Time-related memory effects of vasopressin analogues in rats

The present study was designed to investigate critical time periods for the memory modulating effect of vasopressin and several analogues in rats using a passive avoidance test as the behavioral paradigm. AVP, AVP-(4-8) and AVP-(5-8) were more effective when given immediately after the learning trial (consolidation), while AVP-(1-8) (DGAVP) and AVP-(5-9) were more active when administered one hour prior to the retention test (retrieval). DDAVP and AVP-(4-9) were highly active both when given immediately after the learning trial or 1 hour before the retention test. The period between 12 and 18 hr after the learning trial appeared to be another sensitive period. Administration, in particular of DGAVP, and AVP-(5-9) at 12, 15, and 18 hr after the learning trial induced marked retention of the avoidance response at the 24 hr retention test. Injection at 6 and 21 hr after the learning trial was the least effective in facilitating passive avoidance latencies. The more stable analogue DDAVP facilitated avoidance latencies irrespective of the time of administration. Vasopressin and related peptides exert a long term effect on avoidance behavior. However, DGAVP and AVP-(5-9) facilitated passive avoidance behavior at the 24, 48, and 72 hr retention test if administered immediately after the learning trial. If injection was postponed till 15 hr after the learning trial, passive avoidance behavior was facilitated at the 24 hr retention test only.(ABSTRACT TRUNCATED AT 250 WORDS)     

The disruptive effects of ketamine on passive avoidance learning in mice: involvement of dopaminergic mechanism

The involvement of dopaminergic mechanisms in ketamine-induced disruption of one trial step-through passive avoidance performance was assessed through the coadministration with the dopamine D₁ antagonist SCH 23390, the dopamine D₂ antagonist YM-091512 and the dopamine autoreceptor agonist at low doses, apomorphine, in mice. Pretraining (10 min before) administration of ketamine (0; saline, 2.5, 5 and 10 mg/kg SC) dose-dependently reduced the latency in the retention trial conducted 24 h after the training. However, ketamine did not affect the retention latency when administered immediately after the training or prior to retention. YM-09151-2 (0.01 and 0.03 mg/kg SC) and apomorphine (0.01 and 0.03 mg/kg SC), but not SCH 23390 (0.01 and 0.03 mg/kg SC), ameliorated the impaired reduction by ketamine (10 mg/kg) in a dose-dependent manner. These results suggest that ketamine obstructs the acquisition of the passive avoidance task, and that this effect is induced by stimulation of dopamine D₂ receptors through dopamine release from the presynaptic terminals.     

Investigation of the reported protective effect of cycloheximide on memory

Many findings support the hypothesis that formation of long-term memory requires synthesis of proteins in the nervous system close to the time of learning. This hypothesis has been challenged recently by reports that the protein synthesis inhibitor cycloheximide (CYC) injected 2 hr prior to passive avoidance training in mice or rats attenuated the memory impairment induced by a usually amnestic dose of CYC administered 30 min pretraining. To investigate the reports of a "protective" effect of the prior injection, we attempted to replicate them and test their generality. For replication we administered either paired injections of CYC--120 mg/kg 2 hr prior to training and 30 mg/kg 30 min prior to training--or single injections of CYC (either 120 mg/kg or 30 mg/kg) 30 min pretraining and tested for retention of the passive avoidance habit either 1 or 7 days later. No attenuation of amnesia was observed at 1 day tests. Attenuation of amnesia following the double injection of CYC was observed at 7 day tests. When another protein synthesis inhibitor, anisomycin, was used in the same experimental design, there was no "protective" effect; two injections of anisomycin produced greater memory impairment for the passive avoidance habit than did the single low dose. Also, for active avoidance training, two successive injections of CYC caused significantly greater amnesia than did a single dose; this is the opposite of a "protective" effect. We suggest that the reported "protective" effect of CYC on memory is an as yet unexplained phenomenon that does not generalize to other antibiotic drugs and is specific to the passive avoidance task.     

ACTH4-9 analog (ORG 2766) facilitates acquisition of an inhibitory avoidance response in rats.

