Analysis of the avoidance learning deficit induced by the serotonin releasing compound p-chloroamphetamine

The effects of the serotonin-releasing compound p-chloroamphetamine (PCA, 2.5 mg/kg) on avoidance acquisition, retention and memory retrieval were examined in male Sprague-Dawley rats using a one-way active avoidance and a one-trial passive avoidance task. The drug was injected IP prior to training, following acquisition and prior to the retention test 24 hr after training using a state-dependent design. In the normal context situation pretraining administration of PCA markedly impaired active avoidance acquisition, but PCA-treated rats did not differ from controls in their retention performance when tested 24 hr after training. In the dark/light box test pretraining administration of PCA caused a dose-dependent impairment of both active and passive avoidance retention which could not be explained in terms of changes in locomotor activity or behavioural disinhibition at the time of testing or state-dependent retention. Post-training administration of PCA failed to affect avoidance retention in both tasks. The drug was found to impair memory retrieval in a dose- and time-dependent fashion in the one-way active but not in the passive avoidance test. Pretraining administration of PCA produced a progressive loss of passive and active avoidance performance at increasingly longer retention intervals. The present results suggest that serotonin has dual effects on processes underlying learning and memory involving effects on both associative and non-associative learning processes in the rat. The time-dependent loss of memory retention following 5-HT release indicates that serotonin has a role in the way information is processed in the brain.     

Negative and positive effects of intracerebroventricular scopolamine on memory in mice undergoing passive avoidance and escape tests

The effects of intracerebroventricular administration of scopolamine on memory and learning in the conscious, freely moving mouse were evaluated using step-down passive avoidance and water maze tests. A new technique was used that allows convenient injection into the cerebral ventricles without disturbing the animal's behavior. No significant changes in locomotor activity were observed after low doses of scopolamine (0.1 and 1.0 μg). However, 10 μg produced an increase in locomotor activity, while 100 μg caused an initial decrease followed by an increase in activity. In the passive avoidance test, scopolamine significantly impaired memory acquisition at doses higher than 1.0 μg, consolidation at a dose of 100 μg, and retrieval at doses of 10 and 100 μg. In contrast, a dose of 0.1 μg significantly improved consolidation and retrieval. In the water maze with a bridge, scopolamine either impaired memory acquisition, consolidation, and retrieval, or had no significant effect in the dose range tested. These results suggest that there are differences in the process of memory formation in the passive avoidance and escape tests.     

Enhanced retrieval of unpleasant memory in helpless rats

Several studies in humans have indicated an association between enhanced retrieval of unpleasant events and depressive mood. No analogy has so far been demonstrated in animals, however. The purpose of the present study was to determine the effect of learned helplessness on the retrieval of unpleasant memory in rats. Animals initially exposed to a single unpleasant event in a passive avoidance task were subjected, respectively, to inescapable, escapable, or no shock stress exposure. A retention test conducted 48 hr following stress exposure showed an enhanced performance for the passive avoidance task in rats subjected to inescapable shock stress. This improved performance was not observed in escapable or no shock stress groups. This finding in the learned helplessness condition in rats, is qualitatively similar to that found in humans in depressive mood.     

The influence of adenosine A3 receptor agonist: IB-MECA,on scopolamine- and MK-801-induced memory impairment

The effects of adenosine A3 agonist IB-MECA on scopolamine- and MK-801-induced impairment of spontaneous alternation and learning abilities were examined using Y-maze and passive avoidance tasks in mice. IB-MECA given 20 min before test had no effect on spontaneous alternation performance. Similarly learning abilities tested in passive avoidance were not disturbed after IB-MECA administration before training session. IB-MECA significantly diminished scopolamine- and MK-801-induced impairment of spontaneous alternation in Y-maze and learning abilities in passive avoidance task as well as reduced higher locomotor activity in MK-801-treated group. This ameliorating effect of IB-MECA was not antagonised by adenosine A1 antagonists CPX. Obtained results indicate that adenosine A3 receptor stimulation may ameliorate spatial memory and long term memory impairments in terms of cholinergic and glutamatergic deficits induced by scopolamine and MK-801, respectively.     

