Facilitation of inhibitory avoidance by hypertonic saline is reversed by a vasopressin and a nicotinic antagonist

Hypertonic saline (1 ml of 0.25, 0.50, and 1.00 M NaCl, ip) facilitated retention of a one-trial, step-through inhibitory avoidance task when injected into male Swiss mice 10 min after training, as indicated by retention performance 48 h later. A similar result was obtained after a subcutaneous injection of lysine vasopressin (LVP, 0.03 microgram/kg). Neither hypertonic saline nor LVP modified latencies to step-through of mice that had not received a footshock during training. The enhancement of retention produced both by hypertonic saline and by LVP was prevented by the vasopressin receptor antagonist AAVP (0.01 microgram/kg, sc) given after training, but 10 min before the treatments. The effect of hypertonic saline was also prevented by the central acting cholinergic nicotinic receptor antagonist mecamylamine (5 mg/kg, sc). On the contrary, neither hexamethonium (5 mg/kg, sc), a peripheral acting nicotinic receptor blocker, nor atropine (0.5 mg/kg, sc) or methylatropine (0.5 mg/kg, sc), two anticholinergic drugs which are known to act on cholinergic muscarinic receptors, prevented the effect of post-training hypertonic saline. These results suggest that a peripheral osmotic stimulus, probably through an endogenous release of vasopressin, may be behaviorally significant, and are consistent with the view that vasopressin may modulate the activity of central cholinergic nicotinic mechanisms which are critical for the behavioral change observed.     

The enhancement of retention induced by vasopressin in mice may be mediated by an activation of central nicotinic cholinergic mechanisms.

Immediate post-training subcutaneous administration of lysine vasopressin (LVP, 0.003-1.00 microgram/kg) enhanced retention, whereas the vasopressin antagonist AAVP (0.01-0.30 microgram/kg) impaired it, in male Swiss mice tested 48 h after training in an inhibitory avoidance task. Both effects were dose-dependent. Neither LVP nor AAVP affected response latencies in mice not given the footshock on the training trial. The simultaneous administration of AAVP at a dose (0.01 microgram/kg) which had no effect on retention shifted the dose-response curve of LVP to the right. Nicotine (1.0-30.0 micrograms/kg, sc), a central nicotinic cholinergic agonist, also facilitated retention in a dose-related manner without affecting the retention performance of unshocked mice. The effect of nicotine was prevented by the central acting nicotinic cholinergic receptor antagonist mecamylamine (5 mg/kg, sc.). In contrast, neither hexamethonium (5 mg/kg, sc), a peripheral acting nicotinic receptor blocker, nor atropine (0.5 mg/kg, sc) or methylatropine (0.5 mg/kg, sc), two anticholinergic drugs which are known to act on muscarinic cholinergic receptors, prevented the effect of post-training nicotine. The effects of LVP and nicotine were time-dependent, suggesting that both treatments enhanced retention by influencing post-training processes involved in memory storage. Low doses of nicotine (1.50 microgram/kg, sc) or the central anticholinesterase physostigmine (35 micrograms/kg, sc) and LVP (0.003 microgram/kg, sc), which had no effect on retention when administered alone, produced a synergistic interaction when given together following training. The influence of LVP (0.03 microgram/kg, sc) on retention was prevented not only by AAVP (0.01 microgram/kg, sc) but also by mecamylamine (5 mg/kg, sc), whereas the effects of nicotine (10.0 micrograms/kg, sc) were prevented only by mecamylamine. These results suggest that the enhancement of retention induced by vasopressin is probably due to an activation of central nicotinic cholinergic mechanisms which are critical for memory formation.     

