Huperzine A improves cognitive deficits caused by chronic cerebral hypoperfusion in rats

The effects of (-)-huperzine A, a promising therapeutic agent for Alzheimer's disease, on learning behavior and on alterations of the cholinergic system, the oxygen free radicals and energy metabolites induced by permanent bilateral ligation of the common carotid arteries were investigated in rats. Daily oral administration of huperzine A produced a significant improvement of the deficit in the learning of the water maze task, beginning 28 days after ischemia, correlating to about 33-40% inhibition of acetylcholinesterase activity in cortex and hippocampus. Huperzine A significantly restored the decrease in choline acetyltransferase activity in hippocampus and significantly reduced the increases in superoxide dismutase, lipid peroxide, lactate and glucose to their normal levels. The present findings demonstrate that the improvement by huperzine A of the cognitive dysfunction in the late phase in chronically hypoperfused rats is due to its effects, not only on the cholinergic system, but also on the oxygen free radical system and energy metabolism. Our results strongly suggest that huperzine A has therapeutic potential for the treatment of dementia caused by cholinergic dysfunction and/or decrease of cerebral blood flow.     

Baicalein improves cognitive deficits induced by chronic cerebral hypoperfusion in rats

The aim of this study is to investigate the effects of baicalein on cognitive impairment and neuronal degeneration in a rat model of chronic cerebral hypoperfusion induced by permanent occlusion of bilateral common carotid arteries (2VO). It was found that baicalein (2 or 4 mg/kg/day, i.p.) significantly improved 2VO-induced cognitive deficits and neuropathological changes. Biochemical and histological examinations revealed that baicalein reduced the increased activities of superoxide dismutase (SOD) and malondialdehyde (MDA), and attenuated the decreased activities of glutathione peroxidase (GPx) and catalase in 2VO rats. The results of the present observation suggest that baicalein has therapeutic potential for the treatment of vascular dementia, which is most likely related, at least in part, to its antioxidant action.     

Social interaction deficits caused by chronic phencyclidine administration are reversed by oxytocin.

Chronic administration of phencyclidine (PCP) has been advanced as a valid animal model of the social deficit symptoms of schizophrenia. In these studies, the cumulative time that male rats treated once a day for 14 days with PCP actively engaged in social behavior was decreased approximately 75% relative to saline-treated control animals. In addition, these socially impaired rats had an increase in the relative amount of noncontact interactions compared with saline-injected peers. Social behaviors were preferentially affected by PCP treatment because in two anxiety-related behavioral assays, the open field and light/dark emergence tests, there was a failure to differentiate between the PCP-treated rats and saline-injected control rats. Considering the general importance of the neuropeptides oxytocin and vasopressin in male social behaviors, studies of molecular markers related to these neuropeptides were performed. Hypothalamic oxytocin mRNA expression was significantly decreased while oxytocin receptor binding was increased in the central nucleus of the amygdala following chronic PCP treatment. Given the significance of central nucleus of the amygdala in social behavior, oxytocin was infused into the central nucleus of experimental and control male rats, and their postinfusion social interaction and open field behaviors were analyzed. A bilateral infusion of 1 mug of oxytocin into the central amygdala selectively restored the normal quantity and quality of social behavior in chronic PCP-treated male rats without altering open field behaviors. These findings suggest that deficits in the central oxytocinergic system may underlie the social impairment exhibited in this animal model of schizophrenia.     