Crocus sativus L. extracts antagonize memory impairments in different behavioural tasks in the rat

The effects of extracts of Crocus sativus L. (CSE), on memory were investigated in the rat by using the object recognition and the step-through passive avoidance task. In the first study, post-training administration of CSE (30 and 60 g/kg) successfully counteracted extinction of recognition memory in the normal rat, suggesting that CSE modulates storage and/or retrieval of information. In a subsequent study, pre-training treatment with CSE (30 and 60 mg/kg) significantly antagonized the scopolamine (0.75 mg/kg)-induced performance deficits in the step-through passive avoidance test. These results support and extend prior findings about the implication of CSE in learning and memory mechanisms.     

Effects of intracerebroventricularly administered somatostatin on passive avoidance, shuttle-box behaviour and open-field activity in rats

Behavioural effects of somatostatin after intracerebroventricular (icv) administration have been investigated in male rats. In a passive avoidance learning test, somatostatin (1 microgram), given 30 min before the learning session, increased the avoidance latency at 24 h, but not at 48 h, after the injection, when compared to a 10 micrograms treated group. However, compared to a saline treated group, somatostatin (0.01, 0.1, 1, or 10 micrograms) did not significantly influence the avoidance latency. In a shuttle box experiment somatostatin (1 microgram) facilitated the learning process. In an open-field behaviour test, immediately after the 24 h passive avoidance test, 10 micrograms of the peptide decreased the rearing activity without influencing other open field behaviours, like locomotion, grooming and defecation. In a second open-field experiment somatostatin (1 microgram), given 30 min prior to the test, similarly as in the shuttle box learning experiment, increased the locomotion of the animals. These data suggest that somatostatin influences both the passive avoidance and shuttle box behaviours. The peptide-induced motor performance of the animals may play an important role in influencing the responses observed in these behavioural tests.     

Traumatic brain injury produces impairments in long-term and recent memory

Traumatic brain injury (TBI) in humans typically produces neurological suppression and a longer lasting impairment of memory clinically defined as post-traumatic amnesia. An animal model that reliably reproduces the physiological changes associated with TBI was used to assess the memory deficits following brain injury. Prior to TBI, rats were trained to perform one of four tasks that assessed either motor performance, long-term or recent memory. Rats were randomly assigned to one of three groups (anesthesia only, sham operation or fluid percussion). Following fluid percussion, used to produce TBI, rats were tested for 6 test sessions. The first session occurred 1–2 min after the experimental manipulation. The next 5 sessions followed the training schedule maintained prior to experimental manipulation. Differences in long-term memory occurred only in the first post-operative test session. Differences in recent memory performance were found across all 6 test sessions. The memory deficits were clearly dissociated from motor deficits. The similar memory deficits observed following human head injury and the experimentally produced TBI injury demonstrate that fluid percussion is a useful approach to examine underlying neurobiological mechanisms involved in head injury and possible clinical interventions.     

Effects of concurrent manipulations of cholinergic and noradrenergic function on learning and retention in mice

Interactions between the neuromodulators acetylcholine and norepinephrine (NE) have been reported in both developmental neural plasticity and learning and memory. In a test of the generality of this phenomenon, we assessed the amnestic effects of the muscarinic antagonist scopolamine in normal and NE-depleted mice. Pretraining administration of scopolamine impaired 24-h retention of inhibitory (passive) avoidance training (at doses of 0.1, 0.3 and 1.0 mg/kg) and the acquisition of place-training in a water maze (at a dose of 1.0 mg/kg). NE depletion resulting from systemic administration of DSP-4 did not affect performance on these tasks and did not significantly alter the effects of scopolamine. NE depletion did, however, impair the retention of place learning when mice were retested 16 days after initial training; and this impairment in the retest was additive with one observed in mice originally trained under scopolamine. Normal acquisition but rapid forgetting has also been reported in aged rodents, who display deterioration of the noradrenergic system. Thus, observation of a similar pattern of performance consequent to experimental NE depletion suggests a role for noradrenergic dysfunction in age-related memory decline.     

