Ginkgo biloba normalizes stress- and corticosterone-induced impairment of recall in rats.

Exposure to chronic restraint stress in rats and psychosocial stress in humans has been shown to alter cognitive functions such as learning and memory and has been linked to the pathophysiology of mood and anxiety disorders. Antianxiety or sedative agents used in the management of stress have several disadvantages and side effects. Therefore, in this study, we investigated efficacy of a natural medicine, the extract of Ginkgo biloba (EGB 761), in prevention and treatment of the post-stress memory dysfunctions. The results showed that chronic restraint stress (2h for 21 days) or an 'equivalent' dose of exogenous corticosterone (5 mg kg(-1)) decreased re-entry latencies in the passive avoidance situation showing thus impairment of recall. Preventive doses of EGB 761 (100 mg kg(-1)), given 30 min before each restraint stress episode or corticosterone injection, abolished cognitive deficits seen in unprotected rats. There was no influence of stress, corticosterone, and EGB 761 on the acquisition of conditioned avoidance responses (CARs).     

St John's wort (Hypericum perforatum) diminishes cognitive impairment caused by the chronic restraint stress in rats.

In this study we tested the hypothesis that St John's wort (Hypericum perforatum) may counteract stress-induced memory impairment. Object recognition test and Morris water maze were used to determine whether administration of H. perforatum (350 mg kg(-1) for 21 days), standardized to 0.3% hypericin content, protects against non-spatial and/or spatial memory impairments due to chronic restraint stress (2h daily for 21 days). A group of rats administered the exogenous corticosterone at the dose of 5 mg kg(-1) daily for 21 days, yielding its similar plasma levels as these observed in stress was run in parallel. In the first experiment all rats were tested for recognition memory in the object recognition test. On the following day, the animals were tested in open field and elevated "plus" maze to control for the contribution of respectively, motor and emotional effects of our treatments to the memory tests. In the second experiment, new group of stressed animals was tested for spatial memory in the water maze. We observed that H. perforatum prevented the deleterious effects of both chronic restraint stress and long-term corticosterone on learning and memory as measured in both, the object recognition and the water maze tests. The herb not only prevented stress- and corticosterone-induced memory impairments, but it significantly improved recognition memory (p<0.01) in comparison to control. These results suggest that H. perforatum has a potential to prevent stress memory disorders.     

Alleviation by Hypericum perforatum of the stress-induced impairment of spatial working memory in rats

It is recognized that chronic stress is an important risk factor for the development of several cognitive impairments involving working memory. Working memory refers to the memory in which the information to be remembered changes from trial-to-trial and should be assessed in a task able to detect retrieval of that information. In the present study, we tested the hypothesis that preventive administration of Hypericum perforatum (also named St John’s wort) may counteract the working memory impairments caused by repeated stress. Specifically, we attempted to characterize the preventive action of long-lasting treatment with St John’s wort (350 mg/kg, p.o.) on the spatial working memory impairments caused by chronic restraint stress (2 h daily for 21 days) or durable medication with exogenous corticosterone (5 mg/kg, s.c.) in male Wistar rats. Spatial working memory was tested in Barnes maze (BM) and in the Morris water maze (MWM). We found that H. perforatum prevented the deleterious effects of both chronic restraint stress and prolonged corticosterone on working memory measured in both tests. The herb significantly improved hippocampus dependent spatial working memory in comparison with control (p < 0.01) and alleviated some other negative effects of stress on cognitive functions.     

Chronic restraint stress induced neurobehavioral alterations and histological changes in rat

Several lines of research on human and rodent subjects have demonstrated that stress results in multiple negative outcomes, including increased incidence of psychopathologies. Restraint stress in rats is known to adversely affect the physiological, psychological and reproductive axis in rats. Male rats were subjected to restraint stress for 3 hours consecutively for 14 days. The behavioral studies include Elevated Place Maze, Open Field and Morris Water Maze tests. Our results show that chronic restraint stress involved a development of anxiety in EPM, reduced motor activity in OF, impaired memory spatial in MWM tests, and induced change in testicular function, as reflected by significant decrease in plasma level of testosterone, correlate well with the damages in testis. The Results of the present study confirm that chronic restraint stress induced cognitive dysfunction, enhance anxiety like behavior and induced testicular damage in male rats Wistar.     

