Attenuation of scopolamine-induced amnesia in mice

The dose-response effects of the substituted xanthine 8-cyclopropyltheophylline (CPRT) on sleep and wakefulness (W) after intraperitoneal administration to rats were examined by means of simultaneous electroencephalographic (EEG) and electromyographic (EMG) recordings. Doses of 20 and 40 mg/kg CPRT increased W and decreased slow wave sleep (SWS) in rats, indicating CNS stimulant effects. The greatest CNS stimulation was produced by the lowest (20 mg/kg) dose of CPRT examined, which also increased the latency to SWS. In addition, the 20 mg/kg dose of CPRT also significantly decreased the amount of total sleep (TS), as compared to the vehicle group, during all time periods examined. In contrast, the 80 mg/kg dose of CPRT decreased W and increased both SWS and TS. However, this apparent hypnotic effect of the 80 mg/kg CPRT may be due to toxicity, since 80% of rats treated with this dose of the drug died within 48 h of injection.     

Qualitative analysis of scopolamine-induced amnesia

The neurochemistry of memory remains to be determined. Acetylcholine may be one of the neuotransmitters which mediates memory function, since the anticholinergic drug scopolamine produces amnesia in man. This study of scopolamine-induced memory deficits further defines those cognitive processes which are disrupted. The drug does not diminish attention, as assessed with an auditory vigilance task, or initial signal detection. More complex auditory decoding is affected, however. Scopolamine impairs aspects of initial memory acquisition (e. g., encoding and consolidation) and spontaneous memory retrieval. Retention is unaffected. Precise delineation of the neurochemistry of human memory will require comparative studies of amnesia-producing compounds, systematically examining the neuropsychological processes impaired by each.     

Effect of oxiracetam on scopolamine-induced amnesia in the rat in a spatial learning task.

The effects of the nootropic agent 4-hydroxy-2-oxopyrrolidinoacetamide (oxiracetam) on memory and performance impairments induced by scopolamine were evaluated in the Morris water maze task. No effect was seen on the performance of rats when treated with oxiracetam (30 mg/kg, IP) alone. Task performance of scopolamine (0.2 mg/kg, SC)-treated rats was impaired as compared to that of control animals. The behavioral deficits expressed in the task by scopolamine treatment were attenuated by the same dose of oxiracetam.     

Effects of nootropic drugs in a scopolamine-induced amnesia model in mice

Scopolamine (3 mg/kg IP) given before an acquisition trial, reduced the retention of a one-trial passive avoidance step through response in mice. A single administration of cholinergic agonists such as oxotremorine, BM-5, or arecoline, antagonized this amnesic effect of scopolamine. A significant anti-amnesic effect was also found with nootropic drugs such as piracetam and ucb L059, whereas ucb L060 (the enantiomer of ucb L059), oxiracetam and rolziracetam were shown to be ineffective. Moreover, ucb L059, administered twice daily for 3 days, counteracted the amnesic effects of scopolamine completely, whereas ucb L060 was again inactive. The results demonstrate that: (a) this model of impaired cognition by scopolamine is able to discriminate between closely related chemical substances and even stereoisomers; and (b) nootropic drugs, such as ucb L059, are more effective after repeated rather than after acute administration.     