Effects of oral administration of the competitive N-methyl-D-aspartate antagonist, CGP 40116, on passive avoidance, spatial learning, and neuromotor abilities in mice

The effects were investigated of the potent competitive N-methyl-D-aspartate (NMDA) receptor antagonist CGP 40116[D-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid] on the performance of mice in water maze and passive avoidance tasks, and in wire suspension, rotarod, and cage activity tests. The drug was administered per os (p.o.) in its anticonvulsant dose range. CGP 40116 dose-dependently impaired passive avoidance learning when given before, but not when given after training. The antagonist (5, 10, and 20 mg/kg, administered 4 h before each training session) dose-dependently affected water maze acquisition, and impaired retention test performance in both hidden- and visible-platform water maze tasks. In addition, the drug dose-dependently decreased swimming speed during water maze acquisition. Repeated administration of CGP 40116 (20 mg/kg, p.o.) persistently decreased cage activity and wire suspension test performance, whereas motor coordination and equilibrium on the rotarod apparatus remained unimpaired. In our administration protocol, no tolerance was found to the effects of the drug on passive avoidance learning and neuromotor abilities. The parallel effects of CGP 40116 on memory and motor performance are discussed, and it was concluded that the antagonist impairs neuromotor abilities and also induces memory impairments which cannot be entirely reduced to motor interference.     

Intracranial self-stimulation facilitates memory consolidation, but not retrieval: its effects are more effective than increased training.

To evaluate possible differential effects of lateral hypothalamic intracranial self-stimulation (ICSS) on memory consolidation and retrieval, independent groups of Wistar rats were trained in a single session of two-way active avoidance task (acquisition session) and tested 24 h later (retention session). The post-ICSS groups received an ICSS treatment immediately after the acquisition session, and the pre-ICSS groups received the same treatment immediately before the retention session. Because the ICSS effects on memory seem to be dependent on the initial performance level shown by the subjects, the possible influence of initial training (number of trials) on ICSS effects was also studied. Therefore, we used different control and experimental groups, which received either 30 or 50 trials in the acquisition session. Post-training ICSS facilitated the 24-h retention in both training conditions (30 and 50 trials). In contrast, pre-retention ICSS treatment did not facilitate performance in the retention test. We also observed that post-training ICSS was more effective for improving the 24-h retention than increasing the initial training from 30 to 50 trials. This findings confirm that ICSS treatment improves memory consolidation and suggest that it might not affect memory retrieval mechanisms.     

Effects of different ozone doses on memory, motor activity and lipid peroxidation levels, in rats.

Ozone is one of the main atmospheric pollutants. Its inhalation causes an increase in free radicals, when these free radicals are not compensated by antioxidants, it leads to an oxidative stress state. This oxidative stress state has been implicated in neurodegenerative processes. To determine the effects of oxidative stress caused by exposure to ozone on memory and motor activity, we used 120 male Wistar rats exposed to one of the following ozone doses, (0.0, 0.1, 0.4, 0.7, 1.1 and 1.5 ppm), for four hours. After ozone exposure, short and long term memory of a one trial passive avoidance test were measured, and motor activity was registered for five minutes, in 10 rats of each group. In 16 rats exposed to 0.0, 0.4, 0.7 or 1.1 ppm lipid peroxidation levels from frontal cortex, hippocampus, striatum and cerebellum, were measured. Results show that ozone, causes memory impairment from doses of 0.7 ppm, decrease in motor activity from doses of 1.1 ppm, and increase in lipid peroxidation levels from doses of 0.4 ppm. that increase with the dose.     

Simultaneous modulation of retrieval by dopaminergic D(1), beta-noradrenergic, serotonergic-1A and cholinergic muscarinic receptors in cortical structures of the rat.