Effects of an extract of Ginkgo Biloba (EGB 761) on "learned helplessness" and other models of stress in rodents

The effects of repeated oral administration of an extract of Ginkgo Biloba (EGB 761) on various behavioral models of stress in rodents were investigated. The models in rats included "learned helplessness," shock-suppressed licking (Vogel conflict test) and forced swimming-induced immobility ("behavioral despair"). The models in mice included shock-suppressed exploration (four plates test), spontaneous exploration (staircase test) and food consumption in a novel situation (emotional hypophagia). Further tests in rats examined the effects of EGB 761 on memory (passive avoidance test) and responsiveness to shock to determine whether the preventive effects observed with EGB 761 in the learned helplessness procedure were due either to drug-induced impairment of memory or to reduced shock sensitivity. In all experiments EGB 761 was administered over 5 days at daily doses of 50 and 100 mg/kg PO. In some experiments (Vogel test, four plates test, staircase test, emotional hypophagia) the effects of acute administration were also investigated. The results showed that repeated administration of EGB 761 (50 and 100 mg/kg/day) before exposure to unavoidable shock (preventive treatment) clearly reduced the subsequent avoidance deficits in the learned helplessness procedure but was less effective when first administered after "helplessness" induction (curative treatment). EGB 761 did not affect performance in the passive avoidance task or alter the animals' response to electric shock, suggesting that the effects observed in the learned helplessness procedure were not due to impaired memory or reduced shock sensitivity. Anxiolytic-like activity was also seen in the emotional hypophagia test in mice where repeated administration of EGB 761 increased the amount of food consumed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Combined action of uranium and stress in the rat. I. Behavioral effects

The influence of restraint stress on uranium (U)-induced behavioral effects was assessed in adult male rats. Eight groups of animals received uranyl acetate dihydrate (UAD) in the drinking water at doses of 0, 10, 20 and 40 mg/kg/day during 3 months. Rats in four groups were concurrently subjected to restraint during 2 h per day throughout the study. At the end of the period of uranium exposure, the following behavioral tests were carried out: open-field activity, passive avoidance and Morris water maze. Uranium concentrations in brain were also determined. At 10 and 20 mg/kg/day of UAD restraint significantly affected the total distance traveled in the open-field during the first and third periods tested, respectively, while no significant differences between groups were observed on the passive avoidance test. In the Morris water maze test, the influence of restraint was only significant on the latency time measured on Day 3 in rats exposed at 10 mg/kg/day. Restraint stress did not affect significantly the uranium levels in brain of rats. Although the results of the present study scarcely show uranium-induced behavioral effects at the oral doses of UAD here administered, these effects, as well as the slight influence of restraint stress noted in some tests should not be underrated.     

The in vivo synaptic plasticity mechanism of EGb 761-induced enhancement of spatial learning and memory in aged rats

It has not been uniform to date that the Ginkgo biloba extracts enhance cognitive function in aged animals, and the mechanisms of action remain difficult to elucidate. In this study, the Morris water maze task and electrophysiological methods were used to study the effects of repeated daily administration of EGb 761, a standardized extract from G. biloba leaves, on hippocampal-dependent spatial learning and memory and synaptic plasticity of aged rats. The adult subjects perform the Morris water maze task better than aged rats, as a cellular mechanism, the hippocampal long-term potentiation (LTP) elicited from adult animals is robust (139.29+/-2.7%). In addition, the spatial learning and memory of aged rats that had been fed on an EGb 761-supplemented diet (60 mg kg(-1)) for 30 days were significantly better than those of control aged rats. The magnitude of LTP (116.63+/-3.6%) recorded in vivo from the hippocampus CA1 area of aged rats was significantly enhanced by EGb 761 (60 mg kg(-1)). In conclusion, the spatial learning and memory of aged rats is worse than that of young subjects, and EGb 761, acting as a 'cognitive enhancer', has benefit on synaptic plasticity and cognition in aged rats. The present data further confirmed that enhancement of synaptic plasticity of the hippocampus might ameliorate the deficit in spatial learning and memory in aged rats.     

