The GABA-B antagonist CGP 36742 prevent PTZ-kindling-provoked amnesia in rats.

Deficit in active and inhibitory avoidance behaviour has been found in pentylenetetrazole (PTZ)-kindled rats. This supports the view that memory deficit is an integral part of epilepsy. In the present study we examined the effect of the GABA B antagonist CGP 36742 on memory deficit induced by PTZ-kindling in shuttle-box- and step-down-trained rats. The retention in CGP 36742-treated animals was significantly improved compared to the kindled controls. The mechanisms of action of CGP 36742 is considered. The favourable effect of the GABA B antagonist in cases of amnesia provoked by PTZ-kindling might be of interest in clinical practice.     

Effects of acute doses of oxiracetam in the scopolamine model of human amnesia

The scopolamine model of amnesia has been used to test the pharmacodynamic efficacy of oxiracetam in 12 healthy volunteers. The subjects were divided into four experimental groups, according to a double-blind cross over incomplete randomized block design. After a baseline neuropsychological examination, each subject received in two separate sessions one of the following treatments, as acute oral doses: oxiracetam 800, 1600, 2400 mg or placebo. One hour after treatment scopolamine hydrobromide (0.5 mg) was given subcutaneously. The cognitive performance was tested before and 1, 2, 3 and 25 h after scopolamine administration. Scopolamine caused a deterioration of performance of verbal episodic memory, semantic memory and attention tests. In comparison to placebo, oxiracetam improved the overall test performance, with a statistically significant difference at the dose of 1600 mg on delayed recall of word lists, and showed dose-related antagonism of scopolamine-induced effects also on semantic memory and attention. The efficacy of an acute dose of oxiracetam in reducing scopolamine-induced cognitive impairment supports the potential usefulness of this pharmacological model of amnesia for studying the effects of cognition enhancers in humans.     

Enhancing effects of Hoe 175 on memory in mice

These experiments investigated the effects of the nootropic compound Hoe 175 [3,8-dimethyl-4-phenyl-5,6,7,8-tetrahydro-pyrazolo-(3,4-b) (1,5)-diazepine-1H,4H-5,7-dione] on retention performance of mice in three training tasks. When administered prior to both training and retention testing on a one-trial inhibitory avoidance task, Hoe 175 (6–25 mg/kg PO) attenuated the amnestic effect of transcorneal electroconvulsive shock. Post-training administration of Hoe 175 enhanced retention of otherwise untreated mice in both inhibitory (3–12 mg/kg IP) and active avoidance (1–25 mg/kg IP) learning tasks. The drug was most effective at intermediate doses. The enhancing effect of post-training administration of Hoe 175 was time-dependent: enhancement of retention was obtained with injections administered 2 h but not 6 h after training. The findings are interpreted as suggesting that Hoe 175 affects retention performance through influences on memory storage and retrieval.Experiment I was performed at Hoechst AG. The results were presented, in part, at the FASEB meeting in 1983. All other experiments were performed at the University of California, Irvine     

Luteinizing-hormone-releasing hormone modifies retention of passive and active avoidance responses in rats

The influence of posttraining subcutaneous administration of luteinizing-hormone-releasing hormone (LHRH) was tested on the retention of either active or passive avoidance conditioning in male rats. Injection of LHRH (200/kg) immediately after the acquisition of an active avoidance response (two-way shuttle behavior) enhanced retention of the response, assessed 7 days later. When the neuropeptide was injected immediately after a passive avoidance conditioning training, the effects varied with the intensity of the footshock applied. LHRH enhanced retention of avoidance training with weak footshock (0.20 and 0.35 mA) but impaired retention of training with strong footshock (0.70 and 1.0 mA). The effects of LHRH seem to be unspecific since they are similar to those observed after treatment with several hormones. The results are discussed based on the interactions between peripherally injected hormones and endogenous substances released following footshock. A modulatory effect on the monoaminergic pathway involved in memory storage processes is postulated.     