Retrieval of inhibitory avoidance has been recently shown to require intact glutamate receptors, protein kinases A and C and mitogen-activated protein kinase in the CA1 region of the rat hippocampus and in the entorhinal, posterior parietal and anterior cingulate cortex. These enzymatic activities are known to be modulated by dopamine D(1), beta-noradrenergic, 5HT1A and cholinergic muscarinic receptors. Here we study the effect on retrieval of this task of well-known agonists and antagonists of these receptors infused in the same brain cortical regions and into the basolateral amygdala, in rats. The drugs used were SKF38393 (D(1) agonist), noradrenaline, 8-HO-DPAT (5HT1A agonist), oxotremorine (muscarinic agonist), SCH23390 (D(1) antagonist), timolol (beta antagonist), NAN-190 (5HT1A antagonist) and scopolamine (muscarinic antagonist). All were studied at two different dose levels. The localised infusion of SKF38393, noradrenaline, NAN-190 and oxotremorine into any of the cortical structures mentioned 10 min prior to a 24-h retention test session of one-trial step-down inhibitory avoidance enhanced retention test performance. SCH2330, timolol, 8-HO-DPAT and scopolamine hindered retention test performance. In the basolateral amygdala only an enhancing effect of noradrenaline and an inhibitory effect of timolol were seen. Three hours after the infusions, retention test performance returned to normal in all cases. None of the treatments affected locomotion or rearing in an open field or behaviour in the elevated plus maze. Therefore, their effects on retention testing can be attributed to an influence on retrieval. In conclusion, memory retrieval of this apparently simple task requires the participation of CA1, entorhinal, posterior parietal and anterior cingulate cortex, and is strongly modulated by, dopaminergic D(1), beta-noradrenergic, muscarinic cholinergic and 5HT1A receptors in the four areas. The first three types of receptor enhance, and the latter inhibits, retrieval. Only beta-adrenoceptors appears to be involved in the modulation of retrieval of this task by the amygdala. The results bear on the well-known influence of emotion and mood on retrieval, and indicate that this involves many areas of the brain simultaneously. In addition, the results point to similarities and differences between the modulatory mechanisms that affect retrieval and those involved in the consolidation of the same task.     

Psychotropic effects of angiotensin II and III in rats: locomotor and exploratory vs cognitive behaviour

One nmol of angiotensin II (AII) or angiotensin III (AIII) given intracerebroventricularly (i.c.v.) increased locomotor and exploratory activity in an open field apparatus but not in the electromagnetic field motimeter. Both peptides significantly enhanced stereotyped behaviour produced by apomorphine (2 mg/kg) and amphetamine (6.5 mg/kg) given intraperitoneally. Also, AII and AIII improved consolidation but not retrieval of memory for an appetitively reinforced spatial discrimination task in a T-maze. AII as well as AIII, given prior to the learning session on day 1, increased rate of acquisition of conditioned avoidance responses in a shuttle-box over the next 7 days. Both angiotensins, injected i.c.v. 15 min before the retention testing, remarkably (5-fold) prolonged re-entry latencies in the passive avoidance situation, suggesting facilitation of the retrieval of memory for an aversively motivated behaviour.     

The effects of acute restraint stress and dexamethasone on retrieval of long-term memory in rats: an interaction with opiate system

This study investigated whether application of acute restraint stress or dexamethasone, as a glucocorticoid receptor agonist, impaired retrieval of long-term memory and if pretreatment with opiate antagonist naloxone blocked their effects on memory retrieval. Young adult male rats were trained in one trial inhibitory avoidance task (1 mA, 1.5 s footshock). On retention test given 48 h after training, the latency to re-enter dark compartment of the apparatus was recorded. Thirty minutes before retention test, the rats were exposed to a 10 min of restraint stress in a Plexiglass tube or were injected with dexamethasone (1 mg/kg) with or without prior treatment of naloxone (1 or 2 mg/kg). The results showed that both acute restraint stress and dexamethasone impaired retention performance. Both doses of naloxone were effective in blocking the impairing effect of stress, but only higher dose of naloxone blocked dexamethasone-induced impairment. The applied stress increased circulating corticosterone levels as assessed immediately after the retention test, indicating that stress-induced impairment of memory retrieval is mediated, in part, by increased plasma levels of glucocorticoids. These findings further indicate that acute restraint stress and glucocorticoids impair retrieval of long-term memory, and provide evidence for the existence of an interaction between glucocortioids and opiate system on this process.     