Administration of D,L-fenfluramine to rats produces learning deficits in the Cincinnati water maze but not the Morris water maze: relationship to adrenal cortical output

Fenfluramine (FEN) is an amphetamine derivative with anorectic properties similar to amphetamine, but without the stimulatory or abuse potential. Administration of FEN produces an immediate release of serotonin as well as inhibits reuptake; ultimately FEN produces a decrease in serotonin stores in the central nervous system. We have previously shown that the administration of FEN to rats results in increased adrenal cortical hormones under resting conditions, without simultaneous elevations in adrenocorticotropin hormone (ACTH). We hypothesized that the adrenal output would be altered following stress and that the altered adrenal output would affect learning and memory, since the adrenal hormones influence learning and memory capability. In this series of experiments, we administered D,L-FEN (15 mg/kg) four times every 2 h on a single day to rats and investigated the effect on hormonal output following forced swim and the effect on sequential learning in the Cincinnati water maze and spatial learning in the Morris maze beginning 3 days after FEN administration. Animals that received FEN had increased corticosterone and aldosterone titers following forced swim relative to control animals, although no differences in ACTH or testosterone were noted. Animals exposed to FEN had lasting deficits in the Cincinnati water maze but not in the Morris water maze, regardless of testing order. These deficits in the Cincinnati water maze appear to be mediated by the elevation in adrenal output since adrenalectomy abolished the effect of FEN. Corticosterone levels were shown to be elevated during the behavioral testing period in animals exposed to FEN.     

Anticholinergic sensitivity following chronic nicotine administration as measured by radial-arm maze performance in rats

Chronic nicotine administration in rats has been previously found to improve choice accuracy performance of rats in the radial-arm maze. A nicotine-induced choice accuracy improvement was also seen in the current study. Rats were trained to asymptotic levels of choice accuracy performance on a working memory paradigm in an 8-arm radial maze. During and after 3 weeks of chronic nicotine treatment, rats were tested for sensitivity to acute doses of the nicotinic and muscarinic receptor antagonists, mecamylamine and scopolamine. During the first week of administration, nicotine-treated rats were supersensitive to the sedation caused by mecamylamine. This suggests that nicotine may not have been acting as a simple nicotinic agonist, since in this case, the opposite effect, an attenuated effect of mecamylamine in the nicotine-treated group, would have been expected. Three to 4 weeks after withdrawal from chronic nicotine administration, the treated rats were more sensitive to the choice accuracy deficits caused by the muscarinic blocker scopolamine (0.16 mg/kg) and the nicotinic blocker mecamylamine (10 mg/kg). This supersensitivity may have been due to a lasting change caused by chronic nicotine in the cholinergic bases of memory function.     

Attenuation of oxidative stress, neuroinflammation, and apoptosis by curcumin prevents cognitive deficits in rats postnatally exposed to ethanol

Rationale

Clinical and experimental evidence have demonstrated that alcohol consumption during pregnancy can disrupt brain development, leading to a variety of behavioral alterations including hyperactivity, motor dysfunction, and cognitive deficits in offsprings. Alcohol-induced neurocognitive deficits are associated with activation of oxidative-inflammatory cascade coupled with extensive apoptotic neurodegeneration in different brain regions.

Objectives

The present study was designed with an aim to investigate the protective effect of curcumin, a principal curcuminoid present in the Indian spice turmeric, against alcohol-induced cognitive deficits, neuroinflammation, and neuronal apoptosis in rat pups postnatally exposed to ethanol.

Methods and results

Male Wistar rat pups were administered ethanol (5?g/kg, 12?% v/v) by intragastric intubation on postnatal days (PD) 7, 8, and 9 and were treated with curcumin (30 and 60?mg/kg) from PD 6 to 28. Performance of ethanol-exposed pups that did not receive curcumin was significantly impaired as evaluated in both Morris water maze and elevated plus maze tasks recorded by using computer tracking. Cognitive deficit was associated with enhanced acetylcholinesterase activity, increased neuroinflammation (oxidative-nitrosative stress, TNF-??, IL-1??, and TGF-??1), and neuronal apoptosis (NF-??? and caspase 3) in both cerebral cortex and hippocampus of ethanol-exposed pups. Chronic treatment with curcumin significantly ameliorated all the behavioral, biochemical, and molecular alterations in different brain regions of ethanol-exposed pups.

Conclusions

The current study demonstrates the possible involvement of oxidative-inflammatory cascade-mediated apoptotic signaling in cognitive deficits associated with postnatal ethanol exposure and points towards the neuroprotective potential of curcumin in mitigating alcohol-induced behavioral, biochemical, and molecular deficits.     