GABA(A) receptors determine the temporal dynamics of memory retention

Four experiments studied the role of GABA(A) receptors in the temporal dynamics of memory retention. Memory for an active avoidance response was a nonmonotonic function of the retention interval. When rats were tested shortly (2 min) or some time (24 h) after training, retention was excellent, but when they were tested at intermediate intervals (1-4 h), retention was poor. Activity at GABA(A) receptors was critical for impairing memory retention at the intermediate intervals because injection of the GABA(A) receptor partial inverse agonist FG7142 prior to test significantly improved performance. These retention enhancing effects of FG7142 were dose-dependent and not due to any nonspecific effects of FG7142 on activity. Our results suggest that the temporal dynamics of memory retention may be caused by variations in neurotransmission through the GABA(A) receptor in the post-training period.     

On the delay-dependent involvement of the hippocampus in object recognition memory

The role of the hippocampus in object recognition memory processes is unclear in the current literature. Conflicting results have been found in lesion studies of both primates and rodents. Procedural differences between studies, such as retention interval, may explain these discrepancies. In the present study, acute lidocaine administration was used to temporarily inactivate the hippocampus prior to training in the spontaneous object recognition task. Male C57BL/6J mice were administered bilateral lidocaine (4%, 0.5 microl/side) or aCSF (0.5 microl/side) directly into the CA1 region of the dorsal hippocampus 5 min prior to sample object training, and object recognition memory was tested after a short ( 5 min) or long (24 h) retention interval. There was no effect of intra-hippocampal lidocaine on the time needed for mice to accumulate sample object exploration, suggesting that inactivation of the hippocampus did not affect sample session activity or the motivation to explore objects. Lidocaine-treated mice exhibited impaired object recognition memory, measured as reduced novel object preference, after a 24 h but not a 5 min retention interval. These data support a delay-dependent role for the hippocampus in object recognition memory, an effect consistent with the results of hippocampal lesion studies conducted in rats. However, these data are also consistent with the view that the hippocampus is involved in object recognition memory regardless of retention interval, and that object recognition processes of parahippocampal structures (e.g., perirhinal cortex) are sufficient to support object recognition memory over short retention intervals.     

Involvement of alpha-bungarotoxin-sensitive nicotinic receptors in long-term memory formation in the honeybee (Apis mellifera)

In the honeybee Apis mellifera, multiple-trial olfactory conditioning of the proboscis extension response specifically leads to long-term memory (LTM) which can be retrieved more than 24 h after learning. We studied the involvement of nicotinic acetylcholine receptors in the establishment of LTM by injecting the nicotinic antagonists mecamylamine (1 mM), alpha-bungarotoxin (alpha-BGT, 0.1 mM) or methyllycaconitine (MLA, 0.1 mM) into the brain through the median ocellus 20 min before or 20 min after multiple-trial learning. The retention tests were performed 1, 3, and 24 h after learning. Pre-training injections of mecamylamine induced a lower performance during conditioning but had no effect on LTM formation. Post-training injections of mecamylamine did not affect honeybees' performances. Pre-training injections of MLA or post-training injection of alpha-BGT specifically induced LTM impairment whereas acquisition as well as memory retrieval tested 1 or 3 h after learning was normal. This indicates that brain injections of alpha-BGT and MLA did not interfere with learning or medium-term memory. Rather, these blockers affect the LTM. To explain these results, we advance the hypothesis that honeybee alpha-BGT-sensitive acetylcholine receptors are also sensitive to MLA. These receptors could be essential for triggering intracellular mechanisms involved in LTM. By contrast, medium-term memory is not dependent upon these receptors but is affected by mecamylamine.     

Spatial memory in rats after 25 hours

We investigated the time course of spatial-memory decay in rats using an eight-arm radial maze. It is well established that performance remains high with retention intervals as long as 4 h, but declines to chance with a 24-h retention interval (Beatty, W. W., & Shavalia, D. A. (1980b). Spatial memory in rats: time course of working memory and effect of anesthetics. Behavioral & Neural Biology, 28, 454-462). It is possible that 24 h reflects a genuine retention limitation of rat spatial memory. Alternatively, it may be possible to identify factors that might support memory performance even after very long delays. The current experiment was conducted to test the above two hypotheses. We evaluated performance using two intertrial intervals (24 and 48 h) and two retention intervals (1 and 25 h). Increasing the intertrial interval produced an approximately constant increase in performance for both retention intervals. This improvement is consistent with a trial-spacing effect (i.e., the superiority of spaced over massed trials). Rat spatial memory apparently lasts at least 25 h.     