Scopolamine alters rhesus monkey performance on a novel neuropsychological test battery.

Rhesus monkeys (6) were trained on a test battery including cognitive tests adapted from a human neuropsychological assessment battery (CANTAB; CeNeS, Cambridge, UK) as well as a bimanual motor skill task. The complete battery included tests of memory (delayed non-match to sample, DNMS; self-ordered spatial search, SOSS), reaction time (RT), motivation (progressive ratio; PR) and fine motor coordination (bimanual). The animals were trained to asymptotic performance in all tasks and then were administered two of the four CANTAB tasks on alternate weekdays (PR/SWM; DNMS/RT) with the bimanual task being administered on each weekday. The effect of acute administration of scopolamine (3-24 microg/kg, i.m.) on performance was then determined. Although performance on DNMS was impaired there was no interaction of drug treatment with retention interval, suggesting that scopolamine does not increase the rate of forgetting in this task. Scopolamine administration produced a decrement in SOSS performance that was dependent on task difficulty as well as dose. Scopolamine also impaired motor responses, resulting in increased time required to complete the bimanual motor task and increased movement time in the RT task. Performance in the PR task was decreased in a dose-dependent fashion by scopolamine. The results suggest that scopolamine interferes with memory storage and motor responses but not memory retention/retrieval or vigilance. The findings demonstrate that the test battery is useful for distinguishing the effects of neuropharmacological manipulation on various aspects of cognitive performance in monkeys.     

Application timing of complex magnetic fields delineates windows of posttraining-pretesting vulnerability for spatial and motivational behaviors in rats

Male Wistar rats were trained in a two-session-per-day, non-matching-to-sample radial maze task. During the 2 hr interval between training sessions and testing sessions subjects were exposed for 60 min to either sham fields or to a low intensity (200 to 500 nT) electromagnetic (EM) complex pattern whose electrical (current) equivalent has been shown to elicit long-term potentiation (LTP) in hippocampal slices. This pattern was applied either immediately following the training sessions or immediately antecedent to the testing sessions. Exposures to the experimental field immediately following the training session were associated with an impairment in spatial memory as inferred by increased commissions of reference errors. Exposures immediately prior to the testing session were associated with decreased motivation as inferred by a reduction in speed of responding. These results suggest that the timing of the presentation of patterned magnetic fields may differentially affect the representations of habit strength and drive within the consolidating memory trace.     

Dose- and time-dependent scopolamine-induced recovery of an inhibitory avoidance response after its extinction in rats

The present investigation was aimed at elucidating the dose and time dependency of scopolamine-induced recovery of inhibitory avoidance after its extinction. Two experiments were conducted: in the first, we analyzed the effects of four doses (1, 2, 4, and 8 mg/kg) of the musacrinic receptor antagonist scopolamine, on the expression of this conditioned response once it had been extinguished. Independent groups of rats were trained in a one-trial, step-through inhibitory avoidance task and submitted to daily retention (extinction) tests. After extinction had occurred, animals were injected intraperitoneally 10 min before retention testing, either with saline or scopolamine. Results show that scopolamine produced a dose-dependent recovery of the avoidance response. The second experiment was carried out in the same animals, which were now tested for retention of inhibitory avoidance at 1, 2, 3, 6, and 9 months after completion of the first experiment. All rats received counterbalanced injections of saline or scopolamine 10 min before testing at each time interval. Reliable recovery of the avoidance response was observed at the 1-month interval with a clear dose dependency while, after the second month, only the groups treated with the two higher doses continued responding. The results indicate that recovery of the extinguished response produced by muscarinic blockade follows dose- and time-dependent curves, and can be achieved long after a single training session. These data suggest that the inhibitory avoidance memory trace is retained in the brain after behavioural extinction of this response, thus supporting the view of extinction as new learning that affects the retrieval of the original memory, but does not modify its storage.     