Chrysin improves cognitive deficits and brain damage induced by chronic cerebral hypoperfusion in rats

Chronic cerebral hypoperfusion, induced by permanent occlusion of bilateral common carotid arteries (2VO), is related to neurological disorders and contributes to cognitive decline. Chrysin (5,7-dihydroxyflavone) is an important member of the flavonoid family. The aim of this study is to investigate the effects of chrysin on cognitive deficits and brain damage in this rat 2VO model. At 52days after ligation, the escape latency in Morris water maze was significantly increased in rats subjected to 2VO, the neuronal damage was also increased accompanied by a large proliferation in glial fibrillary acidic protein (GFAP) immunoreactivity with marked white matter lesions, and neuronal cell apoptosis, all of which were significantly alleviated by long treatment of chrysin (30mg/kg). Biochemical examinations revealed that chrysin decreased lipid peroxide, reduced the increased activities of superoxide dismutase, and attenuated the decreased activities of glutathione peroxidase in 2VO rats. The results suggest that chrysin may have therapeutic potential for the treatment of neurodegeneration and dementia caused by decreased cerebral blood flow, which is most likely related, at least in part, to its anti-inflammatory and antioxidant properties.     

Modulation of nitrergic pathway by sesamol prevents cognitive deficits and associated biochemical alterations in intracerebroventricular streptozotocin administered rats

Alzheimer's disease is a neurodegenerative disorder characterized by progressive cognitive decline and widespread loss of neurons and their synapses in the cerebral cortex and hippocampus. Increasing evidence indicates that factors such as oxidative-nitrergic stress, glutathione depletion, impaired protein metabolism and cholinergic deficit can interact in a vicious cycle, which is central to Alzheimer's disease pathogenesis. Intracerebroventricular (i.c.v.) streptozotocin induced-cognitive impairment has been widely used as an experimental paradigm to study Alzheimer's disease. In the present study, i.c.v. streptozotocin produced significant cognitive deficits as measured in Morris water maze and elevated plus maze task coupled with increased serum TNF-α levels and marked rise in brain acetylcholinesterase and oxidative-nitrergic stress in female Wistar rats. Sesamol (5-hydroxy-1,3-benzodioxole or 3,4-methylenedioxyphenol), a potent anti-oxidant and anti-inflammatory molecule markedly improved cognitive impairment, reduced acetylcholinesterase activity, TNF-α levels and attenuated oxidative-nitrergic stress in brain of i.c.v.-streptozotocin treated rats. Administration of L-arginine (125 mg/kg i.p), a nitric oxide donor, alone to i.c.v.-streptozotocin treated rats accentuated behavioral and biochemical deficits and also abolished the protective effect of sesamol (8 mg/kg). L-NAME (10 mg/kgi.p.), a non-specific NOS inhibitor significantly restored all the behavioral and biochemical indices in i.c.v.-streptozotocin rats. Moreover, combination of L-NAME with sub-effective dose of sesamol (4 mg/kg) potentiated its protective effect. Our findings demonstrate the effectiveness of sesamol in preventing intracerebroventricular streptozotocin-induced cognitive deficits by modulating nitrergic signaling and oxido-inflammatory cascade.     

The chronic toxicity of sodium alkylbenzenesulfonate by food and water administration to rats

