Passive Avoidance Reflex Research Articles

Level of neuroactive steroids in the brain and sex-related peculiarities of formation and extinction of conditioned reflex in rats

Sex-related peculiarities of dynamics of brain sex steroids in the process of learning and extinction of the conditioned reflex of passive avoidance have been studied in model experiment. Prior to learning of the conditioned reflex, female rats were found to be distinguished by manifestation of anxiety and fear as compared with male rats. At formation of the conditioned reflex, no significant sex-related differences were detected between males and females, whereas extinction of the conditioned reaction of passive avoidance in males occurred by 2–3 days faster than in females. At learning of conditioned reaction of passive avoidance, in sexually mature male rats there was revealed an increase of the testosterone content in various brain structures, especially in hippocampus and frontal cortex, while its level in blood plasma remained unchanged. Also shown was an elevation of estradiol concentration in female amygdale, whereas at extinction of the conditioned reaction of passive avoidance, a rise of estradiol values was noted in hippocampus and cingular cortex. At the same time, the testosterone level in blood plasma did not change, whereas after extinction of the conditioned reflex the estradiol concentration decreased statistically significantly. Different dynamics of changes of the sex steroid levels in brain and blood plasma can indicate a possibility of their formation in the nervous tissue. The performed correlation analysis confirms the concept of selective involvement of testosterone and estradiol of individual brain structures in realization of processes of learning and memory in sexually mature male and female rats.

Prevention of Neurodegenerative Damage to the Brain in Rats in Experimental Alzheimer’s Disease by Adaptation to Hypoxia

We report here studies addressing the possibility of preventing neurodegenerative changes in the brain using adaptation to periodic hypoxia in rats with experimental Alzheimer's disease induced by administration of the neurotoxic peptide fragment of beta-amyloid (Ab) into the basal magnocellular nucleus. Adaptation to periodic hypoxia was performed in a barochamber (4000 m, 4 h per day, 14 days). The following results were obtained 15 days after administration of Ab. 1. Adaptation to periodic hypoxia significantly blocked Ab-induced memory degradation in rats, as assessed by testing a conditioned passive avoidance reflex. 2. Adaptation to periodic hypoxia significantly restricted increases in oxidative stress, measured spectrophotometrically in the hippocampus in terms of the content of thiobarbituric acid-reactive secondary lipid peroxidation products. 3. Adaptation to periodic hypoxia completely prevented the overproduction of NO in the brains of rats with experimental Alzheimer's disease, as measured in terms of increases in tissue levels of stable NO metabolites, i.e., nitrites and nitrates. 4. The cerebral cortex of rats given Ab injections after adaptation to periodic hypoxia did not contain neurons with pathomorphological changes or dead neurons (Nissl staining), which were typical in animals with experimental Alzheimer's disease. Thus, adaptation to periodic hypoxia effectively prevented oxidative and nitrosative stress, protecting against neurodegenerative changes and protecting cognitive functions in experimental Alzheimer's disease.

Nootropic and Antiamnestic Effects of Tenoten (Pediatric Formulation) in Immature Rat Pups

The antiamnestic effects of tenoten (pediatric formulation) was demonstrated on the model of scopolamine-induced amnesia of passive avoidance reflex and the nootropic effect of this preparation was demonstrated on the model of incomplete conditioning and in rat pups with experimental attention deficit syndrome. The efficiency of the preparation was comparable to that of piracetam and phenibut and even surpassed it by some parameters.

Brain targeting of nerve growth factor using poly(butyl cyanoacrylate) nanoparticles