Temporal factors influencing the pigeon's successive matching-to-sample performance: sample duration, intertrial interval, and retention interval

A successive matching-to-sample procedure that entails the sequential presentation of sample and test stimuli and the monitoring of response rates in a go/no-go discrimination of matching and nonmatching stimuli was studied as an alternative to the familiar delayed-matching paradigm of animal short-term memory. Three within-subject experiments studied the effects of sample duration (1 to 12 seconds), intertrial interval (5 to 50 seconds), and retention interval (1 to 50 seconds) on the pigeon's successive-matching performance. The results revealed that retention was (a) an increasing function of sample duration and intertrial interval, and (b) a decreasing function of retention interval. These results were in accord with those of more traditional short-term memory paradigms, and reveal the suitability of the successive-matching procedure for studying memory processes.     

Glucose effects on memory: behavioral and pharmacological characteristics

Recent findings indicate that post-training glucose injections can modulate memory storage for inhibitory (passive) avoidance training. Experiment I extended these findings to determine whether glucose, like other memory modulating treatments, enhances memory storage when administered after training with low footshock and impairs memory storage after high footshock training. In Experiment I, male Sprague-Dawley rats were trained in a one-trial inhibitory avoidance task using either a brief footshock (0.5 mA, 0.7 s) or slightly more intense footshock kept on until escape (0.7 mA, mean escape latency = 3.4 s). Immediately after training, each rat received a subcutaneous injection of glucose (100 mg/kg). When tested for retention performance 24 h later, the glucose-injected animals exhibited enhanced retention performance for low footshock training and impaired retention for high footshock training. Experiment II determined whether pretreatment with adrenergic antagonists blocked the effects of glucose on memory. Pretreatment with the alpha- or beta-adrenergic receptor antagonists, phenoxybenzamine, or propranolol, respectively, had no effect on acquisition or retention in animals trained with the brief footshock and did not affect glucose facilitation of that memory. In animals trained to escape footshock, phenoxybenzamine did not attenuate the amnesia produced by glucose. Propranolol-pretreated animals had impaired retention whether or not they received post-training amnestic injections of glucose; glucose had no effect on retention in these amnestic animals. These findings add further support to the view that glucose release after training and treatment may represent a physiological response subsequent to epinephrine release in modulating memory storage processing.     

Retention deficit after d-amphetamine treatment: memory defect or performance change?

Retention deficits in discrete trial delayed alternation and delayed matching to sample tasks following administration of d-amphetamine have been interpreted to support the view that arousal facilitates the decay of information from shortterm memory (STM) (Kesner, 1973). But since amphetamine causes numerous changes in performance, alternative explanations of the deficit are also plausible. In an attempt to separate drug effects on memory from those on performance, the effects of d-amphetamine on spatial memory in the radial maze were studied in rats. The unusually long span of accurate working memory in this setting permits drug administration within the retention interval as well as prior to the to-be-remembered event (TBRE). In rats tested at a 5-hr retention interval d-amphetamine (2 mg/kg) disrupted retention when given 0.5 hr before or 4.5 hr after the TBRE, but the same treatment 0 or 2 hr after the TBRE or 3 hr before the TBRE was without effect. At a 5-hr retention interval 3 mg/kg d-amphetamine impaired performance if given 2 hr after the TBRE, but not when given 0 hr after the TBRE or 3 hr before the TBRE. However, when the retention interval was lengthened to 7 hr, administering 3 mg/kg d-amphetamine 2 hr after the TBRE did not disrupt performance. The effects of d-amphetamine on spatial memory are best explained in terms of the well established effects of the drug on motor activity and appetite. Similar changes in performance may account for the "memory" impairments observed after amphetamine treatment in other tasks.     