Ganglioside GM1 attenuates scopolamine-induced amnesia in rats and mice

 Some experimental evidence suggests that the beneficial effects of monosialoganglioside GM1 on learning and memory could be related to an improving effect in central cholinergic function. The present study investigates the effects of GM1 on the memory impairment induced by scopolamine in rats or mice tested in passive (PA) and discriminative avoidance (DA) tasks, respectively. Wistar EPM-1 male rats and Swiss EPM-M1 male mice were treated daily IP with 50 mg/kg GM1 or saline for 7 or 14 days, respectively. Twenty-four hours after the last injection, GM1-treated animals received 1 mg/kg scopolamine (GM1-SCO) and saline-treated animals received 1 mg/kg scopolamine (SAL-SCO) or saline (SAL-SAL) IP. Twenty minutes later, the animals were submitted to PA or DA conditioning, and tests were performed 24 h later. The latency in entering the dark chamber of the PA apparatus (LD) presented by SAL-SCO rats was significantly decreased when compared to that presented by SAL-SAL animals. GM1-SCO animals showed an increased LD when compared to SAL-SCO animals and were not significantly different from SAL-SAL rats. GM1-SCO and SAL-SAL (but not SAL-SCO) mice spent significantly less time in the aversive enclosed arm of the discriminative avoidance apparatus when compared to the time spent in the non-aversive enclosed arm. The results are consistent with the interpretation that GM1 attenuates scopolamine-induced amnesia. Although not eliminating the participation of other transmitter systems, the present study indicates a possible role of central cholinergic transmission in the action of this compound on learning and memory. Received: 21 October 1997 / Final version: 8 June 1998     

Dihydroergocristine and memory alterations of aged male rats

The ergot alkaloid derivative dihydroergocristine (DHECS) was injected acutely or subchronically to aged male rats of the Sprague-Dawley strain, 26 months old, at the dose of 0.05 or 0.1 mg/kg. Learning and memory ability of the animals were studied with tests of avoidance behavior. The acquisition of active avoidance behaviour was also studied. A step-throug type of passive avoidance task In the latt, the extinction of active avoidance behavior was also studied. A step-through type of passive avoidance task was used to examine the retention of passive avoidance responses. The acquisition of the active avoidance behavior and the retention of the passive avoidance response were reduced in aged animals as animals as compared to those of young animals. Acute treatment of old rats with DHECS was followed by a facilitation of acquisition of active avoidance behavior in the shuttle box and of retention of passive avoidance responses in the dark box. The effect on the acquisition and extinction of pole-jumping behavior after a single injection of DHECS at the beginning of the acquisition session was restricted tot he first acquisition trial. A more potent effect on the acquisition of the shuttle-box behavior and on the retention of passive avoidance reaction was found in animals treated subchronically with the ergot derivative (0.05 and 0.1 mg/kg for 10 days). These rats also showed a facilitation of acquisition and an inhibition of extinction of pole jumping behavior.     

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.     

A near-lethal dose of ethanol,given intraperitoneally,does not affect memory consolidation of two different avoidance tasks

Ethanol (3 g/kg, given i.p. as a 33% w/v solution), was given to adult Wistar rats 1 min after training in (1) a 50-trial session of shuttle avoidance, using buzzers and shocks, and (2) an inhibitory avoidance experience in a step-through apparatus. The animals were retested 7 days after training in condition (1), and 3 days after training in condition (2). There was no difference in retention scores between the ethanoltreated, saline-treated, or untreated animals. In addition, there was no evidence of an aversive effect of ethanol per se under any of the two training conditions, in spite of the fact that the dose of ethanol used caused a very profound ataxia, and was lethal for 14.3% of the animals (a slightly higher dose, 4 g/kg, is lethal for about 80% of our rats). These data do not favor the hypothesis that an acute administration of ethanol may influence memory consolidation.     