Acute stress impairs spatial memory in male but not female rats: influence of estrous cycle

We investigated how sex and estrous cycle influenced spatial recognition memory in the Y-maze after exposure to acute restraint stress. In Experiment 1, intact male and female rats were restrained for 1 h and then 2 h after the start of restraint, rats were trained on the Y-maze. After a 4 h delay, hippocampal-dependent spatial recognition memory was assessed. Acute stress produced opposite patterns between the sexes with spatial memory being impaired in males and facilitated in females. Serum corticosterone measures indicated that both sexes showed a robust corticosterone response after restraint and a moderate corticosterone response after Y-maze exposure. Serum corticosterone levels in response to restraint and Y-maze were not statistically different between the sexes. Experiment 2 examined the influence of the estrous cycle on spatial memory ability after acute stress. Acute stress facilitated spatial memory in females compared to controls, regardless of the estrous cycle phase (estrus and proestrus). Moreover, females in proestrus showed higher serum corticosterone levels during restraint compared to females in estrus. No differences in corticosterone levels were observed at baseline or following 2 h of recovery from restraint. These data show important differences in how sex and estrous cycle influence cognitive functions following acute stress.     

Chronic periadolescent cannabinoid treatment enhances adult hippocampal PSA-NCAM expression in male Wistar rats but only has marginal effects on anxiety, learning and memory

Pubertal and adolescent exposure to cannabinoids is associated with enduring alterations in anxiety and memory. However, periadolescence virtually remains unexplored. Here, we measured anxiety in the Elevated Plus Maze (EPM) in adult Wistar rats treated at periadolescence (P28–P38) with the cannabinoid agonist CP 55,940 (CP) (0.4 mg/kg; 2 ml/kg i.p., 1 daily injection), and we also defined their recognition memory in the novel object paradigm and spatial learning and memory in the water maze. Additionally, we measured the expression of hippocampal PSA-NCAM (Polysialic Acid-Neural Cell Adhesion Molecule) and long-term potentiation (LTP) as well as, given their role in mnemonic processing, the levels of plasma corticosterone and estradiol. We found that CP had no robust effects on anxiety or in recognition memory. In the water maze, only a slight decreased percentage of failed trials in the reference memory task and an improvement in an indirect index of attention were observed. However, we detected an up-regulation of hippocampal PSA-NCAM expression, only in CP-males, although this effect was not related to changes in LTP. No hormonal alterations were evident. Based on our data, minimal long-term effects on anxiety, learning and memory appear to result from cannabinoid exposure during the periadolescent period.     

Chronic periadolescent cannabinoid treatment enhances adult hippocampal PSA-NCAM expression in male Wistar rats but only has marginal effects on anxiety,learning and memory

Pubertal and adolescent exposure to cannabinoids is associated with enduring alterations in anxiety and memory. However, periadolescence virtually remains unexplored. Here, we measured anxiety in the Elevated Plus Maze (EPM) in adult Wistar rats treated at periadolescence (P28–P38) with the cannabinoid agonist CP 55,940 (CP) (0.4 mg/kg; 2 ml/kg i.p., 1 daily injection), and we also defined their recognition memory in the novel object paradigm and spatial learning and memory in the water maze. Additionally, we measured the expression of hippocampal PSA-NCAM (Polysialic Acid-Neural Cell Adhesion Molecule) and long-term potentiation (LTP) as well as, given their role in mnemonic processing, the levels of plasma corticosterone and estradiol. We found that CP had no robust effects on anxiety or in recognition memory. In the water maze, only a slight decreased percentage of failed trials in the reference memory task and an improvement in an indirect index of attention were observed. However, we detected an up-regulation of hippocampal PSA-NCAM expression, only in CP-males, although this effect was not related to changes in LTP. No hormonal alterations were evident. Based on our data, minimal long-term effects on anxiety, learning and memory appear to result from cannabinoid exposure during the periadolescent period.     