The nerve growth factor (NGF) is essential for the survival of both peripheral ganglion cells and central cholinergic neurons in the basal forebrain. The accelerated loss of central cholinergic neurons during Alzheimer’s disease may be a determinant cause of dementia, and this observation may suggest a possible therapeutic benefit from treatment with NGF. In recent years, convincing data have been published involving neurotrophic factors for the modulation of dopaminergic transmission within the brain and concerning the ability of NGF to prevent the degeneration of dopaminergic neurons. In this connection, the administration of NGF may slow down the progression of Parkinson’s disease. However, NGF, as well as other peptidic neurotrophic factors, does not significantly penetrate the blood–brain barrier (BBB) from the circulation. Therefore, any clinical usefulness of NGF as a potential CNS therapy will depend on the use of a suitable carrier system that enhances its transport through the BBB. The present study investigates brain delivery of NGF adsorbed on poly(butyl cyanoacrylate) (PBCA) nanoparticles coated with polysorbate 80 and the pharmacological efficacy of this delivery system in the model of acute scopolamine-induced amnesia in rats as well as in the model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonian syndrome. As shown by the passive avoidance reflex (PAR) test, the intravenous administration of the nanoparticle-bound NGF successfully reversed scopolamine-induced amnesia and improved recognition and memory. This formulation also demonstrated a significant reduction of the basic symptoms of Parkinsonism (oligokinesia, rigidity, tremor). In addition, the efficient transport of NGF across the BBB was confirmed by direct measurement of NGF concentrations in the murine brain. These results demonstrate that the PBCA nanoparticles coated with polysorbate 80 are an effective carrier system for the transport of NGF to the central nervous system across the BBB following intravenous injection. This approach may improve the NGF-based therapy of age-related neurodegenerative diseases.

Effects of the LHRH antagonist Cetrorelix on the brain function in mice

The decapeptide Cetrorelix, an LHRH antagonist, inhibits gonadotropin and sex steroid secretion. Cetrorelix is used for IVF-ET procedures and for the treatment of patients with prostate carcinoma, benign prostatic hyperplasia, endometriosis, leiomyomas and, ovarian cancer. However little is known about the effects of Cetrorelix on the brain function. In the present work the influence of Cetrorelix on different aspects of the brain function was studied following its administration into the lateral brain ventricle in mice. The effects tested included the impairment of the consolidation of a passive avoidance reflex caused by beta-amyloid 25-35, anxiolytic action in the plus-maze, antidepressive action in a forced swimming test and a tail suspension test and open-field behavior. In the passive avoidance test, beta-amyloid 25-35 administered immediately after the learning trial impaired the consolidation of passive avoidance learning. Cetrorelix fully blocked the impairment of the consolidation of passive avoidance learning when given icv 30 min following beta-amyloid 25-35 administration. If beta-amyloid 25-35 and Cetrorelix icv were given simultaneously, the Cetrorelix attenuated, but did not block the action of the beta-amyloid 25-35. Cetrorelix elicited anxiolytic action in the plus-maze, depending on the dose used. In the forced swimming and tail suspension tests, Cetrorelix demonstrated antidepressive-like action. Concerning open-field behavior, Cetrorelix displayed no action on locomotion, rearing or grooming. The results demonstrate that Cetrorelix affects brain function: and is able to correct the impairment of the memory consolidation caused by beta-amyloid 25-35. Cetrorelix also elicits anxiolytic and antidepressive action, but it does not influence the open-field activity. Further experimental work with Cetrorelix is necessary, but the results imply the possible merit of a clinical trial with Cetrorelix in patients with anxiety, depression and Alzheimer's disease.

Comparative study for brain delivery of tacrine using polysorbate 80-coated poly(butylcyanoacrylate) and pegylated-poly(butylcyanoacrylate) nanoparticles

Many studies indicated that polysorbate (PS) 80-coated polybutylcyanoacrylate (PBCA) nanoparticles can deliver drugs that poorly penetrate BBB to the brain. Also, the polyethylene glycolated-polybutylcyanoacrylate (PEG-PBCA) nanoparticles have a good safety profiles and sustained drug release. The purpose of this study is to compare between the ability of both PS80-coated PBCA nanoparticles and PEG-PBCA nanoparticles in targeting of tacrine to the brain. Rats treated with tacrine intravenously in three forms: 1) simple solution; 2) loaded on PS80-coated PBCA nanoparticles; 3) loaded on PEG-PBCA nanoparticles. Tacrine antiamnesic effect was tested using the passive avoidance reflex (PAR) test. Also tacrine concentrations in brain and liver were measured using HPLC. Results demonstrated that, both PS-80 coated and PEG-PBCA nanoparticles successfully enhanced brain delivery of tacrine in rats while PEG-PBCA nanoparticles have higher brain targeting ability and less liability to be up taken by the liver, this provides it more safety and longer duration.

Effect of low doses of polidan on the conditioned passive avoidance reflex in rats

The effects of the DNA-containing biologically active compound polidan on conditioning in rats were investigated. Passive avoidance conditioning was used as a model of memory. Polidan at a dose of 10−10 M had a positive effect on memory.