These experiments examined the effects of an ACTH4-9 analog (ORG 2766) on an inhibitory avoidance response in rats. Graded doses of ORG 2766 were administered either 1 hr prior to training, immediately after training, or 1 hr prior to the retention test. The animals were tested 24 hr after training. A 5.0 mg/kg dose was administered prior to training significantly facilitated acquisition of the response. ORG 2766 did not significantly affect retention when administered after training or prior to the retention test. Since ORG 2766 only affected acquisition of the response, it is suggested that the drug acts by influencing sensory, motivationl or attentional variables rather than directly affecting memory consolidation or retrieval processes.     

Double dissociation between the effects of muscarinic antagonists and benzodiazepine receptor agonists on the acquisition and retention of passive avoidance

Both muscarinic antagonists, such as scopolamine, and benzodiazepine receptor (BZR) agonists, such as diazepam, produce a reliable impairment in the performance of one trial passive avoidance. Such deficits are frequently interpreted as drug-induced amnesia. However, these deficits could also result from a learning impairment. The present experiments compared the effects of two BZR agonists, lorazepam (0, 0.125, 0.25, and 0.375 mg/kg, IP) and diazepam (0, 0.78, 1.56, and 3.13 mg/kg, IP) with the effects of two muscarinic antagonists, scopolamine (0, 0.6, 0.8 and 1.0 mg/kg, SC) and atropine (0, 15, 30 and 60 mg/kg, IP) on a multiple trial passive avoidance task. In this procedure, the rats were trained with a 5-min inter-trial interval until a learning criterion was achieved. Retention was assessed 24 h later. This enabled the effects of the drugs on the acquisition and the retention of a passive avoidance response to be dissociated. Both atropine and scopolamine produced a marked impairment in the acquisition of the passive avoidance response, but did not impair retention. In contrast, diazepam and lorazepam did not alter the acquisition of a passive avoidance response, but did produce a dose-dependent impairment of retention. These results therefore demonstrate a double dissociation between the effects of muscarinic antagonists and BZR agonists on the acquisition and retention of passive avoidance.     

Systemically administered N-methyl-D-aspartate interferes with acquisition of a passive avoidance response in rats

The effect of several doses of systemically administered N-methyl-D-aspartate (NMDA) was studied on step-through passive avoidance (PA) retention in rats. Retention of single trial PA was significantly reduced by preacquisition (30 minutes) doses of NMDA (3, 10, 30, and 50 mg/kg SC). Preacquisition amnesia was found when NMDA (30 mg/kg SC) was administered between two and 60 minutes. At shorter and longer pretreatment times (0.5 and 180 minutes) NMDA (30 mg/kg SC) did not disrupt retention testing. Across the same dose range and pretreatment times, NMDA failed to interfere with PA retention when given after acquisition or before retention testing. The results suggest that systemic NMDA administration can interfere with the acquisition of a PA response but does not alter consolidation of information or retrieval.     

Can vasopressin alone act as an unconditioned stimulus to produce passive avoidance behaviour in rats in a typical memory experiment?

The claim that vasopressin improves memory has been largely based on results obtained from shock avoidance experiments. In the majority of these studies, "memory" was defined operationally as the hesitation of a rat to enter the darkened compartment of a box in which it had once received an electric foot-shock. A single post-trial injection of arginine vasopressin (AVP) enhances such passive avoidance behaviour. In view of the recent demonstration that AVP has aversive effects, it was argued that vasopressin alone (without giving the rats foot-shock, prior to the peptide) might be a sufficient inhibitory stimulus to produce passive avoidance behaviour in a typical memory experiment. This hypothesis was tested in the present study. The results of these experiments indicate that a behaviourally active dose of AVP (10 micrograms/kg; s.c.) was a sufficient stimulus to produce passive avoidance behaviour in the rats. A small dose of AVP (1.25 micrograms/kg; s.c.) was without effect. However, AVP (10 microgram/kg) was only effective with repeated administration (Experiment 1). This result is in contrast with the post-trial effect of the peptide on inhibitory avoidance behaviour, which is obtained with just one injection in the normal single trial step-through experiment. However, it was found that if the rats were injected with AVP (10 micrograms/kg) and placed in the dark compartment of the apparatus for 20 min, thereby ensuring that the animals made the explicit connection between the aversive effects of the peptide and the dark environment, they displayed avoidance behaviour after a single trial (Experiment 2).(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Cholinergic drugs reverse AF64A-induced impairment of passive avoidance learning in rats