Meserine对胆碱酯酶活性及东莨菪碱诱导痴呆小鼠学习记忆的影响

目的：考察新型胆碱酯酶抑制剂Meserine对胆碱酯酶活性及东莨菪碱（Scopolamine）诱导的胆碱能障碍痴呆模型小鼠学习记忆的影响。方法：选取小鼠脑匀浆、血浆、人源重组AChE（rHuAChE）为体外酶源,测定Meserine抑制AChE／BuChE的活性、选择性及酶动力学。通过鼻腔给药后检测脑部AChE活性和ACh浓度评价Meserine对小鼠脑内胆碱能系统的调节。选用避暗及水迷宫实验考察Meserine对痴呆模型小鼠学习记忆功能的影响。结果：Meserine对AChE和BuChE都具有较好的抑制活性,IC50分别为（65．2±3．2）nmol／L和（86．7±4．9）nmol／L,并对rHuAChE呈现非竞争性抑制。经鼻给药Meserine可显著抑制脑内AChE活性、升高ACh水平,且二者变化的时程具有一致性,给药15min后,AChE抑制活性最强（26．9％）,ACh浓度最高（1269．0ng／g）。行为学实验结果显示,经鼻给药Meserine（10μg／kg）能显著改善东莨菪碱诱导的痴呆模型小鼠的工作记忆及空间学习能力,较模型组具有统计学差异（P〈0．OlVS东莨菪碱组）。结论：上述结果提示Meserine为强效非竞争性胆碱酯酶抑制剂,经鼻给药Meserine可通过调节脑内胆碱能系统有效改善东莨菪碱诱导的痴呆模型小鼠的学习记忆功能。     

Reversal of scopolamine-induced amnesia by phosphatidylserine in rats

Scopolamine (2 mg/kg IP) and propranolol (55 mg/kg IP), given before a single learning trial, reduce retention of a passive avoidance response in rats. Phosphatidylserine, 30–60 mg/kg IP, antagonizes the amnesic effect of scopolamine but not that of propranolol. The retention of the passive avoidance response is not affected by phosphatidylserine given alone. The results indicate that this phospholipid selectively counteracts the action of scopolamine on passive avoidance acquisition, probably via a cholinergic mechanism.     

Effects of four non-cholinergic cognitive enhancers in comparison with tacrine and galanthamine on scopolamine-induced amnesia in rats

Amnesia can be induced in rats in the passive avoidance paradigm by administration of scopolamine, a central muscarinic receptor antagonist. Tacrine or galanthamine, inhibitors of acetylcholinesterase, given in conjunction with scopolamine partially reversed the scopolamine-induced deficit in passive avoidance performance. Four so-called cognitive enhancers, all widely used for the treatment of the symptoms associated with mental aging, cerebral insufficiency and senile memory disorder, were investigated in this paradigm. Piracetam, an extract of Ginkgo biloba, dihydroergocristine and a combination of raubasine with dihydroergocristine, all attenuated the amnesia induced by scopolamine. In contrast, nicergoline had no significant effect. Raubasine alone also failed to significantly attenuate scopolamine-induced amnesia, although some doses of raubasine had a non-significant tendency (P<0.10) to reduce the amnesia.     

Time dependent changes in anterograde scopolamine-induced amnesia in rats

These experiments studied the effect of scopolamine on memory formation and subsequent memory recall. Different groups of rats were trained on a Y-maze brightness discrimination task 20 min after IP injection of 2 mg/kg scopolamine HBr, an anticholinergic. Retention tests were then conducted 1 day or 2, 4, or 6 weeks after training. Deficits in retention performance were observed at 1 day and 2 weeks after training but not at the longer intervals. In addition, other rats were trained in the same manner and after the same dose of scopolamine but were then retention tested 20 min after 0.5 mg/kg physostigmine salicylate, a cholinesterase inhibitor. These subjects also showed deficits at 1 day and 2 weeks but were not different from controls at the longer intervals. Amnesia was not, however, produced after treatment with scopolamine methyl nitrate or by injections of scopolamine HBr administered immediately after training. These results suggest that scopolamine, present in the central nervous system during training or within the first few moments thereafter, modifies the formation of the memory trace in such a way that memory is not available for recall for a period of weeks.     