Noopept efficiency in experimental Alzheimer disease (cognitive deficiency caused by β-amyloid25–35 injection into Meynert basal nuclei of rats)

Experiments on adult Wistar rats showed that injection of beta-amyloid25-35 (2 microg) into Meynert basal nuclei caused long-term memory deficiency which was detected 24 days after this injection by the memory trace retrieval in conditioned passive avoidance reflex (CPAR). The effects of noopept, an original nootropic and neuroprotective dipeptide, on the severity of this cognitive deficiency were studied. Preventive (for 7 days before the injury) intraperitoneal injections of noopept in a dose of 0.5 mg/kg completely prevented mnestic disorders under conditions of this model. Noopept exhibited a significant normalizing effect, if the treatment was started 15 days after the injury, when neurodegenerative changes in the basal nuclei, cortex, and hippocampus were still acutely pronounced. The mechanisms of this effect of the drug are studied, including, in addition to the choline-positive effect, its multicomponent neuroprotective effect and stimulation of production of antibodies to beta-amyloid25-35. Noopept efficiency in many models of Alzheimer disease, its high bioavailability and low toxicity suggest this dipeptide for further studies as a potential agent for the treatment of this condition (initial and moderate phases).

Interaction of total blood calcium levels and brain catecholamines during the formation and reinforcement of memory traces in hypoparathyroidism

Interactions between the total blood calcium level and catecholamine contents in limbic brain structures during the formation and extinction of a conditioned passive avoidance reflex were studied in rats with hypoparathyroidism. Impairments of calcium support for the processes of conditioned reflex activity were seen after removal of the parathyroid glands. Animals with hypoparathyroidism not only showed changes in basal dopamine and noradrenaline levels in limbic structures, but also impairments of catecholamine dynamics during the acquisition and forced extinction of a conditioned passive avoidance reflex. These results demonstrate changes in the functional dynamics of the dopaminergic and noradrenergic systems of the brain in conditions of abnormal calcium homeostasis in the body, which underlie abnormalities of conditioned reflex activity and the acquisition of the adaptive behavioral strategies.

Comparative analysis of the persistence of a conditioned passive avoidance reflex in rats with different forms of inherited hypertension

The characteristics of anxiety behavior and reproduction of a conditioned passive avoidance reflex acquired in response to a single combination with an unconditioned aversive stimulus were studied in NISAG rats with inherited stress-sensitive arterial hypertension and spontaneously hypertensive SHR rats. SHR rats were characterized by hyperactive behavior, very low levels of anxiety, and poor reproduction of the conditioned reflex as compared with NISAG and control Wistar and WAG rats. Intermediate-anxiety NISAG rats showed no difficulties in acquiring and subsequently retaining the conditioned reflex. These differences in the ability to undergo single-combination learning in rats with different forms of hypertension suggest that memory processes are independent of elevated arterial blood pressure. The effects of the genetic characteristics of behavior and emotional status of these animals on memory are discussed.

Characteristics of extinction of a conditioned passive avoidance reflex in mice with different levels of anxiety

The relationship between the extinction of a conditioned passive avoidance reflex and the initial anxiety level was studied in mice. The time spent in the open arms of an elevated cross maze was used to classify the mice into high-, intermediate-and low-anxiety individuals. Each level of anxiety was found to correspond to a defined extinction dynamic. Highly anxious mice were characterized by the absence of extinction of the conditioned passive avoidance reflex and stability of good reproduction of the memory trace on testing to as long as 15 days. In intermediately anxious individuals, a deficit in performance of the avoidance reflex appeared from day 7 of extinction. In low-anxiety mice, memory trace reproduction deteriorated from test day 11.

Effects of activation of D1 dopamine receptors on extinction of a conditioned passive avoidance reflex and amnesia in aggressive and submissive mice

The studies reported here demonstrate the relationship between the effect of activation of D1 dopamine receptors on the reproduction of a conditioned passive avoidance reflex during extinction and amnesia and the aggressive and submissive behavioral stereotypes. During extinction, the D1 receptor agonist SKF 38393 at a dose of 5 mg/kg given before acquisition of the conditioned reflex and on test day 12 suppressed the reproduction of the conditioned skill in aggressive mice and improved reproduction in submissive mice. The effects of activation of D1 receptors were also opposite relative to the stereotype in amnesia. In aggressive mice, SKF 38393 significantly decreased the resistance to amnesia characteristic of these animals; in submissive mice, SKF 38393 weakened the amnestic effects of the delay in the "dangerous" sector and restored memory traces. The possible mechanisms of the selectivity of the actions of D1 receptors in mice with alternative behavioral stereotypes in retaining memory traces related to aversive stimulation during extinction and amnesia are discussed.