The cholinergic neurotoxin AF64A was administered to rats in order to produce learning impairment to test the effect of cholinergic drugs. Seven days after receiving an intracerebroventricular injection of AF64A (2.5–7.5 nmol), rats were subjected to one-trial passive avoidance acquisition and tested 24 h later. Learning was significantly impaired at 3.75 nmol AF64A, a dose at which significant reduction in acetylcholine level and choline acetyltransferase and acetylcholinesterase activity in the hippocampus was observed but changes in monoamine levels in the hippocampus, general behavior, or sensory sensitivity were not observed. Arecoline (4 mg/kg, IP) and physostigmine (0.1 mg/kg, IP) significantly decreased the learning impairment produced by AF64A (3.75 nmol) when given before the acquisition of passive avoidance learning but not when given after the acquisition or before the 24 h retention test. These drugs and oxotremorine (0.1 mg/kg, IP) given immediately after the acquisition, however, improved passive avoidance retention when the interval between the acquisition and the test was shortened to 1 h. These results indicate that the impairment of learning in AF64A-treated rats is caused by a memory retention deficit and suggest that such impairment can be effectively ameliorated by cholinergic drugs.     

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.     

The effects of dexmedetomidine, an alpha 2 agonist, on learning and memory, assessed using passive avoidance and water maze tasks in rats.

The effects of dexmedetomidine, a specific and potent alpha 2 agonist, on the performance of rats in passive avoidance and water maze tasks were studied. Pre-training administration of subanaesthetic dose (9.0 micrograms/kg) of dexmedetomidine impaired the retention of the passive avoidance task (assessed 24 hr after training) but it did not affect the training of this task. Smaller doses (0.3, 0.9 and 3.0 micrograms/kg) did not affect the training or retention of this aversively motivated task. On the other hand, pre-training administration of 0.3 and 0.9 microgram/kg dexmedetomidine impaired the acquisition of the water maze task, whereas larger doses (3.0 and 9.0 micrograms/kg) had no significant effect on spatial learning. Pre-training administration of dexmedetomidine (0.3-9.0 micrograms/kg) increased swimming speed in rats. Only a large dose (300 micrograms/kg) of dexmedetomidine, administered immediately after training, impaired the retention of the passive avoidance task and the acquisition of the water maze task. These data agree with previous findings that pharmacological manipulation of the noradrenergic system affects the retention of aversively-motivated (passive avoidance) tasks. The present results suggest that the dose-response curve of dexmedetomidine for impairment of learning/memory differs between the passive avoidance and water maze tasks.     

Effect of an inhibitor of dopamine-beta-hydroxylase on the acquisition and retention of four different avoidance tasks in mice

The effect of [bis-(4-methyl-1-homopiperazinylthiocarbonyl)-disulfide] (FLA-63) (40 mg/kg, i.p.) on acquisition and retention in four different avoidance tasks was evaluated in mice. In all tasks animals were submitted to a training session on one day and to a retest session 24 h later. The drug or its vehicle were given either 2 h prior to training and/or retest (pretrial treatments) or immediately after the end of the training session (posttrial treatments). Two hours after injection, FLA-63 was found to lower brain norepinephrine (NE) levels by 51% without affecting those of dopamine (DA). Pretrial administration of the drug resulted in poorer performance of step-through and step-down passive avoidance as well as of step-up active avoidance in retest sessions. There was no apparent posttrial effect of the drug nor any effect on acquisition in these tasks. The drug was without influence on either acquisition or retention in an any-way passive avoidance task in which the response required from the animals was immobility. No evidence for statedependent learning was detected in any of the tasks. The data are consistent with the hypothesis of an involvement of NE either in memory processes or in events parallel and related to memory processes. The present results rule out, however, several such possible parallel events (effects on acquisition, motor disturbances, and effects on reactivity to shocks).Work carried out at the Department of Psychology, Carleton University, Ottawa, supported by grants from the National Research Council (A9845) and the Medical Research Council (MA6486) of Canada to H. Anisman.     