Effect of Beta-Asarone on Impairment of Spatial Working Memory and Apoptosis in the Hippocampus of Rats Exposed to Chronic Corticosterone Administration

β-asarone (BAS) is an active component of Acori graminei rhizoma, a traditional medicine used clinically in treating dementia and chronic stress in Korea. However, the cognitive effects of BAS and its mechanism of action have remained elusive. The purpose of this study was to examine whether BAS improved spatial cognitive impairment induced in rats following chronic corticosterone (CORT) administration. CORT administration (40 mg/kg, i.p., 21 days) resulted in cognitive impairment in the avoidance conditioning test (AAT) and the Morris water maze (MWM) test that was reversed by BAS (200 mg/kg, i.p). Additionally, as assessed by immunohistochemistry and RT-PCR analysis, the administration of BAS significantly alleviated memory-associated decreases in the expression levels of brain-derived neurotrophic factor (BDNF) and cAMP-response element-binding protein (CREB) proteins and mRNAs in the hippocampus. Also, BAS administration significantly restored the expression of Bax and Bcl-2 mRNAs in the hippocampus. Thus, BAS may be an effective therapeutic for learning and memory disturbances, and its neuroprotective effect was mediated, in part, by normalizing the CORT response, resulting in regulation of BDNF and CREB functions and anti-apoptosis in rats.     

Protective Effect of Arabinoxylan against Scopolamine-Induced Learning and Memory Impairment

The purpose of this study is to investigate the memory enhancing effect and underlying molecular mechanism of arabinoxylan (AX), a major component of dietary fiber in wheat against scopolamine (SCO)-induced amnesia in Sprague-Dawley (SD) rats. Diverse behavior tests including Y-maze, Morris water maze, and passive avoidance tests were performed to measure cognitive functions. SCO significantly decreased the spontaneous alterations in Y-maze test and step-through latency in passive avoidance test, whereas increased time spent to find the hidden platform in Morris water maze test compared with the sham control group. In contrast, oral administration of AX (25 mg/kg and 50 mg/kg) effectively reversed the SCO-induced cognitive impairments in SD rats. Furthermore, AX treatment up-regulated the expression of brain-derived neurotrophic factor (BDNF) in the cortex and hippo-campus via promoting activation of cAMP response element binding protein (CREB). Therefore, our findings suggest that AX can improve SCO-induced learning and memory impairment possibly through activation of CREB and up-regulation of BDNF levels, thereby exhibiting a cognition-enhancing potential.     

Roman strains as a psychogenetic model for the study of working memory: behavioral and biochemical data.

Performances of male rats of the Roman High- (RHA), Roman Control- (RCA) and Roman Low- (RLA) Avoidance strains were compared in two working memory tests, a spatial one, the radial maze, and a nonspatial one, an object recognition test. The same rats were subjected to measures of emotional reactivity and of different forms of motor activity and finally to measures of cholinergic and aminergic activities in the hippocampus, frontal cortex and striatum. Compared to RHA, RLA performed better in the two working memory tests, displayed "anxiety" and had also lower levels of exploratory locomotor activity. Hippocampal ChAT activity was higher in RLA than in RHA. Levels of DA and DOPAC in the striatum were higher in RLA compared to RHA, whereas in the frontal cortex they were lower. For most of these measures, RCA were intermediate between RLA and RHA. These results confirm and extend the finding that the Roman strains are not only a genetic model for two-way avoidance conditioning but also for working memory.     