Acquisition and extinction of a conditioned passive avoidance reflex in mice with genetic knockout of monoamine oxidase A

We report here the results obtained from comparative analysis of learning and the dynamics of extinction of a conditioned passive avoidance response in mice with genetic knockout of monoamine oxidase A (MAO A) and the progenitor line C3H. Mice of both lines acquired the conditioned passive avoidance reaction efficiently. Mice with genetic knockout of MAO A were characterized by prolonged retention of reproduction of the memory trace, as compared with rapid extinction in C3H mice. Smaller numbers of transfers, and vertical rearings on days 7-13 and the numbers of glances into and rom the dark sector on days 11-13 of extinction in MAO A-knockout mice appear to reflect their more marked fear reactions when confronted with the "dangerous" sector, along with increased anxiety, these facilitating longer-lasting retention of the memory trace.

Design of new cognition enhancers: from computer prediction to synthesis and biological evaluation.

To discover new cognition enhancers, a set of virtually designed synthesizable compounds from different chemical series was investigated using two computer-aided approaches. One of the approaches is prediction of biological activity spectra for substances (PASS) and the second is prediction of toxicity, mutagenicity, and carcinogenicity (DEREK). To increase the probability of finding new chemical entities, we investigated a heterogeneous set of highly diverse chemicals including different types of heterocycles: five-membered (thiophenes, thiazoles, imidazoles, oxazoles, pyrroles), six-membered (pyridines, pyrimidines), seven-membered (diazepines, triazepines), fused five+six-membered heterocycles (indoles, benzothiazoles, purines, indolizines, neutral, mesoionic, and cationic azolopyridines). A database including 5494 structures of compounds was created. On the basis of the PASS and DEREK prediction results, eight compounds with the highest probability of cognition-enhancing effect were selected. The cognition-enhancing activity testing showed that all of the selected compounds had a pronounced antiamnesic effect and were found to reduce significantly scopolamine-induced amnesia of passive avoidance reflex (PAR). The action of compounds at doses of 1 and 10 mg/kg caused a statistically significant increase in latent time of reflex and in the number of animals, which did not enter the dark chamber when testing the PAR. Therefore, on the basis of computer prediction, new cognition-enhancing agents were discovered within the chemical series, in which this activity was not known previously.

Brain function in Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is the second most commonly occurring genetically inherited disease in humans. It is an X-linked condition that affects approximately one in 3300 live male births. It is caused by the absence or disruption of the protein dystrophin, which is found in a variety of tissues, most notably skeletal muscle and neurones in particular regions of the CNS. Clinically DMD is characterized by a severe pathology of the skeletal musculature that results in the premature death of the individual. An important aspect of DMD that has received less attention is the role played by the absence or disruption of dystrophin on CNS function. In this review we concentrate on insights into this role gained from investigation of boys with DMD and the genetically most relevant animal model of DMD, the dystrophin-deficient mdx mouse. Behavioural studies have shown that DMD boys have a cognitive impairment and a lower IQ (average 85), whilst the mdx mice display an impairment in passive avoidance reflex and in short-term memory. In DMD boys, there is evidence of disordered CNS architecture, abnormalities in dendrites and loss of neurones, all associated with neurones that normally express dystrophin. In the mdx mouse, there have been reports of a 50% decrease in neurone number and neural shrinkage in regions of the cerebral cortex and brainstem. Histological evidence shows that the density of GABA(A) channel clusters is reduced in mdx Purkinje cells and hippocampal CA1 neurones. At the biochemical level, in DMD boys the bioenergetics of the CNS is abnormal and there is an increase in the levels of choline-containing compounds, indicative of CNS pathology. The mdx mice also display abnormal bioenergetics, with an increased level of inorganic phosphate and increased levels of choline-containing compounds. Functionally, DMD boys have EEG abnormalities and there is some preliminary evidence that synaptic function is affected adversely by the absence of dystrophin. Electrophysiological studies of mdx mice have shown that hippocampal neurones have an increased susceptibility to hypoxia. These recent findings on the role of dystrophin in the CNS have implications for the clinical management of boys with DMD.