Ganglioside GM1 attenuates scopolamine-induced amnesia in rats and mice

 Some experimental evidence suggests that the beneficial effects of monosialoganglioside GM1 on learning and memory could be related to an improving effect in central cholinergic function. The present study investigates the effects of GM1 on the memory impairment induced by scopolamine in rats or mice tested in passive (PA) and discriminative avoidance (DA) tasks, respectively. Wistar EPM-1 male rats and Swiss EPM-M1 male mice were treated daily IP with 50 mg/kg GM1 or saline for 7 or 14 days, respectively. Twenty-four hours after the last injection, GM1-treated animals received 1 mg/kg scopolamine (GM1-SCO) and saline-treated animals received 1 mg/kg scopolamine (SAL-SCO) or saline (SAL-SAL) IP. Twenty minutes later, the animals were submitted to PA or DA conditioning, and tests were performed 24 h later. The latency in entering the dark chamber of the PA apparatus (LD) presented by SAL-SCO rats was significantly decreased when compared to that presented by SAL-SAL animals. GM1-SCO animals showed an increased LD when compared to SAL-SCO animals and were not significantly different from SAL-SAL rats. GM1-SCO and SAL-SAL (but not SAL-SCO) mice spent significantly less time in the aversive enclosed arm of the discriminative avoidance apparatus when compared to the time spent in the non-aversive enclosed arm. The results are consistent with the interpretation that GM1 attenuates scopolamine-induced amnesia. Although not eliminating the participation of other transmitter systems, the present study indicates a possible role of central cholinergic transmission in the action of this compound on learning and memory. Received: 21 October 1997 / Final version: 8 June 1998     

Anti-amnesic effect of Ficus religiosa in scopolamine-induced anterograde and retrograde amnesia

Context:?Ficus religiosa Linn (Moraceae) is a variety of fig tree. Its figs are known to contain a high serotonergic content, and modulation of serotonergic neurotransmission plays a crucial role in the pathogenesis of amnesia. Thus, the present study was envisaged.

Objective:?To investigate the effect of the methanol extract of figs of Ficus religiosa (FRFE) on scopolamine-induced anterograde and retrograde amnesia in mice.

Materials and methods:?Transfer latency (TL) to the preferred niche in the elevated plus-maze (EPM) and learning avoidance of passive behavior to avoid punishment in the modified passive avoidance paradigm (MPA) served as behavioral models for the assessment of memory. Scopolamine (1?mg/kg, i.p.) was administered before training for induction of anterograde amnesia and before retrieval for induction of retrograde amnesia in both models. TL in the EPM, step down latency (SDL), number of trials, and number of mistakes in the MPA were determined in vehicle control, FRFE treated (10, 50, and 100?mg/kg, i.p.), and standard groups (piracetam 200?mg/kg, i.p.). Cyproheptadine, a non-selective 5-HT_1/2 blocker (4?mg/kg, i.p.), was administered along with the FRFE to investigate the involvement of serotonergic pathways in the anti-amnesic effect of FRFE.

Results and discussion:?FRFE resulted in a significant improvement of memory, as its treatment attenuated the scopolamine-induced anterograde and retrograde amnesia dose-dependently. Further, cyproheptadine pretreatment significantly reversed the anti-amnesic effect of FRFE.

Conclusion:?FRFE has anti-amnesic activity against scopolamine-induced amnesia, in a dose-dependent manner. Inhibition of the anti-amnesic effect of FRFE by cyproheptadine substantiates the involvement of serotonergic pathways for its activity.     

康寿灵对东莨菪碱痴呆模型大鼠学习记忆的保护作用

目的：观察康寿灵对东莨菪碱诱导的记忆障碍大鼠学习记忆的影响，并探讨其可能的作用机制。方法：各组大鼠分别用生理盐水（正常对照组、模型组）、康寿灵（低、中、高剂量组）和石杉碱甲（阳性对照组）灌胃37d。第31天起进行Morris水迷宫行为测试，连续7d。行为测试结束后，进行大鼠脑组织丙二醛（MDA）、超氧化物歧化酶（SOD）、谷胱甘肽过氧化物酶（GSH-Px）及ATPase活性测定。结果：预先给予大鼠康寿灵30d可改善东莨菪碱导致的记忆障碍，使大鼠脑组织中抗氧化酶SOD、GSH-Px及ATPase活性升高，而MDA含量降低。结论：康寿灵对东莨菪碱引起的大鼠学习记忆能力障碍有明显保护作用，其作用机制可能与抗氧化作用密切相关。     