Effect of N‐Acetyl Cysteine against Aluminium‐induced Cognitive Dysfunction and Oxidative Damage in Rats

Abstract: Aluminium is a potent neurotoxin involved in the initiation and progression of various cognitive disorders like Alzheimer's disease. Chronic aluminium exposure induces oxidative stress and increases amyloid beta levels in vivo. The role of oxidative stress has been well‐suggested in these cognitive problems. Therefore, the present study was designed to explore the possible role of N‐acetyl cysteine against aluminium mediating cognitive dysfunction and oxidative stress in rats. Aluminium chloride (100 mg/kg, p.o.) was given to rats daily for 6 weeks. N‐acetyl cysteine (per se; 50 and 100 mg/kg, i.p.) pre‐treatment was given 30 min. before aluminium daily for 6 weeks. On the third (21st day) and sixth week (42nd day) of the study, various behavioural tests (Morris water maze and elevated plus maze task paradigms) and locomotion (photoactometer) were done to evaluate cognitive tasks. The rats were killed on the 43rd day following the last behavioural test, and various biochemical tests were performed to assess the extent of oxidative damage. Chronic aluminium chloride administration resulted in poor retention of memory in Morris water maze, elevated plus maze task paradigms and caused marked oxidative damage. It also caused a significant increase in the acetylcholinesterase activity. Chronic administration of N‐acetyl cysteine significantly improved memory retention in tasks, attenuated oxidative damage and acetylcholinesterase activity in aluminium‐treated rats. The study suggests a neuroprotective effect of N‐acetyl cysteine against aluminium‐induced cognitive dysfunction and oxidative damage.     

Influence of haloperidol and clozapine on some behavioral effects in rats

The experiments presented in the following paper aimed to investigate the influence of atypical antipsychotic clozapine (CLO, CAS 578-21-0) classified also as normothymic drug on spatial memory in rats in Morris water maze test. The study also investigated the probably occurring side effects (measuring cataleptic activity and motor coordination) following single and chronic administration of CLO compared to haloperidol (HAL, CAS 52-86-8), a conventional antipsychotic. All the tests were carried out on male Wistar rats. CLO 10 mg/kg was administered orally 30 min before the tests and HAL 0.15 mg/kg was administered orally 60 min before the tests. In the Morris test memory improvement only after chronic administration of CLO on the 7th and 14th day of treatment was observed, whereas after 14 days of HAL treatment spatial memory impairment was noted. CLO did not induce catalepsy after single as well as chronic administration, but administrated chronically induced a tendency for its occurrence. HAL evoked a strong cataleptic effect both after acute and chronic treatment. CLO had no impact on motor coordination in the chimney test except on day 14 when statistically significant impairments were observed. HAL disturbed motor coordination in rats after single as well as chronic administration. The wide and unique spectrum of receptor activity of CLO in comparison with HAL as well as some neurotransmitters' interactions may explain its usefulness in long-term therapy of bipolar affective disorder and schizoaffective disorder with co-occurred cognitive deficits.     

AM251, cannabinoids receptors ligand, improves recognition memory in rats

High density of cannabinoid receptors type 1 (CB1) in the brain suggests that endocannabinoid system plays an important role in the functioning of the central nervous system. Natural and synthetic cannabinoids are known to attenuate learning and memory processes. The adverse effects of cannabinoids are reversed by SR141716A, at first reported to be a selective CB1 receptor antagonist, later shown to possess also inverse agonist properties. The present study was performed in an attempt to determine the influence of different doses of AM251, a member of the same cannabinoid group as SR141716A, on recognition memory evaluated in an object recognition test. Because cannabinoids may alter motor function and affect anxiety, the influence of AM251 on psychomotor activity and anxiety was assessed in an "open-field" test and elevated plus maze, respectively. While the lowest dose of AM251 (1.0 mg/kg) significantly improved recognition memory, higher doses (2.5 mg/kg and 5.0 mg/kg) did not have an influence on it. Moreover, AM251 did not affect anxiety but in the highest dose significantly attenuated psychomotor activity in rats. The main finding of the present study indicates that AM251, at the dose of 1.0 mg/kg, improves recognition memory in rats without alteration of their psychomotor activity and anxiety. The pro-cognitive effect exerted by compounds belonging like AM251 to diarylpyrazole group may be beneficial in therapeutic use of these compounds, especially in patients with cognitive dysfunctions.     