Nefiracetam (DM-9384): effect on eyeblink classical conditioning in older rabbits

The nootropic compound nefiracetam was evaluated in 88 older rabbits in a 750-ms delay paradigm of eyeblink classical conditioning (EBCC). Rabbits (mean age=28.7 months) were assigned in groups of eight to one of six conditions in experiment 1: paired tone conditioned stimulus (CS)-corneal airpuff unconditioned stimulus (US) presentations and 1, 3, or 10 mg nefiracetam/kg or sterile saline vehicle; explicitly unpaired CS and US presentations and 3 mg nefiracetam/kg or sterile saline vehicle. Animals in the paired conditions received 10 daily sessions of 90 paired trials and animals in the unpaired conditions received 10 daily sessions of 180 unpaired CS and US presentations. The six conditions in experiment 2 were 5, 10, and 15 mg nefiracetam/kg and vehicle in 15 sessions of paired presentations; 10 mg nefiracetam/kg and vehicle in 15 sessions of unpaired conditioning. In both experiments 1 and 2, acquisition measured by trials to learning criterion was significantly faster at the 10 mg/kg dose of nefiracetam. In the repeated measures analyses comparing six doses in the paired conditions, all dependent measures [percentage conditioned responses (CRs), CR amplitude, and response latency] indicated significantly better conditioning in rabbits treated with 10 mg nefiracetam/kg, but this dose did not increase motor responding or responding in the unpaired condition. Nefiracetam facilitated acquisition of EBCC in older rabbits. EBCC is performed poorly by older humans and is seriously impaired in Alzheimer's disease. These preclinical data in an animal model with clear parallels in humans suggest that nefiracetam may prove effective as a cognition enhancer in clinical trials.     

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.     

Effect of naloxone and amphetamine on acquisition and memory consolidation of active avoidance responses in rats

Pretraining IP injection of naloxone (0.3 mg/kg) or amphetamine (2 mg/kg) enhanced performance during acquisition, but did not improve retention of active avoidance responses in rats. Naloxone (0.1 or 3 mg/kg) had no effect on acquisition or on retention. The combination of naloxone (0.3 mg/kg) plus amphetamine (2 mg/kg) did not produce the facilitation observed when each of the two drugs was administered alone. Pretreatment with the higher dose of naloxone (3 mg/kg) blocked the facilitative effect of amphetamine on acquisition. Post-training administration of naloxone (0.3 mg/kg) or amphetamine (2 mg/kg) improved retention. Naloxone (0.1 or 3 mg/kg) had no effect. When naloxone and amphetamine were combined, at respective doses of 0.3 mg/kg and 2 mg/kg, the improvement did not occur, i.e., the higher dose of naloxone prevented the facilitative effect of amphetamine. In addition, an ineffective dose of amphetamine (0.5 mg/kg), given either pre-or post-training together with the lower dose of naloxone (0.1 mg/kg), produced a significant enhancement of acquisition or consolidation, respectively. The results are consistent with the possibility that naloxone might exert its facilitative action on acquisition and memory consolidation through the release of catecholaminergic systems from inhibitory influences of opioids.     

The novel anticonvulsant loreclezole (R 72063) does not produce diazepam-like anterograde amnesia in a passive avoidance test in rats

Summary Rats were injected intraperitoneally with loceclezole (R 72063), diazepam, or scopolamine 60 min prior to acquisition of a passive avoidance task and tested 18 h later for retention of the learned (passive) behavior. The known impairment of performance produced by diazepam in this test is believed to be a model for the clinically observed diazepam-induced anterograde amnesia in humans. We report in this study that (1) consistent with the literature, pretreatment with diazepam (2.0 –16.0 mg/kg i.p.) or scopolamine (3.0 mg/kg i.p.) produced impairment in passive avoidance performance of rats (anterograde amnesia), but (2) pretreatment with loreclezole (R 72063) (2.0–80.0 mg/kg i.p.) did not impair the acquisition, retention, or the retrieval (tested 18 h later) of passive avoidance behavior by rats at any dose. The results suggest that the anticonvulsant activity of loreclezole is mediated by a mechanism distinct from the one coupled to diazepam-like disruption of cognitive functions involved in the acquisition or posttraining information processing of passive avoidance behavior.Send offprint requests to R. B. Raffa at the above address     

