiment, one group of mice was given cycloheximide before each of two training sessions while another group received cycloheximide before the first training session and saline before the second. The group given cycloheximide before each training session was amnesic for both sessions to an equal degree, while the other group was amnesic for only the first session. The final test performance of the latter group was similar to that of a saline group not given any pretraining experience. These data seem to indicate that pretraining has limited effect on subsequent cycloheximide induced amnesia, and that such amnesia is the result of impaired memory formation rather than impaired memory retrieval.     

Intraventricular N-acetyl-L-glutamate induces retrograde amnesia in chicks

Two-day-old chicks were injected intraventricularly with saline or an N-acetyl-L-glutamate solution. The amino acid analog produced retrograde amnesia without concomitant electrophysiological seizure activity. A mechanism involving the disruption of activity at memory-related glutamate synapses was suggested for the observed amnestic effect.     

The nature of lorazepam-induced amnesia

The effect of lorazepam (2.5 mg) was assessed in two tests of short-term retention (digit-span and Benton Visual Retention), and in verbal learning and picture recognition tests. Lorazepam was without effect in a test of digit-span, but it impaired performance in the Benton Visual Retention and picture recognition tests. In the verbal learning test lorazepam caused a severe anterograde amnesia. Increasing arousal during the presentation of material partially overcame this effect, but also improved the performance of controls. Lorazepam-treated subjects were able to learn a backwards-reading task at a rate no different from controls. The deficits caused by lorazepam are similar to those that have been observed in patients with the amnesic syndrome.     

Hippocampal monoamine metabolism and the CO2 induced retrograde amnesia gradient in rats.

It was found that in rats a gradient of retrograde amnesia for a passive avoidance response could be established when carbon dioxide (CO2) was used as the amnesic agent. The extent of passive avoidance increased as the period between application of a mild foot shock and CO2 treatment was increased. The amnesia gradient was found to cover a period of at least 60 min. Changes in hippocampal serotonin metabolism parallelled the amnesia gradient. Thus, the concent increased. The changes in hippocampal noradrenaline and dopamine did not correlate with the amnesia gradient.     

The effect of scopolamine on the amnesia induced by electroconvulsive shock

Rats previously allowed to drink water from a spout received a mouth-shock at the spout as one-trial avoidance training. In animals where a pair of ECSs followed the mouth-shock, a retention test 48 hr later revealed a reliable amnesia relative to sham ECS animals. When scopolamine was injected 30 min prior to the test trials, the amnesia was unchanged. The present results do not confirm previous suggestions that scopolamine can completely reverse ECS-induced amnesia.     

Recovery as a function of the degree of amnesia due to protein synthesis inhibition

Retrograde amnesia following inhibition of cerebral protein synthesis has generally been explained as either a failure of consolidation or impairment of a retrieval mechanism. Major evidence for the retrieval hypothesis is provided by studies which utilize a reminder (usually footshock) to attenuate the effect of the protein inhibitor. To examine this question, mice were injected subcutaneously with anisomycin (1 mg/animal, 7 mg/animal, or 1 mg/animal every 2 hr x 7) and given one training trial in a passive avoidance box. All animals received a single retention test on each of four consecutive days, starting either 1, 7, or 21 days after training. One-half of the mice in each group received a footshock reminder 1 hr after their initial test. The footshock reminder did not attenuate the inhibitor-induced amnesia, but multiple testing did produce partial recovery in animals demonstrating some memory of training (both Saline and Anisomycin animals). Animals injected with anisomycin whose testing began 1 day after training demonstrated partial recovery irrespective of drug dosage level. The extent of amnesia and recovery were dependent upon both drug dosage and training-test interval. Implications for the consolidation and retrieval hypotheses are discussed.     

Reversal of guanethidine- and diethyldithiocarbamate-induced amnesia by peripherally-administered catecholamines

The effect of peripherally-administered catecholamines on guanethidine- and diethyldithiocarbamate-induced amnesia of a PA training in mice was investigated. The amnesic effect of guanethidine could be blocked with 50 mg/kg DA, or 0.75 mg/kg NE when given either before, immediately, or 10 min after but not 90 min following PA. Epinephrine or a lower dose of DA could be attenuate the guanethidine-induced amnesia. The amnesic effect of diethyldithiocarbamate could be blocked with 50 mg/kg DA, 0.75 mg/kg NE or 0.5 mg/kg E when given either before, immediately or 10 ming after but not 90 min following PA. The amnesic effects of these compounds were interpreted in terms of their peripheral antiadrenergic actions.     

Reversal of scopolamine-induced amnesia by phosphatidylserine in rats

Scopolamine (2 mg/kg IP) and propranolol (55 mg/kg IP), given before a single learning trial, reduce retention of a passive avoidance response in rats. Phosphatidylserine, 30–60 mg/kg IP, antagonizes the amnesic effect of scopolamine but not that of propranolol. The retention of the passive avoidance response is not affected by phosphatidylserine given alone. The results indicate that this phospholipid selectively counteracts the action of scopolamine on passive avoidance acquisition, probably via a cholinergic mechanism.     

Peripheral catecholamines and memory: characteristics of syrosingopine-induced amnesia.

The effect of syrosingopine on retention of a passive avoidance trial in mice was investigated. The drug given in doses of 2.5, 4.0 or 6.0 mg/kg 2 hr before training, but not when given 24 or 0.5 hr or immediately after training, resulted in amnesia 7 days later. Dopamine or norepinephrine administered systemically 15 min before to 10 min after training was able to block the syrosingopine-induced amnesia. The role of peripheral catecholamines in memory formation was discussed.