Two critical periods of protein and glycoprotein synthesis in memory consolidation for visual categorization learning in chicks

A protein synthesis inhibitor, anisomycin (ANI), and an inhibitor of glycoprotein synthesis, 2-deoxygalactose (2-D-gal), were used to investigate memory consolidation following visual categorization training in 2-day-old chicks. ANI (0.6 micromole/chick) and 2-D-gal (40 micromoles/chick) were injected intracerebrally at different time intervals from 1 hr before to 23 hr after the training. Retention was tested 24 hr post-training. Both ANI and 2-D-gal injections revealed two periods of memory sensitivity to pharmacological intervention. ANI impaired retention when injected from 5 min before to 30 min after the training or from 4 hr to 5 hr post-training, thus demonstrating that consolidation of long-term memory in this task requires two periods of protein synthesis. 2-D-Gal first produced an amnesia when it was injected in the interval from 5 min before to 5 min after the training. Injections made between 5 min and 5 hr post-training were without effect on the retention. The second period of memory impairment by 2-D-gal started at 5 hr post-training and lasted until 21 hr after the training. Administration of 2-D-gal made 23 hr after the training did not influence retention in the test at either 24 hr or 26 hr. These results are consistent with the hypothesis that two waves of protein and glycoprotein synthesis are necessary for the formation of long-term memory. The prolonged duration of performance impairment by 2-D-gal in the present task might reflect an extended memory consolidation period for a categorization form of learning.     

Acute exposure to a 50 Hz magnetic field impairs consolidation of spatial memory in rats

This study was planned to evaluate the effect of an exposure to magnetic fields on consolidation and retrieval of hippocampus dependent spatial memory using a water maze. In Experiments 1 and 2, rats were trained in a hidden version (spatial) of water maze task with two blocks of four trials. The retention of spatial memory was evaluated 48 h later. Exposure to a 50 Hz 8 mT, but not 2 mT magnetic fields for 20 min immediately after training impaired retention performance. The same time exposure shortly before retention testing had no effect. In Experiment 3, rats were trained in a cued version of water maze with two blocks of four trials. Exposure to magnetic field at 8 mT for 20 min immediately after training did not impair retention performance. These findings indicate that acute exposure to a 50 Hz magnetic field at 8 mT for short time can impair consolidation of spatial memory.     

A vasopressin metabolite produces qualitatively different effects on memory retrieval depending on the accessibility of the memory

A vasopressin metabolite, AVP4-9, was injected 1 h prior to retention tests at 1, 6, 11, and 16 days after learning to test the hypothesis that the peptide exerts qualitatively different effects on memory retrieval depending on the accessibility of the memory. The findings provided strong support for this hypothesis: At a retention interval associated with excellent recall in control animals, pretest administration of AVP4-9 (3.0 micrograms/kg) significantly impaired memory, while this same treatment significantly improved recall at an interval associated with poor retention in controls. At retention tests associated with intermediate recall in controls, retrieval was not significantly affected by the peptide treatment. This pattern of results indicates that the peptide treatment is interacting with endogenous changes that correspond to the accessibility of the memory.     

Mecamylamine prevents the enhancement of retention induced by lysine vasopressin in mice

Lysine vasopressin (0.03 microgram/kg, sc) enhanced retention of a one-trial, step-through inhibitory avoidance task when injected into male Swiss mice immediately post-training, as indicated by retention performance 48 h later. A low dose of the vasopressin antagonist, AAVP (0.01 microgram/kg, sc), did not significantly affect retention, whereas a higher dose (0.03 microgram/kg, sc) impaired retention. Neither lysine vasopressin nor AAVP modified latencies to step-through of mice that had not received a footshock during training. The simultaneous injection of AAVP (0.01 microgram/kg, sc) prevented the enhancement of retention induced by lysine vasopressin. The influence of lysine vasopressin on retention was antagonized by the simultaneous administration of mecamylamine (5 mg/kg, sc) but not by hexamethonium (5 mg/kg, sc), atropine (0.5 mg/kg, sc), or methylatropine (0.5 mg/kg, sc). A modulatory role of vasopressin on the activity of central cholinergic nicotinic mechanisms which participate in memory formation is suggested.     