Effects of electrical stimulation of the nucleus basalis on two-way active avoidance acquisition, retention, and retrieval

This study assessed the role of the nucleus basalis magnocellularis (NBM) in specific memory phases of two-way active avoidance conditioning. We evaluated the effects of NBM electrical stimulation applied during different phases of the avoidance task. Rats were trained in a 30-trial acquisition session, and were tested again 24 and 48 h later. NBM stimulation was applied at different stages of memory formation of the conditioning: (1) immediately before the first training session to determine the effects on acquisition of the two-way avoidance task; (2) immediately after the first training session to evaluate effects on memory consolidation; and (3) immediately before the 24-h retention session to analyze the effects on the retrieval process. NBM stimulation before training significantly improved the acquisition of the task, without affecting subsequent retention at either 24 or 48 h. Stimulation of the NBM immediately after the first training session slightly impaired performance in the 24-h retention session. Stimulation of the NBM immediately before the 24-h retention session did not affect performance in either the 24 or 48-h retention sessions. Therefore, the NBM may play a more important role in acquisition of memory in aversively motivated conditioning tasks than in consolidation or retrieval of such memories. These results are discussed in the context of attention enhancement and cortical and amygdala activation.     

Differential effects of tumor necrosis factor-alpha co-administered with amyloid beta-peptide (25-35) on memory function and hippocampal damage in rat

Effects of concurrent intracerebroventricular administration of amyloid-beta peptide 25-35 (Abeta(25-35)) and the proinflammatory cytokine tumor necrosis factor-alpha (TNFalpha) to rats were investigated. A battery of behavioral tests including radial arm maze, passive avoidance, elevated plus-maze and forced swim test as well as histological methods were used. A single administration of Abeta(25-35) induced delayed behavioral deficits manifested in reference and working memory disturbances in the radial maze task involving spatial memory. However, no effects of Abeta(25-35) on learning or retention in a passive avoidance test could be revealed. Abeta(25-35) appeared to decrease anxiety without affecting depression-like behavior in the rats. Abeta(25-35)-induced cognitive deficits could be related to the moderate neuronal cell loss found in the hippocampal CA1 field. Though administration of TNFalpha did not impair learning and memory of rats in the radial maze, it induced gross changes in their behavior during passive avoidance training. Though TNFalpha did not protect against Abeta(25-35)-induced neuronal cell loss in the CA1 field of hippocampus, co-administration of TNFalpha with Abeta(25-35) resulted in an improvement of reference memory impaired by the amyloid peptide, but not of working memory.     

Different effects of scopolamine on the retrieval of spatial memory and fear memory

Retrieval of memory is fundamental for our life as individuals. The participation of cholinergic system in memory consolidation process has been extensively studied, but there are few data concerning the function of this system in memory retrieval process. In the current study, we inject non-selective muscarinic antagonist scopolamine peripherally 20 min before training or testing to see whether cholinergic modulation has effects on the acquisition or retrieval of spatial memory by water maze task and fear memory by inhibitory avoidance task. We find that the cholinergic system is essential for the acquisition of both spatial memory and fear memory. As for the memory retrieval, the cholinergic system has a positive role in the retrieval of spatial memory, because mice injected with scopolamine 20 min before the testing in the water maze show impaired spatial memory retrieval. Whereas injection of scopolamine 20 min before the testing in the inhibitory avoidance task does not cause memory retrieval deficits. That indicates the cholinergic system is not essential for the retrieval of fear memory.