Effect of NC-1900, an active fragment analog of arginine vasopressin, and inhibitors of arachidonic acid metabolism on performance of a passive avoidance task in mice

In this study, we investigated the effect of administration of inhibitors of each of the arachidonic acid metabolism pathways and the effect of co-administration of these inhibitors with NC-1900, a fragment analog of arginine vasopressin, on step-through passive avoidance task performance. All drugs were administered just after the acquisition trial in the passive avoidance task. Intracerebroventricular (i.c.v.) administration of nordihydroguaiaretic acid (NDGA, 1 and 10 microg), a phospholipase A2 (PLA2) and lipoxygenase (LOX) inhibitor, and of arachidonyl trifluoromethyl ketone (ATK, 1 and 10 microg), a specific PLA2 inhibitor caused reductions in latency on the retention trial. The i.c.v. administration of either of baicalein (0.1-10 microg), a 12-LOX inhibitor, or AA-861 (0.1-10 microg), a 5-LOX inhibitor, did not influence the latency. Intraperitoneal administration of indomethacin (20 mg/kg), a non-specific COX inhibitor, or NS-398 (10 mg/kg), a specific COX-2 inhibitor, impaired performance on the retention trial in the task, while piroxicam (20 mg/kg), a specific COX-1 inhibitor, did not. Subcutaneous administration of NC-1900 (0.1 ng/kg) ameliorated the reduction of latency caused by NDGA, ATK, indomethacin, or NS-398. These results suggested that the COX-2 pathway of arachidonic acid metabolism may be important for learning and/or memory in the passive avoidance task in mice, and that the ameliorating effect of NC-1900, in part, is due to mimicking of the effects of metabolites of the COX-2 pathway.     

The improvement of memory retention and retrieval of a novel vasopressin fragment analog NC-1900

The effects of a novel vasopressin (AVP) fragment analog NC-1900 (pGlu-Asn-Ser-Pro-Arg-Gly-NH2 acetate) were studied on the performance of memory retention and retrieval in mice. NC-1900 of one time application of 1 hr after the acquired trial (electric shock) extended the latent period of passive avoidance task 21 days after the acquired trial. Though the extended response was also recognized with AVP4-9, the potency was approx. 1/1000 of NC-1900. The potentiation wasn't recognized with vasopressin. NC-1900 showed a significantly high correct answer after 21 days after the last trial in the search task. While, V1 antagonist Pmp1-Tyr (Me)2-AVP shortened the latent period of passive avoidance task. On the other hand, NC-1900 extended the reaction latency 21 days after the acquired trial by the application 1 hr before the retention trial. Though this improvement of memory retrieval was recognized with vasopressin and AVP4-9, the potency was 1/100-1/1000. NC-1900 improved the retrieval 24 h after the CO2 exposure. V1 antagonists Pmp1-Tyr-Me2-AVP or Deamino-Pen1, O-Me-Tyr2-AVP, and PMA had no effects on the retrieval 21 days after the acquired trial. These results suggest that NC-1900 may have the memory retention and retrieval potentiating action, and that phospholipase C-protein kinase C system may be involved in the former action, and the latter action not be involved.     

Fluoxetine enhances memory processing in mice

Fluoxetine (FLU) increases brain concentrations of serotonin by blocking its uptake, without appreciably affecting the dopamine or norepinephrine systems. The present experiments provide evidence that a subcutaneous injection of FLU enhanced post-memory processing (“consolidation”) and retrieval, but not acquisition in young adult mice. FLU (15 mg/kg) enhanced 1-week memory retention when injected 2 min post-training. Similar enhancement was obtained with intracerebroventricular injection (20 μg per mouse). FLU enhanced retention when administered prior to training (1–5 mg/kg). FLU (2.5 mg/kg) enhanced recall scores when injected 1 h before the 1-week retention test, indicating an enhancing effect on memory retrieval. Neither the pre-training nor pre-testing effects depended on improved acquisition, since FLU did not improve acquisition of T-maze foot-shock avoidance over the dose range 0.5–35 mg/kg. The sensitive period for post-training enhancement by FLU (15 mg/kg) was less than 90 min, as shown by the temporal gradient typical of memory-enhancing drugs. The amnesia induced by a protein synthesis inhibitor anisomycin, or by an anticholinergic drug scopolamine, was blocked by FLU (15 mg/kg) injected post-training. Finally, FLU (15 mg/kg) injected after one-trial passive avoidance training enhanced 1-week retention, demonstrating effectiveness in this task as well as in the active avoidance task.     