Time-dependent effects of post-trial amphetamine treatment in rats: evidence for enhanced storage of representational memory

Two studies were conducted to test the ability of post-trial amphetamine treatment to improve later recall in a nonaversively motivated task. These studies utilized 8- and 12-arm radial mazes, respectively, with an 11-h retention interval imposed after the rat traversed half the arms of the maze (termed, the to-be-remembered-event, or TBRE). In Experiment 1, the rats were injected with amphetamine (0, .25, and .50 mg/kg) immediately after the TBRE. Because the drug treatment improved retention, a time dependency study was conducted in which the drug (0 and .33 mg/kg) was administered 0, 3, and 6 h after the TBRE. The finding that amphetamine injection at 0, but not 3, h post-trial improved later recall indicates that the benefit derived from the former treatment is not due to proactive influences at the time of the retention test. Drug treatment 6 h post-trial produced a borderline improvement of recall; possible mechanisms are discussed. Two conclusions can be drawn from these results: (1) amphetamine administration can improve recall under conditions in which this effect cannot be attributed to alterations in information processing during either the learning or the retention sessions, indicating that the drug modulates memory storage processes; and (2) amphetamine treatment can improve working memory, thus excluding an alternative interpretation for the previous reports of impaired short-term memory in animals, all of which entailed assessments of working memory. The possibility remains, however, that the impairment seen in these tasks reflects the requirement for erasure of information from previous trials within each daily session, rather than the duration of the retention interval.     

Arousal and memory: phasic measures of arousal in a free recall task.

EEG alpha activity and skin potential were monitored during word presentation in a single trial free recall task. Phasic changes in EEG alpha and skin potential, co-occurring with word onset, were positively related to recall at an immediate retention interval (2 min) but not after a delay (45 min). The results were interpreted as supporting the extension of Routtenberg's (1968) two-arousal system hypothesis to human memory. Arousal was viewed as affecting memory during the attribute encoding stage of memory storage.     

Glucose modulation of memory storage processing

Epinephrine, derived from the adrenal medulla, enhances memory storage for several forms of learning. One physiological action of this hormone is to liberate hepatic glucose stores. This experiment tested the possibility that glucose could itself enhance memory. Rats were water deprived, pretrained to drink, pretrained to drink in the behavioral apparatus, and then trained in a one-trial inhibitory (passive) avoidance task. Immediately after the training footshock, the animals each received an injection of glucose (1.0-500 mg/kg). When tested for retention 24 h later, the animals which received 10 or 100 mg/kg doses of glucose exhibited enhanced retention performance; higher and lower doses had no significant effect on the memory tests. Also, glucose injections (100 mg/kg) delayed by 1 h after training had no effect on the retention tests. These findings suggest that the increase in plasma glucose levels subsequent to epinephrine injection may contribute to the effects of epinephrine on memory. In addition, the results suggest that peripheral glucose levels may exert important influences on memory storage.     

Inhibition of Intermediate-Term Memory Following Passive Avoidance Training in Neonate Chicks by a Presynaptic Cholinergic Blocker

The effects of a specific presynaptic cholinergic antagonist, toosendanin, on memory formation following a passive avoidance training experience in day-old chicks was investigated. Bilateral injection of toosendanin into the neostriatal/hyperstriatal region of the chick forebrain produced memory impairment in a dose-dependent manner. Retention deficits were apparent from 20 min following training in chicks treated with toosendanin, regardless of the injection time relative to training. Chicks that received injections of the drug at corresponding times prior to retention tests showed normal retention levels, suggesting that toosendanin has no effect on performance and memory retrieval. These results indicate an involvement of cholinergic transmission during an early stage of memory formation.     