A two-year feeding study has been completed in which rats received 0.1% (1000 ppm) and 0.5% (5000 ppm) of alkylbenzenesulfonate in the diet.No adverse effects were produced by the ABS with respect to growth, reproduction, survival, food consumption, hematologic values, blood chemistry, or urine analyses. Microscopic evaluation of tissues revealed no pathologic changes resulting from the intake of ABS. Scattered differences were observed in organ: body weight ratios.Another two-year study has been completed in which rats received ABS in their drinking water supply. The level administered (about 0.05%) represented at least a 500-fold exaggeration in daily consumption, on a body weight basis, over the possible human figure of less than 1 ppm.No adverse effects were observed with respect to survival, growth, food consumption, organ weights, hematologic values, blood chemistry, or urine analyses. A histopathologic survey of the essential organ systems revealed no evidences of toxicity. Increased organ: body weight ratios occurred in the livers of males and the empty ceca of females in the test group. These differences were not accompanied by microscopic evidence to toxic changes.Lifetime administration of ABS to rats by two routes, diet and drinking water, produced no evidence of toxicity as judged by the criteria evaluated. To the extent that animal tests provide a basis for the assay of toxicity to humans, it would appear that these investigations assure that considerable amounts of ABS (much in excess of the amounts that might find their way into the drinking water) could be consumed over long periods without harm.     

L-3-n-butylphthalide improves cognitive deficits in rats with chronic cerebral ischemia

3-n-Butylphthalide (NBP) has been shown to have protective effects against ischemic stroke. In the present study, we investigated effects of l-3-n-butylphthalide (l-NBP) on the learning and memory impairment induced by chronic cerebral ischemia in rats. Male Wistar rats were administered 20 mg/kg l-NBP by gavage daily for 30 days after the bilateral common carotid artery clamping (two-vessel occlusion, 2-VO). Results showed that daily treatments of 20 mg/kg l-NBP significantly attenuated spatial learning deficits in Morris water maze (MWM) task. Results of long-term potentiation (LTP) indicated that treatment with 20 mg/kg l-NBP attenuated the inhibition of LTP in rat model of 2-VO. Moreover, l-NBP reduced glial fibrillary acidic protein (GFAP)-positive astrocytes induced by chronic cerebral ischemia. The present findings demonstrate the protective effect of l-NBP on chronic cerebral ischemia-induced hippocampus injury, which supports using l-NBP for therapy of cerebral ischemia in the future.     

Prenatal exposure to sodium phenytoin in rats induces complex maze learning deficits comparable to those induced by exposure to phenytoin acid at half the dose

Gravid Sprague-Dawley CD (VAF) rats were administered sodium phenytoin suspended in corn oil by gavage once per day on embryonic days 7–18 at a dose of 100 mg/kg. Controls were administered corn oil alone by gavage on E7-18. Litters were randomly culled to 10. Offspring were regularly weighed, mortality noted, and males checked for preputial separation. At approximately 50 days of age offspring were evaluated in a straight water-filled channel for swimming proficiency and motivation to escape. Following this, rats were tested in the Cincinnati multiple T-water maze and scored for errors, latency to find the goal, and presence of phenytoin-induced abnormal circling behavior while swimming. Sodium phenytoin-exposed dams gained weight normally and delivered normally. Offspring mortality in the sodium phenytoin group was not increased above controls. No treatment effects on preputial separation or offspring growth were observed. No differences between groups in swimming proficiency in straight channel performance were obtained. In the Cincinnati maze, phenytoin offspring committed significantly more errors and had longer latencies to find the goal than controls. Among the phenytoin offspring, those exhibiting abnormal circling committed more errors than noncircling animals. When compared to previous data using the same maze and test protocol, it was found that 100 mg/kg of sodium phenytoin induced performance deficits similar to those induced by a dose of 200 mg/kg of phenytoin acid. Accordingly, the present data help explain why other investigators have reported sodium phenytoin to be more developmentally neurotoxic than phenytoin acid. Because the prenatal neurotoxic effects seen with the salt of phenytoin occur at lower doses, it suggests that phenytoin is more developmentally neurotoxic than previously believed.     