Persistence of retrieval enhancement by amphetamine following scopolamine-induced amnesia

Little information is available on the permanence of pharmacologically-induced retrieval enhancement following amnesia. This was studied by comparing the rate of forgetting of a memory reactivated by d-amphetamine after amnesia with spontaneous forgetting of undisturbed fear conditioning. Mice were treated with either saline or scopolamine before conditioning and retention was tested three days later. Scopolamine-treated mice received either saline or amphetamine before testing while the saline controls received a second saline injection. The scopolamine-saline group exhibited robust amnesia, whereas both saline-saline and scopolamine-amphetamine groups showed good retention. To test the persistence of these effects mice in the three groups were subdivided and given a second retention test either 1 day, 1 week or 1 month after the first test. Amphetamine was not administered before the second test. The scopolamine-saline mice continued to exhibit amnesia for up to 1 month while the scopolamine-amphetamine and saline-saline groups continued to show strong memory with only a modest decrement in performance by 1 month after the first test. These results show that amphetamine results in a permanent recovery from scopolamine amnesia.     

中药复方海康灵对东莨菪碱所致痴呆小鼠学习记忆影响及其机制的实验研究

目的：观察中药复方海康灵对东莨菪碱诱导的记忆障碍小鼠学习记忆的的影响，并进一步探讨其可能的作用机制。方法：各组小鼠除正常对照组、东莨菪碱组（模型组）灌服生理盐水外，海康灵药物组（低、中、高3个剂量组）灌服海康灵合剂，石杉碱甲组（阳性对照组）灌服哈伯因（HupA），连续灌胃22d。从第16天起进行Morris水迷宫行为测试，连续7d。行为测试结束后，进行小鼠脑组织和血清中生化指标检测，包括丙二醛（MDA）、超氧化物歧化酶（SOD）、谷胱甘肽过氧化物酶（GSHPx）及乙酰胆碱酯酶（AchE）的含量测定，以及血清中三酰甘油（TG）、高密度脂蛋白（HDL）和总胆固醇（T-CHO）的含量测定。结果：预先给予小鼠海康灵22d可改善东莨菪碱导致的小鼠记忆障碍，使脑组织和血清中抗氧化酶SOD、GSH-Px及Ache活性升高，而MDA含量降低，与模型组相比，海康灵药物组血清中三酰甘油和总胆固醇水平均明显降低，高密度脂蛋白水平明显升高。结论：海康灵对东莨菪碱引起的小鼠学习记忆能力障碍有改善作用，其作用机制可能与其对抗小鼠体内自由基生成、降低胆固醇和血脂水平及改善中枢胆碱能系统功能有关。     

Coadministration of huperzine A and ligustrazine phosphate effectively reverses scopolamine-induced amnesia in rats

In the present study, whether coadministration of huperzine A (HA) and ligustrazine phosphate (LP) could effectively improve the memory deficits in association with ameliorating cholinergic impairment and oxidative stress in the scopolamine-induced amnesia rats was assessed. The effects of treatment with Coa [HA (0.14 mg/kg, i.g.) and LP (110 mg/kg, i.g.)] on amnesia were investigated in Morris water maze. Furthermore, the effects on the activities of acetylcholinesterase (AChE) and antioxidant enzymes within the cerebral cortex and hippocampus were evaluated, and the lipid peroxidation product malondialdehyde (MDA) was also analyzed. As a result, coadministration of HA and LP for 10 consecutive days could markedly reverse the scopolamine-induced learning and memory impairment determined by the Morris water maze test. Moreover, AChE activity was significantly inhibited, and superoxide dismutases (SOD) and glutathione peroxidase (GSH-Px) activities were significantly increased with a remarkable reduction in the level of MDA. In conclusion, coadministration of HA and LP effectively prevented cholinergic impairment and oxidative damage, thereby resulting in improvement of spatial learning memory in rats induced by scopolamine. The results suggested that coadministration of HA and LP might offer a novel poly-therapeutic drug regimen for preventing Alzheimer's disease (AD).     

