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.     

Memory deficits of aged male rats can be improved by pyrimidine nucleosides and n-acetyl-glutamine

The pyrimidine nucleosides uridine (URI) and cytidine (CYT), alone or associated with n-acetyl-glutamine (NAG), were injected acutely or subchronically to aged (26 months old) male rats of the Sprague-Dawley strain. Learning and memory abilities of the animals were studied with tests of avoidance behavior. The acquisition of active avoidance behavior was studied with the shuttle-box test. 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 compared with those of young animals. Neither the acute treatment of old rats with URI and CYT alone nor that associated with NAG exerted any effect on the behavioral tests. In contrast, the subchronic treatment with URI and CYT 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. 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 pyrimidine nucleosides associated with NAG. These effects may be related to the role of pyrimidines in the synthesis of ribonucleic acid, which is indispensable for learning and memory processes.     

Lesioning of the rat basal forebrain leads to memory impairments in passive and active avoidance tasks

Effects of the bilateral electrolytic lesioning of the basal forebrain (BF), including the ventral globus pallidus, on passive or active avoidance tasks, were studied in male Wistar rats. A severe deficit in acquisition of passive avoidance response was produced by the lesioning in the posterior level of BF. The retention of the passive avoidance response was markedly disrupted with post-training lesioning. Time-dependent but only slight recovery from the memory impairments was observed in the passive avoidance task given 4,8 or 16 weeks after BF lesions. The acquisition of active avoidance response using a two-way shuttle ☐ was also disturbed by BF lesioning. Retention of active avoidance response was clearly impaired by post-training lesions of the BF. The BF lesioned rats gradually acquired the passive avoidance performance when trained repeatedly at 24- or 48-h intervals, by giving a foot shock in case of avoidance failure. Extinction of the acquired passive avoidance response rapidly occurred in the BF lesioned rats. Furthermore, neurotoxic lesions of BF with kainic acid produced a significant impairment in acquisition of passive avoidance response.These results suggest that bilateral BF lesions impair the acquisition and retention of passive or active avoidance response, and that these impaired rats may be useful as an experimental model for Alzheimer's disease and senile dementia.     

Prolonged fear responses in mice lacking dopamine D1 receptor

Dopamine is an important neurotransmitter involved in learning and memory including emotional memory. The involvement of dopamine in conditioned fear has been widely documented. However, little is known about the molecular mechanisms that underlie contextual fear conditioning and memory consolidation. To address this issue, we used dopamine D1-deficient mice (D1-/-) and their wild-type (D1+/+) and heterozygote (D1+/-) siblings to assess aversive learning and memory. We quantified two different aspects of fear responses to an environment where the mice have previously received unsignaled footshocks. Using one-trial step-through passive avoidance and conditioned freezing paradigms, mice were conditioned to receive mild inescapable footshocks then tested for acquisition, retention and extinction of conditioned fear responses 5 min after and up to 45-90 days post-training. No differences were observed among any of the genotypes in the acquisition of passive avoidance response or fear-induced freezing behavior. However, with extended testing, D1-/- mice exhibited prolonged retention and delayed extinction of conditioned fear responses in both tasks, suggesting that D1-/- mice are capable of acquiring aversive learning normally. These findings demonstrate that the dopamine D1 receptor is not important for acquisition or consolidation of aversive learning and memory but has an important role in modulating the extinction of fear memory.     

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.     

Noradrenaline and avoidance learning in the rat

The selective neurotoxin 6-hydroxydopamine was used to deplete forebrain noradrenaline to less than 5% of control values and the learning capabilities of the depleted animals examined on a two-way active avoidance task. Noradrenaline depleted animals learned the two-way active avoidance task more quickly than controls and required fewer training trials to reach acquisition criterion. Twenty-four hour retention was not altered by the lesion, but significant resistance to extinction was seen when electric footshock was no longer presented. More detailed analysis of the improved acquisition shown by the lesioned animals revealed that the major effect lay in a reduced freezing response to footshock. This freezing tended to slow down learning in the control animals, since it was incompatible with the required two-way active avoidance response. No alteration was seen in sensory detection thresholds for electric footshock or in spontaneous locomotor activity in the absence of shock.These results are discussed in relation to theories of noradrenaline function in learning and memory and, more recently, in fear and anxiety.     