Memantine prevents the cognitive impairment induced by 3,4-methylenedioxymethamphetamine in rats

Amphetamine abuse is an important risk factor for the development of cognitive impairment involving learning and memory. Since in previous studies we have demonstrated the effectiveness of alpha-7 nicotinic receptor antagonists in preventing the neurotoxicity induced by amphetamine derivatives, the present paper seeks to determine whether pre-treatment with memantine (MEM) (an antagonist of both nicotinic and NMDA receptors) counteracts the memory impairment induced by 3,4-methylenedioxymethamphetamine (MDMA or ecstasy) administration in male Long Evans rats. In mice, MDMA and MEM induced a locomotor stimulant response but with a different profile. Moreover, MEM inhibited the rearing and thygmotaxis behaviour induced by MDMA. Non-spatial memory was tested in the object recognition test and the spatial learning and memory was tested in the Morris water maze. In our experimental conditions, rats receiving MEM pre-treatment recovered the ability to discriminate between the familiar and the novel object that had been abolished by MDMA treatment. Animals treated with MDMA showed impaired learning in the Morris water maze. Results of the probe trial demonstrated that MDMA-treated rats did not remember the location of the platform, but this memory impairment was also prevented by the MEM pre-treatment. Moreover, MEM alone improved the learning task. No differences were observed between the different groups as regards swim speed. In conclusion, MEM significantly improved the learning and memory impairment induced by MDMA and constitutes the first approach to the treatment of the long-term cognitive deficits found in ecstasy users.     

Chronic administration of docosahexaenoic acid improves the performance of radial arm maze task in aged rats

1. In the present study, we investigated the effect of docosahexaenoic acid (DHA) on spatial memory related learning ability in aged (100 weeks) male Wistar rats. 2. Rats were fed a fish oil-deficient diet through three generations and were then randomly divided into two groups. Over 10 weeks, one group was per orally administered 300 mg/kg per day DHA dissolved in 5% gum Arabic solution and the other group was administered the vehicle alone. Five weeks after the start of the administration, rats were tested with the partially baited eight-arm radial maze to estimate two types of spatial memory related learning ability displayed by reference memory error and working memory error. 3. Chronic administration of DHA significantly decreased the number of reference memory errors and working memory errors. 4. The level of lipid peroxide (LPO) in the hippocampus tended to decrease with chronic DHA administration and demonstrated a positive correlation with the number of reference memory errors. 5. These results suggest that the accumulation of hippocampal LPO reduces spatial memory related learning ability in aged rats. Moreover, chronic administration of DHA was effective in decreasing the level of hippocampal LPO, then improving learning ability.     

吡拉西坦对大鼠慢性脑缺血所致认知功能障碍和神经元损伤的保护作用

目的:观察吡拉西坦(别名脑复康)对慢性脑部低灌注所致认知功能障碍和神经元损伤的改善作用。方法:采用大鼠双侧颈总动脉永久性结扎模型,30只SD大鼠分为假手术组、脑缺血组和吡拉西坦治疗组,每组10只。吡拉西坦治疗组用吡拉西坦600 mg/kg灌胃,1次/d,从手术当天开始,持续37 d。Morris水迷宫实验用于检测空间学习记忆行为。生化测量脑内花生四烯酸代谢产物血栓素B2(TXB2)和6-酮前列腺素F1α(6-酮-PGF1α)的水平。HE染色观察大脑皮层和海马神经元的组织形态学改变,免疫组化分析p53蛋白及Bax蛋白的表达。结果:慢性脑部低灌注能够引起大鼠学习记忆损伤,表现为逃离潜伏期的延长和在目标象限中游泳时间的缩短,伴随着TXB2和6-酮-PGF1α水平的升高,p53和Bax蛋白的高表达以及皮层和海马神经元延迟性损害。吡拉西坦灌胃可显著提高损伤大鼠的学习记忆能力,降低TXB2水平,抑制p53和Bax蛋白的过量表达,改善神经元结构异常。结论:吡拉西坦对大鼠慢性脑缺血有保护作用,提示其可能在血管性痴呆的治疗中发挥积极有效的作用。     

Refining the critical period for methamphetamine-induced spatial deficits in the Morris water maze