Cycloheximide induced amnesia and recovery as a function of training parameters

Mice were given 2 or 3 training trials in a passive avoidance task following an injection of cycloheximide or saline. They were tested 1, 1.5, 3, 24, or 72 hr after training and tested again 72 hr after the first test trial. All the cycloheximide groups except the 1 hr groups were inferior to saline controls on the first test trial, and there was no suggestion of spontaneous recovery over the intervals tested. Test 2 performance was generally inferior to Test 1 performance for all groups, but the cycloheximide groups showed the greatest drop in performance. A second experiment extended train/test intervals to 144, 146, 148, and 192 hr. Spontaneous or test induced recovery again did not occur. The discussion attempts to reconcile these results with prior reports of recovery in terms of differential conditioning of different components of passive avoidance memory by the different training procedures. This results in partial sparing of some components of passive avoidance memory by cycloheximide, which has the appearance of recovery under certain test conditions.     

Postnatal orotate treatment: Effects on learning and memory in adult rats

During the postnatal period, male Wistar rats were treated with orotate, either from the 6th to 15th, 16th to 25th, or 26th to 35th day of life. Learning and memory were tested in adulthood. Rats that received orotate from the 6th to 15th day showed a better retention of a learned brightness discrimination (Y-maze) than controls. An active avoidance (pole jumping) was learned more quickly by the rats orotatetreated from the 6th to 15th day than by controls. The spontaneous locomotor activity of previously orotatetreated rats was the same as in controls. Body weight measurements revealed no differences between orotate rats and control rats. The results suggest that memory retention in adulthood can be improved by postnatal orotate treatment.     

Temporal and pharmacological parameters of puromycin-induced amnesia

Mice were trained in step-down passive avoidance behavior. Bitemporal injections of puromycin (PM) were given either immediately or delayed until 24 hrs after training. PM produced a marked amnesia in both cases during retention testing 3 days later. The amnesia persisted during a second retention test 6 days after training. Of all the antibiotics, only PM is effective as an amnestic agent when injections are delayed 24 or more hours after training. Cycloheximide (CXM) was also injected bitemporally immediately after training. However, CXM produced a weaker amnestic effect even though it produced a much greater inhibition of cerebral protein synthesis, more rapidly, and of longer duration. In an effort to attenuate the amnesia produced by PM, in separate experiments, the mice were injected with combined injections of PM and CXM (bitemporally); mice were also given combined injections of PM (bitemporally) and amphetamine (subcutaneously). The amnesia produced by immediate injections of PM was not attenuated by either CXM or amphetamine. However, the amnesia produced by delayed injections of PM was attenuated by both CXM and amphetamine. These results suggest that delayed injections of PM (24 hours after training) block the e expression or retrieval of memory. This study also supports the contention that puromycin has two separate effects on memory with different temporal parameters depending on when the drug is injected relative to initial training.     

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     

Cocaine enhances retention of avoidance conditioning in rats

The effects of post-training cocaine administration were tested on retention of a one-way active avoidance task in rats. A 5.0 mg/kg IP dose of cocaine enhanced retention of the avoidance task, in three separate experiments, as indicated by an increase in the number of avoidances made when animals were tested 24 h after training, while both a lower (2.5 mg/kg) and a higher (7.5 mg/kg) cocaine dose had no effect. Lidocaine (4–8 mg/kg) administered post-training did not reliably affect retention in the same task. Cocaine's ability to enhance retention depended on the interval between training and drug injection such that only cocaine administered directly after training enhanced retention the following day. The results show that post-training cocaine administration enhances retention of an active avoidance task in rats, and that this effect is probably independent of the anesthetic properties of the drug.     

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.     

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.     

Effect of lysine vasopressin on pentylenetetrazol-induced retrograde amnesia in rats

Lysine vasopressin (1 microgram/rat SC) administered 1 hr prior to either the acquisition trial or 24 hr retention trial facilitated passive avoidance retention. Amnesia was produced when a single 50 mg/kg (IP) injection of pentylenetetrazol was given immediately following the passive avoidance acquisition trial. A single injection of lysine vasopressin (1 microgram/rat SC) administered 1 hr prior to either the acquisition trial or 24 hr retention trial antagonized the amnesia.