Interactions between angiotensin II and baclofen in shuttle-box and passive avoidance performance

In experiments on male rats, we established that angiotensin-II (AT II) at a dose of 0.1 micrograms injected intracerebroventricularly immediately after training improved memory when retention tests (active and passive avoidance) were given 24 hours later. Baclofen at doses of 2, 5 and 10 mg/kg injected intraperitoneally immediately after training also improved retention in both active and passive avoidance tasks. Baclofen at a dose of 20 mg/kg was without effect on active avoidance performance. Combination of AT II and baclofen (2, 5 and 10 mg/kg) facilitated memory in active avoidance as compared to controls, but impaired retention as compared to the AT II-treated group. The impairment of the AT II-improved retention was stronger when the dose of baclofen in the combination was 20 ng/kg. Combination of AT II and baclofen (10 mg/kg) did not impair retention in passive avoidance. These data favor the view that GABA receptors may interfere with the AT II effects on memory consolidation or retention and that interactions of GABA (GABAA and GABAB) receptors with AT II receptors are of importance for memory processes.     

Cysteamine-induced depletion of somatostatin produces differential cognitive deficits in rats

The effects of a variety of doses of systemically administered cysteamine (a somatostatin depletor) were studied on step-through passive avoidance retention, as well as acquisition and performance of a delayed spatial alternation task and a signaled extinction discrimination task in rats. Retention of single trial passive avoidance was significantly reduced by a pretraining (60-min) dose of cysteamine at 50, 100, 150 and 200 mg/kg s.c. This effect was shown to be sensitive to behavioral manipulation; in a second experiment, a retention deficit was found only at the two highest doses tested (150 and 200 mg/kg s.c.) after a second exposure to the footshock. In the operant conditioning studies, biweekly injections (Monday and Wednesday) of cysteamine administered one hour before testing produced no statistically significant changes in acquisition or performance of either the delayed spatial alternation or the signaled discrimination task. The results of these series of experiments suggest that active somatostatin release or chronic somatostatin depletion may selectively affect performance maintained by different behavioral procedures.     

Action of PMA (phorbol myristate acetate), scopolamine, propranolol, and oxotremorine on memorization of an active or passive avoidance test

The role of various second messengers in the learning and retention of a passive or active avoidance has been investigated in mice. Scopolamine at 3 mg/kg i.p. inhibits muscarinic M1 and M2 receptors and thus acetylcholine activation of the phosphoinositide cycle. This results in amnesia of passive avoidance but has no effect on active avoidance learning. Oxotremorine at 0.05 mg/kg i.p., whose preferential M2 muscarinic action limits acetylcholine release and also inhibits adenylate cyclase activity, causes amnesia of the retention of a passive avoidance and antagonizes the learning of an active avoidance. DL-propranolol at 40 mg/kg i.p., which inhibits cAMP formation, does not affect retention of a passive avoidance but antagonizes that of an active avoidance. Similarly, phorbol myristate acetate a 0.1 mg/kg i.p., which activates protein kinase C, has no effect on the retention of a passive avoidance but antagonizes that of an active avoidance. The results tend to show a distinct role for cAMP-dependent protein kinase, which would participate in memorization processes of an active avoidance, and for protein kinase C, which would participate in that of a passive avoidance. The authors discuss the involvement of different neurophysiological mechanisms as a function of the type of behavior, depending on whether or not it is related to the control of environmental situations.     