Epinephrine fails to enhance performance of food-deprived rats on a delayed spontaneous alternation task

Increases in blood glucose levels after epinephrine injection appear to contribute to the hormone's effects on learning and memory. The present experiment evaluated whether epinephrine-induced enhancement of spontaneous alternation performance would be attenuated in fasted rats that had blunted increases in circulating glucose levels after injections of epinephrine. Rats deprived of food for 24 h prior to injection of epinephrine exhibited significant attenuation of the increase in blood glucose levels seen in fed rats. When the rats were tested on a delayed spontaneous alternation task, epinephrine enhanced performance in fed rats but not in rats deprived of food for 24 h. These findings are consistent with the view that hyperglycemia subsequent to epinephrine injections contributes to the memory-enhancing effects of epinephrine.     

A systemically administered beta-adrenoceptor antagonist blocks corticosterone-induced impairment of contextual memory retrieval in rats

Several studies have reported that glucocorticoids impair memory retrieval. The present study examined in male Sprague-Dawley rats the effects of systemically administered corticosterone on retrieval of memory for inhibitory avoidance training. Corticosterone (3.0mg/kg, s.c.) injected 30min before retention testing, 48h after training, significantly impaired retention performance, as compared to vehicle treatment, of rats tested in the training context. In contrast, corticosterone administration did not impair retrieval when rats were tested for retention in a different context. Corticosterone did also not impair retention performance of rats given a mild-intensity footshock that resulted in only weak, non-contextual memory. These findings strongly suggest that corticosterone selectively impaired retrieval of contextual information associated with the training context. The centrally acting beta-adrenoceptor antagonist propranolol (2.0mg/kg), co-administered in a dose that did not affect retention performance alone, blocked the impairment in contextual memory retrieval induced by corticosterone. These findings provide evidence for the view that glucocorticoids interact with noradrenergic mechanisms in influencing memory retrieval.     

MK-801 improves retention in aged rats: implications for altered neural plasticity in age-related memory deficits

Alterations in N-methyl-d-aspartate receptor (NMDAR)-dependent synaptic plasticity, characteristic of aged rodents, may contribute to impaired memory with advanced age. The purpose of the current research was to examine whether NMDARs contribute to rapid forgetting on a spatial memory task. Aged (22-24 months) and adult (3-6 months) male Fischer 344 rats received 18 training trials, over a period of 3 to 4 h, on the spatial version of the Morris water maze. Immediately after training, a standard free-swim probe trial was administered to assess the acquisition of spatial bias, which was determined by the percent of time spent in the goal quadrant and the number of platform crossings. Rats then received injections of the noncompetitive NMDAR antagonist, (+)-10, 11-dihydro-5methyl-5H-dibenzo(a,b)cycloheptene-5,10 imine (MK-801, 0. 05 mg/kg, i.p.), or a vehicle injection of equal volume. Approximately 24 h later, rats were administered a second free-swim probe trial to assess retention of spatial bias. All age/drug groups exhibited a spatial bias on the acquisition probe, with adults generally outperforming the aged rats. On the retention probe, this spatial bias continued to be shown by adult rats, regardless of treatment. For the aged group, in contrast, only MK-801-injected rats maintained a spatial bias on the retention probe, suggesting that NMDAR activity may be involved in rapid forgetting during aging. Because blockade of NMDARs also may impair new learning, which may, in turn, protect previously stored information from retroactive interference, rats in a second experiment received post-training injections of scopolamine (0.05 mg/kg), a compound known to inhibit learning. However, scopolamine did not enhance retention in the aged group, consistent with the hypothesis that MK-801 influenced memory in aged rats through its actions on NMDAR-dependent synaptic plasticity.