Metoclopramide potentiates d-amphetamine-induced hypermotility and stereotypy in rat

The substituted benzamide metoclopramide has been reported to block the behavioral effects of dopamine agonists, whereas its congener sulpiride potentiates these effects. We injected metoclopramide 2.0, 4.0, or 8.0 mg/kg PO into rats 2 hr before d-amphetamine 1.5 mg/kg IP and measured locomotion for 3 hr. We injected metoclopramide 8.0 mg/kg PO into rats 2 hr before d-amphetamine 1.5, 3.0, or 6.0 mg/kg IP and measured stereotypy for 3 hr. Metoclopramide potentiated the effects of all doses of d-amphetamine on both measures; peak effects occurred in the second or third hr after d-amphetamine injection. Metoclopramide alone tended to reduce behavior. The results suggest that metoclopramide is qualitatively similar to sulpiride in its interaction with d-amphetamine, and that metoclopramide's mechanism of action is not a simple dopaminergic antagonism. Clinicians are advised that metoclopramide, which is presently extensively for gastrointestinal and other disorders, may interact adversely with drugs that affect dopaminergic function.     

Effects of nimodipine, felodipine and amlodipine on electroconvulsive shock-induced amnesia in the rat

The effects of various doses (0.03, 0.1, 0.3 or 1.0 mg/kg) of the Ca²⁺ channel blockers nimodipine, felodipine and amlodipine on the learning ability of rats exposed to electroconvulsive shock were examined. The animals were trained in a passive avoidance procedure. The drugs tested were injected 30 min before the learning trial started. The electroconvulsive shock was given immediately after the learning trial response had been acquired. A passive avoidance retention test was performed 24 h later. It was found that electroconvulsive shock strongly impaired the retention of the passive avoidance response. Nimodipine, felodipine and amlodipine did not influence the passive avoidance behavior in the sham electroconvulsive shock group, but significantly improved the retention deficits in the animals exposed to electroconvulsive shock. These findings support the hypothesis that perturbations in Ca²⁺ homeostasis can contribute to the memory deficits associated with electroconvulsive shock. The antiamnestic effects of the substances tested make them interesting candidates for clinical trials in patients with cognitive impairment caused by electroconvulsive shock therapy.     

DAU 6215, a novel 5-HT3-receptor antagonist,selectively antagonizes scopolamine-induced deficit in a passive-avoidance task,but not scopolamine-induced hypermotility in rats

Abstract— This study examined the effects of DAU 6215, a selective 5-HT₃-receptor antagonist, on either impairment of a passive-avoidance task or hypermotility, both caused by scopolamine in rats. In the first experiment, scopolamine (0·75 mg kg^?1, i.p.) disrupted acquisition of a one-trial ‘step through’ passive-avoidance response. Pretreatment with DAU 6215 (1, 10, 30 and 100 μg kg^?1, i.p.) antagonized this deficit induced by scopolamine, with a bell-shaped dose-response curve. Scopolamine (0·75 mg kg^?1, i.p.) produced a significant increase in locomotor activity which was unaffected by pretreatment with DAU 6215 (10 and 30 μg kg^?1, i.p.). The present results further support the suggestion that 5-HT₃-receptor antagonists may prevent the memory disturbance caused by a reduction in central cholinergic function in the rat. The inefficacy shown by DAU 6215 on hyperactivity induced by scopolamine appears to rule out the possibility of a pharmacokinetic interference between DAU 6215 and scopolamine.     