Studies of the interaction between behavioral stereotypes and the effects of activation of presynaptic dopamine receptors during extinction and amnesia in mice.

The involvement of presynaptic dopamine receptors in the retention of a conditioned passive avoidance reflex through extinction and amnesia was studied in C57BL/6J mice selected in a 20-day aggressive conflict test for aggressive and submissive behavioral stereotypes. These experiments showed that in aggressive mice, activation of presynaptic receptors with the agonist (+)3-(3-hydroxyphenyl)-N-n-propylpiperidine [(+)3PPP] at a dose of 2 mg/kg degraded learning, significantly decreased the retention time of the acquired conditioned habit in extinction, and increased the effect of an amnesia-inducing treatment. Mice showing submissive behavior in daily confrontations with aggressors responded to administration of (+)3PPP with long-lasting reproduction of the conditioned passive avoidance reaction during extinction and showed no changes in the development of amnesia. These data on the relationship between the effects of activating presynaptic dopamine receptors in reproduction of the memory trace in conditions of trace disruption on the one hand and behavioral status on the other are assessed from the point of view of different basal levels of dopaminergic system operation in aggressive and submissive mice.

Pharmacological reminders of emotional state facilitate the retrieval of traces from amnesiac memory.

The experiments reported here show that animals with different levels of acquisition of a conditioned passive avoidance reflex retrieved the reflex differently on systematic testing over a period of 28 days. Animals with the highest and high levels of training reproduced the reflex stably. Animals with an intermediate level of training reproduced the reflex with significant variation. Convulsions induced by pentylenetetrazole (75 and 50 mg/kg. i.p.) resulted in amnesia. The amnestic effect of pentylenetetrazole convulsions depended on the ratio of the intensity of training and the intensity of the induction of convulsions. Reminding, provided by presentation of an unconditioned stimulus, removed the amnestic effect of the convulsive state. Training led to significant decreases in the parameters determining the severity of the convulsive state. The convulsive state was a dissociative state, as subconvulsive doses of pentylenetetrazole (30 mg/kg, i.p.) removed the amnestic effect of convulsive doses. The dissociated state was reproduced by pharmacological reminding of the state of anxiety and fear which was formed during training. A subcataleptic dose of haloperidol (0.25 mg/kg, i.p.) induced a state of fear and removed the amnestic effect of the convulsive state. The same dose of haloperidol improved retrieval of the reflex in animals with low levels of training, i.e., those in which retrieval hardly occurred in normal conditions.

Behavioural impairment induced by calcitonin gene-related peptide (CGRP) antiserum in passive avoidance reflex in rats

The effects of CGRP antiserum on passive avoidance behaviour were tested in rats. Intracerebroventricular (i.c.v.) administration of CGRP antiserum immediately after a single learning trial attenuated the passive avoidance responses when the animals were tested for 24 h retention. Significant decreases in avoidance latency were found at CGRP antiserum dilutions of 1:20 and 1:40. The data supported the assumption that endogenous brain CGRP may be a modulator in learning-associated memory processes.

Mono- and polysynaptic connections between identified neurons in the system of the passive avoidance reflex of the snail.

The structure of the synaptic connections between identified sensory and giant command neurons of the parietal ganglia of the snail is examined. It is shown that the excitatory postsynaptic potential arising in the giant neuron in response to the generation of a single action potential in the presynaptic neuron consists of several monosynaptic components and may include polysynaptic components. It is hypothesized that monosynaptic components of the elementary excitatory postsynaptic potential that differ in the duration of the latent period and the dynamics of habituation may be associated with the activation of synaptic buttons on axon terminals of varying length.

Adrenocortical function in rats adapted to the experimental environment during passive avoidance learning

In the investigation described below the concentration of ll-hydroxycorticosteroids (IIHCS) was studied in the blood plasma of rats during formation and extinction of a conditioned passive avoidance reflex (CPAR). Since factors such as handling the animals and putting them in a new environment have an activating effect on the adrenal cortex [4, 5, 8-12], the rats were preadapted to the experimental conditions.