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.     

The comparative effects of benzodiazepines,progabide and PK 9084 on acquisition of passive avoidance in mice

Acquisition of passive avoidance following aversive conditioning to a dark compartment was measured in mice under the influence of one of seven bezodiazepines, the GABA-mimetic drug progabide or PK 9084, a nonbenzodiazepine ligand on benzodiazepine receptors.The drugs were administered prior to the training trial and retention was measured in the absence of the drug 24 h later. Oral administration (dose in mg/kg in parentheses) of flunitrazepam (0.1), lorazepam (1.0), nitrazepam (3.0), diazepam (10), flurazepam (10) and chlordiazepoxide (30), all prevented retention whereas progabide (100–800) and PPK 9084 (10–100) were ineffective. In comparison to effects on motor capacity none of the benzodiazepines was outstanding in its acquisition interfering effects.     

State dependent learning produced by post trial intrathoracic administration of sodium pentobarbital

The state dependent learning paradigm was used with a one-trial, passive avoidance task. Forty male rats were equally distributed among four groups: One group received intrathoracic injections of sodium pentobarbital immediately after the acquisition trial and immediately before the retention test trial; a second group received equivalent injections of 0.9% saline; a third group was drugged after acquisition and given saline prior to retention testing and the fourth group was given saline after acquisition and drug prior to retention testing. All groups showed increased latencies on the retention trial but marked group differences in retention test latencies indicate that there was significantly more retention of training when drug states were the same during the memory storage interval and the memory retrieval interval. Intrathoracic injection proved to be a practical substitute for intravenous injection in assuring rapid onset of drug effect.     

A comparison of the effects of scopolamine and diazepam on acquisition and retention of inhibitory avoidance in mice

Administration of either the muscarinic antagonist scopolamine or the benzodiazepine diazepam prior to training produced a dose-dependent impairment in the retention of one-trial inhibitory avoidance training in mice. To investigate the nature of this drug effect, the effects of scopolamine and diazepam were subsequently assessed on both acquisition and retention of inhibitory avoidance using a multiple-trial, training-to-criterion procedure. The training was conducted using either continuous trials in which the mouse was free to shuttle back and forth between shock and safe compartments or discrete trials in which the mouse was moved from the shock compartment of the safe compartment at the start of each trial. In either case, training continued until the mouse refrained from crossing into the shock compartment for a specified length of time on a single trial. Scopolamine (1.0 mg/kg) administered before training significantly increased the number of trials required to attain criterion, but did not affect retention when these mice were tested 2, 16, or 28 days later. In contrast, diazepam (1.0 mg/kg) did not significantly alter the number of trials necessary to reach criterion, but impaired retention of the inhibitory response in mice trained using discrete trials. The differences in the amnestic effects of scopolamine and diazepam revealed by this detailed analysis suggest that diazepam does not impair inhibitory avoidance performance through an effect on cholinergic function.     

Enhancement by secoverine and physostigmine of retention of passive avoidance response in mice

A one-trial passive avoidance test in the mouse, in which drugs were injected intraperitoneally immediately after the shocked acquisition trial, was used. The effects of enhancing central cholinergic transmission on retention of passive avoidance was investigated using secoverine, which blocks muscarinic autoreceptor-mediated inhibition of acetylcholine release, and using physostigmine, an acetylcholinesterase inhibitor. Secoverine (1.0–5.0 mg/kg) and physostigmine (0.1–0.4 mg/kg) were found to improve retention of the avoidance response measured 24 h after acquisition. These effects were augmented when the two drugs were given in combination. In contrast, atropine (5.0 mg/kg) tended to impair retention of passive avoidance and blocked the facilitatory effects of physostigmine. The results support the hypothesis of a novel approach to treatment of memory disorders based on blockade of muscarinic autoreceptors, to augment central cholinergic activity.