Comparative studies on the memory-enhancing actions of captopril and losartan in mice using inhibitory shock avoidance paradigm

Renin angiotensin system (RAS) in the central nervous system participates in the processing of sensory information, learning and memory processes. Inhibitors of RAS, particularly angiotensin converting enzyme (ACE) inhibitors and angiotensin II (Ang II) receptor antagonists are reported to have potential nootropic effects in various learning and memory paradigms. The neurochemical basis underlying nootropic effect of ACE inhibitors are unclear due to wide range of substrate for this enzyme. In this study, we compared the effect of ACE inhibitor captopril and a selective AT(1)receptor antagonist losartan in a step-up shock avoidance (active avoidance) task. Captopril (5-10 mg/kg) but not losartan (5-10 mg/kg) improved learning in the second trial of the acquisition test. However, both these drugs were equally effective in enhancing retention of memory when administered prior to training. Retention enhancing effect of captopril and losartan were reversed by post-acquisition test administration of L-NAME (15 mg/kg), dizocilpine (0.05 mg/kg) and scopolamine (0.1 mg/kg). On the basis of above observations, it is concluded that decrease in endogenous Ang II activity in the brain might result in improved cognitive performance by enhancing cGMP pathways. However facilitation of acquisition only by captopril may be due to other putative mechanisms.     

Memory impairments following basal forebrain lesions

The functional contribution of the nucleus basalis magnocellularis (NBM) and medial septal area (MSA) to memory was evaluated in 4 behavioral tasks. The tasks were postoperative acquisition of a win-stay spatial discrimination in a T-maze, a win-shift spatial discrimination on a radial arm maze, active avoidance in a shuttle box, and passive avoidance in a shuttle box. Bilateral lesions were made by injecting ibotenic acid (IBO) into the NBM or MSA. Control rats received operations in which no neurotoxin was injected. When compared to controls, rats with lesions in either the NBM or MSA had significantly impaired choice accuracy in the T-maze and radial maze tasks, took significantly fewer trials to reach criterion in the acquisition, but not the retention of an active avoidance task, and significantly more trials to reach criterion in the passive avoidance task. The results show that equivalent behavioral changes are obtained from lesions in the NBM and MSA in tasks that vary in their type of motivation, reinforcement, response-reinforcement contingency, and response. These behavioral changes suggest that the NBM and MSA may both be involved in memory.     

Delayed memory dysfunction by transient hypoxia, and its prevention with forskolin

Rats exposed to 40 min hypoxia 3 h before a one-trial learning passive avoidance task showed impaired memory retention 24 h later. This model was used to assess the ability of forskolin to restore the delayed memory dysfunction. Significant amelioration of memory retention was observed when forskolin (500 μg/kg, i.p.) was injected just after hypoxia. Forskolin is suggested to enhance cerebral blood flow and to facilitate memory function through the action of increased cyclic adenosine monophosphate (cAMP).     

Effects of discrete kainic acid-induced hippocampal lesions on spatial and contextual learning and memory in rats

Substantial information is available concerning the influence of global hippocampal lesions on spatial learning and memory, however the contributions of discrete subregions within the hippocampus to these functions is less well understood. The present investigation utilized kainic acid to bilaterally lesion specific areas of the rat hippocampus. These animals were subsequently tested on a spatial orientation task using a circular water maze, and on an associative/contextual task using passive avoidance conditioning. The results indicate that both the dorsal CA1 and the ventral CA3 subregions play important roles in learning. Specifically, CA1 lesions produced a deficit in the acquisition of the water maze task and a significant memory impairment on the passive avoidance task. CA3 lesions also caused learning deficits in the acquisition of the water maze task, and produced even greater impairments in performance on the passive avoidance task. We conclude that CA1 and CA3 hippocampal subregions each play significant roles in the overall integration of information concerning spatial and associative learning.     