Cognitive deficits caused by late gestational disruption of neurogenesis in rats: a preclinical model of schizophrenia.

Late gestational disruption of neurogenesis in rats has been shown to induce behavioral abnormalities thought to mimic aspects of positive and negative symptoms of schizophrenia. Furthermore, it has been shown that the morphological changes produced by the perturbation are relevant to schizophrenia with reduced thickness of the hippocampus, thalamus, and cortical regions. In addition to the positive and negative symptoms, schizophrenia is associated with deficits in a wide variety of cognitive domains. In the present studies, we assessed whether the cognitive deficits are modeled by disruption of neurogenesis late during gestation (gestational day 17) in the rat. In the battery of tests utilized, we describe that rats in which neurogenesis was disrupted have deficits in a reversal-learning paradigm of the Morris water maze and in object recognition, and that they exhibit perseveration in the Porsolt forced swimming test. Additionally, we found deficient associative learning in an acquisition of an active avoidance paradigm and deficits in latent inhibition. No deficits were observed in the reference memory version of the Morris water maze and in a non-match-to position experiment, showing that the deficits are limited to certain aspects of cognition.     

Single dose of H3 receptor antagonist - ciproxifan - abolishes negative effects of chronic stress on cognitive processes in rats

Rationale

The role of histamine neurons in stress evoked cognitive impairments remains unclear. Previous research has indicated that the blockade of H(3)-type histamine receptors may improve attention and memory in naïve rodents.

Objectives

The purpose of this study was to determine if ciproxifan, (cyclopropyl-(4-(3-1H-imidazol-4-yl) propyloxy) phenyl) ketone, an H(3) receptor antagonist, could alleviate cognitive deficits observed in chronically stressed rats.

Methods

Specifically, we attempted to characterize the preventive action of single dose of ciproxifan (3 mg/kg, i.p.) against an impairment caused by chronic restraint stress (2 h daily for 21 days) on recognition memory tested in an object recognition task and on the long-term memory tested in a passive avoidance test.

Results

We found that administration of ciproxifan potently prevented deleterious effects of chronic restraint stress, when administered prior to learning, or immediately after learning, or before retrieval on both the recognition (p<0.001) and the passive avoidance behavior (p<0.001).

Conclusions

These data support the idea that modulation of H(3) receptors represents a novel and viable therapeutic strategy in the treatment of stress evoked cognitive impairments.     

Chronic stress alters amphetamine effects on behavior and synaptophysin levels in female rats

Previous studies show that stress cross-sensitizes with or alters amphetamine (AMPH) effects in male rats; however, few studies include females. We investigated combining daily restraint stress (21 days for 6 h/day) with chronic AMPH (10 injections every other day) on locomotor activity, exploratory activity in an open field and object recognition, a memory task, in female rats. A synaptic protein, synaptophysin, was also quantified by radioimmunocytochemistry (RICC) in brain to determine possible mechanisms for behavioral changes. Beginning at 5 days after cessation of treatments, AMPH increased locomotion, modified exploration, impaired object recognition, and increased serum corticosterone (CORT) levels. Stress did not alter these parameters but blocked AMPH effects on exploration and object recognition, potentiated AMPH-dependent locomotor effects, and did not alter increased CORT levels. AMPH treatment decreased synatophysin expression in the hippocampus. In the caudate nucleus, the AMPH group showed increased synaptophysin expression which was reversed by stress. These results in females corroborate previously shown cross-sensitizations between stress and AMPH for locomotion in males and demonstrate that chronic stress counteracts AMPH-dependent impairments in recognition memory. Stress may counteract AMPH effects on the memory task by blocking both the induction of AMPH anxiety-like effects and neuroplastic changes in the caudate nucleus of female rats.