Effect of hippocampal and neocortical ablation on scopolamine-induced activity in the rat

To test the hypothesis that the hippocampus may be an important site of action for anticholinergic drugs, scopolamine was administered to rats with hippocampal lesions produced by aspiration and to appropriate control groups, and their activity measured. The experimental design was a four-way analysis of variance with three lesion groups, three drug levels, eight measurements in a two-hour session, and four weeks. At the two higher drug doses (0.20 and 1.0 mg/kg), rats with hippocampal or cortical lesions had significantly greater activity than the sham operates (p<0.01 and p<0.05, respectively). A group of Ss with electrolytic hippocampal lesions tested at 0.20 mg/kg scopolamine had transitory activity increases. Therefore the hippocampus is not necessary for the motor activating effects of the drug nor is its ablation unique in producing increases in drug-induced activity.This study is based on a doctoral dissertation submitted in partial fulfillment of the requirements for the Ph. D. degree granted jointly by the Department of Psychology and Center for Brain Research, University of Rochester. Thanks are due L. G. Abood for his help and encouragement in this research, which was conducted while the author was a USPHS Trainee.     

Efficacy study of Prunus amygdalus (almond) nuts in scopolamine-induced amnesia in rats

Objective:

Cognitive disorders such as amnesia, attention deficit and Alzheimer’s disease are emerging nightmares in the field of medicine because no exact cure exists for them, as existing nootropic agents (piractam, tacrine, metrifonate) have several limitations. The present study was undertaken to investigate the effect of Prunus amygdalus (PA) nuts on cognitive functions, total cholesterol levels and cholinesterase (ChE) activity in scopolamine-induced amnesia in rats.

Materials and Methods:

The paste of PA nuts was administered orally at three doses (150, 300 and 600 mg/kg) for 7 and 14 consecutive days to the respective groups of rats. Piracetam (200 mg/kg) was used as a standard nootropic agent. Learning and memory parameters were evaluated using elevated plus maze (EPM), passive avoidance and motor activity paradigms. Brain ChE activity and serum biochemical parameters like total cholesterol, total triglycerides and glucose were evaluated.

Results:

It was observed that PA at the above-mentioned doses after 7 and 14 days of administration in the respective groups significantly reversed scopolamine (1 mg/kg i.p.)-induced amnesia, as evidenced by a decrease in the transfer latency in the EPM task and step-down latency in the passive avoidance task. PA reduced the brain ChE activity in rats. PA also exhibited a remarkable cholesterol and triglyceride lowering property and slight increase in glucose levels in the present study.

Conclusion:

Because diminished cholinergic transmission and increase in cholesterol levels appear to be responsible for the development of amyloid plaques and dementia in Alzheimer patients, PA may prove to be a useful memory-restorative agent. It would be worthwhile to explore the potential of this plant in the management of Alzheimer’s disease.     

Effect of pregabalin on fear-based conditioned avoidance learning and spatial learning in a mouse model of scopolamine-induced amnesia

Objectives: Cognitive deficits are one of the frequent symptoms accompanying epilepsy or its treatment.

Methods: In this study, the effect on cognition of intraperitoneally administered antiepileptic drug, pregabalin (10?mg/kg), was investigated in scopolamine-induced memory-impaired mice in the passive avoidance task and Morris water maze task. The effect of scopolamine and pregabalin on animals’ locomotor activity was also studied.

Results: In the retention phase of the passive avoidance task, pregabalin reversed memory deficits induced by scopolamine (p?p?p?p?Discussion: In passive avoidance task, pregabalin reversed learning deficits induced by scopolamine. In the Morris water maze, pregabalin did not influence spatial learning deficits induced by scopolamine. These results are relevant for epileptic patients treated with pregabalin and those who use it for other therapeutic indications (anxiety, pain).