Enhancement of learning behaviour by a potent nitric oxide-guanylate cyclase activator YC-1

Memory is one of the most fundamental mental processes, and various approaches have been used to understand the mechanisms underlying this process. Nitric oxide (NO), cGMP and protein kinase G (PKG) are involved in the modulation of synaptic plasticity in various brain regions. YC-1, which is a benzylindazole derivative, greatly potentiated the response of soluble guanylate cyclase to NO (up to several hundreds fold). We have previously shown that YC-1 markedly enhances long-term potentiation in hippocampal and amygdala slices via NO-cGMP-PKG-dependent pathway. We here further investigated whether YC-1 promotes learning behaviour in Morris water maze and avoidance tests. It was found that YC-1 shortened the escape latency in the task of water maze, increased and decreased the retention scores in passive and active avoidance task, respectively. Administration of YC-1 30 min after foot-shock stimulation did not significantly affect retention scores in response to passive avoidance test. Administration of scopolamine, a muscarinic antagonist, markedly impaired the memory acquisition. Pretreatment of YC-1 inhibited the scopolamine-induced learning deficit. The enhancement of learning behaviour by YC-1 was antagonized by intracerebroventricular injection of NOS inhibitor L-NAME and PKG inhibitors of KT5823 and Rp-8-Br-PET-cGMPS, indicating that NO-cGMP-PKG pathway is also involved in the learning enhancement action of YC-1. YC-1 is thus a good drug candidate for the improvement of learning and memory.     

Effects of cholinergic drugs on learning impairment in ventral globus pallidus-lesioned rats

The excitotoxin kainic acid (10 nmol/microliter) was used to produce bilateral lesions in the nucleus basalis magnocellularis (NBM) of rats which provides extensive cholinergic innervation to the cerebral cortex. The behavioral effects of physostigmine, THA (9-amino-1,2,3,4-tetrahydroacridine hydrochloride) and NIK-247 (9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinoline monohydrate hydrochloride) were investigated by observing locomotor activity, shock sensitivity and passive avoidance response in the NBM-lesioned rats. Evaluation of locomotor activity and shock sensitivity in the experimental animals did not reveal any sensorimotor disturbances caused by the lesions. Oral administration of 1 and 2 mg/kg physostigmine reduced the locomotor activity in the NBM-lesioned rats, while physostigmine (0.5 mg/kg), THA (1 or 3 mg/kg) and NIK-247 (1 or 3 mg/kg) had no effect on locomotor activity. Compared with the sham-operated controls, the NBM-lesioned rats exhibited a significantly lesser deficit in the retention of the passive avoidance response. THA (1 or 3 mg/kg) and NIK-247 (1 or 3 mg/kg) elicited good retention of the passive avoidance response. Rats with NBM lesions showed impaired acquisition of a passive avoidance response when trained repeatedly at 24-h intervals. Also, when post-training NBM lesions were induced, there was rapid extinction of the acquired passive avoidance response. THA or NIK-247 administered at doses of 3 mg/kg significantly increased response latencies of post-trained NBM-lesioned rats. THA or NIK-247 administered once a day in doses of 1 or 3 mg/kg p.o. produced a very significant increase of acetylcholine in the cerebral cortex of NBM-lesioned rats after the 21st administration. These finding suggest that THA and NIK-247 exert an ameliorating effect on memory disturbance induced by NBM lesions in rats.     

Age-related deterioration of ability of acquisition in memory and learning in senescence accelerated mouse: SAM-P/8 as an animal model of disturbances in recent memory

Memory, learning and behavior of senescence accelerated mouse (SAM-P/8) were investigated by using passive avoidance response, T-maze and open field and the findings were compared with those from senescence resistant mouse (SAM-R/1 control). SAM-P/8 mice showed a remarkable age-related deterioration in ability of memory and learning in passive avoidance response. This age-related memory and learning deficit was linked to a deterioration in the ability of acquisition and was not due to impairment in the ability of retention and hyperactivity, as observed in the open field. In the alternation T-maze tests, SAM-P/8 showed as high a rate of alternations as did the SAM-R/1 and in the T-maze avoidance tests, SAM-P/8 also showed as intact a memory ability as seen in the SAM-R/1, despite a memory deficit in the passive avoidance response. Thus, SAM-P/8 may prove to be a pertinent model for researching mechanisms related to the memory deficit seen in senile humans.     