Rationale Neonatal administration of methamphetamine (MA) to rats from postnatal day (P) 11 to 20, but not from P1 to P10, produces lasting deficits in spatial learning and memory. The preweaning period of development in the rat corresponds to human third trimester hippocampal development and because of the increased use of MA in women of childbearing age, there is a greater likelihood that fetuses will be exposed to this drug. Development of the hippocampus is dependent upon many factors, including an optimal level of corticosterone (CORT). We have demonstrated that the CORT response of animals on P11 to MA is protracted relative to administration on P15 or P20. Interestingly, the P11 animals are still in the stress hyporesponsive period. Objectives We postulated that because of the prolonged CORT response on P11, the effects of MA on spatial learning and memory may be confined to a shorter period of exposure. Methods Neonatal rats were administered MA (10 mg/kg) 4 times daily from either P11 to P15 or from P16 to P20, raised to adulthood and tested against animals only administered saline (SAL) from P11 to P20 for anxiety, swimming ability, and spatial learning and memory. Results Animals exposed to MA, regardless of exposure period, tended to be less anxious in the Zero maze relative to SAL animals. No differences were noted for swimming ability. Only animals exposed to MA from P11 to P15 demonstrated deficits in spatial learning and memory during acquisition as well as during a shifted platform phase where learning a new position was required. Conclusions The results demonstrate that spatial learning and memory deficits produced by MA administration are dependent upon when the exposure of the animal occurs and appears to be during the period of development in the rat when the response to threatening environments, stressors, is greatly reduced.     

MK-801 prevents cognitive and behavioral deficits produced by NMDA receptor overstimulation in the rat hippocampus

The overstimulation of receptors for L-glutamate, particularly those of the N-methyl-D-aspartate (NMDA) type, has been suggested to play a role in mediating damage in a variety of neurodegenerative conditions or disorders ranging from ischemia/hypoxia to senile dementia of the Alzheimer's type (SDAT). We report here that the functional deficits and histological damage mediated by the overactivation of NMDA receptors in the Fischer 344 rat hippocampus can be blocked effectively by systemic administration of the noncompetitive NMDA antagonist, MK-801. These results suggest that MK-801 may be effective clinically in attenuating memory loss and hippocampal damage in disorders associated with the overstimulation of NMDA receptors.     

Rutin protects against cognitive deficits and brain damage in rats with chronic cerebral hypoperfusion

BACKGROUND AND PURPOSE

Chronic cerebral hypoperfusion is a critical causative factor for the development of cognitive decline and dementia in the elderly, which involves many pathophysiological processes. Consequently, inhibition of several pathophysiological pathways is an attractive therapeutic strategy for this disorder. Rutin, a biologically active flavonoid, protects the brain against several insults through its antioxidant and anti-inflammatory properties, but its effect on cognitive deficits and brain damage caused by chronic cerebral hypoperfusion remains unknown. Here, we investigated the neuroprotective effect of rutin on cognitive impairments and the potential mechanisms underlying its action in rats with chronic cerebral hypoperfusion.

EXPERIMENTAL APPROACH

We used Sprague-Dawley rats with permanent bilateral common carotid artery occlusion (BCCAO), a well-established model of chronic cerebral hypoperfusion. After rutin treatment for 12 weeks, the neuroprotective effect of rutin in rats was evaluated by behavioural tests, biochemical and histopathological analyses.

KEY RESULTS

BCCAO rats showed marked cognitive deficits, which were improved by rutin treatment. Moreover, BCCAO rats exhibited central cholinergic dysfunction, oxidative damage, inflammatory responses and neuronal damage in the cerebral cortex and hippocampus, compared with sham-operated rats. All these effects were significantly alleviated by treatment with rutin.

CONCLUSION AND IMPLICATIONS

Our results provide new insights into the pharmacological actions of rutin and suggest that rutin has multi-targeted therapeutical potential on cognitive deficits associated with conditions with chronic cerebral hypoperfusion such as vascular dementia and Alzheimer''s disease.     

Assessment of a cholinergic contribution to chlordiazepoxide-induced deficits of place learning in the Morris water maze.