Prolonged fear responses in mice lacking dopamine D1 receptor

Dopamine is an important neurotransmitter involved in learning and memory including emotional memory. The involvement of dopamine in conditioned fear has been widely documented. However, little is known about the molecular mechanisms that underlie contextual fear conditioning and memory consolidation. To address this issue, we used dopamine D₁-deficient mice (D₁−/−) and their wild-type (D₁+/+) and heterozygote (D₁+/−) siblings to assess aversive learning and memory. We quantified two different aspects of fear responses to an environment where the mice have previously received unsignaled footshocks. Using one-trial step-through passive avoidance and conditioned freezing paradigms, mice were conditioned to receive mild inescapable footshocks then tested for acquisition, retention and extinction of conditioned fear responses 5 min after and up to 45–90 days post-training. No differences were observed among any of the genotypes in the acquisition of passive avoidance response or fear-induced freezing behavior. However, with extended testing, D₁−/− mice exhibited prolonged retention and delayed extinction of conditioned fear responses in both tasks, suggesting that D₁−/− mice are capable of acquiring aversive learning normally. These findings demonstrate that the dopamine D₁ receptor is not important for acquisition or consolidation of aversive learning and memory but has an important role in modulating the extinction of fear memory.     

Protective effect of the calcium antagonist nimodipine on discrimination learning deficits and impaired retention behavior caused by prenatal nitrite exposure in rats

Discrimination learning behavior and retention of a passive avoidance response were studied in male adult offspring of gestating rats exposed to drinking water containing 2 g/l sodium nitrite, throughout the second half of pregnancy. Both in an auditory and visual discrimination learning paradigm NaNO2-exposed rats were inferior to controls. The long-term retention of a passive avoidance response was also impaired. The acquisition of simple learning tasks was not significantly disturbed. The concomitant prenatal daily treatment with the calcium antagonist nimodipine in a dose of 10 mg/kg p.o. interfered with the nitrite neurotoxicity and prevented the development of adult behavioral deficits. The results support the hypothesis that Ca2+ homeostasis of neurons is an important factor for normal development of brain and behavior.     

Ascorbic acid supplementation could affect passive avoidance learning and memory in rat

Ascorbic acid (vitamin C) is required for health and, in particular, its supplementation has beneficial effects in some pathological conditions. There are conflicting reports regarding the usefulness of ascorbic acid in the treatment of dementia. In this study, we investigated the effects of acute, short- and long-term pre-training administration of ascorbic acid (60,120 mg/kg) on passive avoidance learning (PAL) and memory in rats. Retention test was done 24 h after training. The results showed that acute injection of ascorbic acid had no significant effect on PAL. On the other hand, both in the short- and long-term ascorbic acid treated groups trials to acquisition were less than control group. Also, ascorbic acid prolonged the step-through latency (STL) and decreased the time spent in the dark compartment in retention test. Thus, it can be concluded that short- and long-term supplementation with ascorbic acid has facilitatory effects on acquisition and retrieval processes of passive avoidance learning and memory in rats.     

Effects of histamine precursor and (R)-alpha-methylhistamine on the avoidance response in rats.

The aim of this work is to clarify the role of histamine in learning and memory processes. In order to do this, the effect of administration of the histamine precursor, L-histidine (HIS) and of the agonist of the H(3) receptor, (R)-alpha-methylhistamine (RAMH), on active avoidance response in rats is studied. Treatment with RAMH (10 mg/kg i.p.) increased the number of avoidance responses produced during acquisition and retention of the learning. In contrast, administration of L-his (500 mg/kg i.p.) impairs performance in the shuttle-box. These results are consistent with a role for histamine in cognitive processes and suggest that a increase in cerebral histamine levels impair the acquisition of avoidance response, whereas reduced levels facilitate this acquisition.