This investigation sought to characterize the interaction between benzodiazepine and cholinergic systems in place learning in the Morris water maze. In the first experiment, rats were treated with scopolamine (1 mg/kg) alone or concomitantly with one of two doses of flumazenil (15 and 30 mg/kg) or with chlordiazepoxide (5 mg/kg) alone or concomitantly with flumazenil (15 mg/kg). Chlordiazepoxide and scopolamine severely impaired place learning but not cue learning. The low dose of flumazenil completely reversed the impairment produced by chlordiazepoxide and both high and low doses of flumazenil attenuated the place learning deficit produced by scopolamine. Neither dose of flumazenil affected place learning when administered alone. In the second experiment, rats were administered chlordiazepoxide (5 mg/kg) or scopolamine (1 mg/kg) alone or concomitantly with one of four doses of physostigmine (0.05, 0.10, 0.25, and 0.5 mg/kg). Once again, both chlordiazepoxide and scopolamine impaired place but not cue learning. Physostigmine reversed the impairment produced by scopolamine in a dose-dependent manner but failed at every dose to attenuate the impairment produced by chlordiazepoxide. The higher doses of physostigmine impaired place learning when administered alone. None of the drug treatments impaired cue learning. Together, these results suggest that the scopolamine-induced impairment of place learning is due to an increase in benzodiazepine/GABA activity, and contradict the notion that benzodiazepines impair memory by cholinergic mechanisms.     

Candesartan prevents impairment of recall caused by repeated stress in rats

Rationale

Deleterious effects of psychological stress on memory are increasingly important. Overexpression of the AT₁ angiotensin receptors in brain has been found to participate in several negative effects of chronic stress including hypertension and a cognitive impairment.

Objective

In this study, we searched for the protective effects the AT₁ angiotensin receptor blockade with candesartan against the adverse effects of repeated stress on recall of aversively and appetitively motivated behaviours in rats.

Methods

Two groups of male Wistar rats were repeatedly stressed by keeping them daily (2 h/21 days) in tight plastic tubes. The subjects of the group 1 received candesartan (0.1 mg/kg, orally) each day before the stressing procedure. The rats of the group 2 received vehicle. Another two groups of rats (3 and 4) receiving candesartan and vehicle, respectively, were appropriately handled but not stressed. Next day, after ending the repeated stress procedure, all rats were tested in two cognitive paradigms: inhibitory avoidance (IA) and object recognition (OR).

Results

Stressed animals displayed decreased recall of the IA behaviour (p?<?0.01) and decreased OR (p?<?0.05). These effects were not seen in the animals stressed and concomitantly treated with candesartan. The auxiliary tests designed to control for the possible unspecific contribution of motor (open field) and emotional (elevated “plus” maze) effects of the experimental procedures to results of the cognitive tests showed no such contribution.

Conclusion

These data strongly suggest that the AT₁ angiotensin receptor blockade effectively counteracts deleterious effects of stress on recall of aversively and appetitively motivated memories in rats.     

Reversal caused by n-butylidenephthalide from the deficits of inhibitory avoidance performance in rats

The present study was designed to investigate the mechanism of action of n-butylidenephthalide on the deficits of inhibitory avoidance performance induced by drugs in rats with piracetam as a positive control. n-Butylidenephthalide attenuated the scopolamine-induced and mecamylamine-induced acquisition impairment, and also attenuated the acquisition impairment induced by scopolamine plus mecamylamine. Furthermore, scopolamine methylbromide, a peripheral cholinergic muscarinic receptor antagonist, did not block the counteracting effect of n-butylidenephthalide on the scopolamine-induced acquisition impairment. n-Butylidenephthalide attenuated the impairment of inhibitory avoidance performance induced by the central acetylcholinergic neurotoxin AF64A administered intracisternally. From the above results, we suggest that n-butylidenephthalide attenuated the deficits of inhibitory avoidance performance induced by drugs, which are the effects related to activating the central but not the peripheral cholinergic neuronal system via muscarinic and nicotinic receptors.