Absence of long-term behavioral effects after sub-chronic administration of low doses of methamidophos in male and female rats

Putative long-term learning and memory effects of low-dose exposure to the cholinesterase inhibitor organophosphate methamidophos (Tamaron) early in life were studied in two parallel studies in middle-aged rats. Methamidophos was administered via the drinking water to female and male Wistar rats using nominal concentrations of 0 (control), 0.5, 1.5 and 4.5 ppm active ingredient for 16 weeks. Animals were then maintained for a recovery period of about 14 months without treatment. They were tested in the standard and repeated acquisition version of the Morris water escape task in two series of tests starting 33 and 55 weeks after termination of the methamidophos treatment. Functional observations and motor activity measurements preceded each series of testing. Exposure to methamidophos was confirmed by measurement of brain cholinesterase (ChE-B) at the end of the 16 weeks of treatment in satellite animals. At 4.5 ppm a biologically relevant reduction in ChE-B activity was observed without clinical signs of intoxication (males: 66%, females: 64% of control activity). Mid- and low-dose exposure to methamidophos revealed ChE-B activity of 90% and 100% in males and 88% and 97% in females, respectively. General examinations of the animals during treatment revealed no clinical signs suggesting cholinergic stimulation. Functional observations and motor activity measurements exhibited no relevant differences between treatment groups and controls. Neither the performance in the standard Morris water escape task that predominantly measures spatial reference memory, nor in the repeated acquisition task in the Morris tank, which predominantly measures spatial working memory, was affected by treatment with methamidophos. A small number of statistically significant differences were noted in the mean performance level between treatment groups, or between treatment by sex groups in both versions of the Morris task. However, these findings appeared to be idiosyncratic for a particular experiment and were not supported by findings from the other. They were consequently not considered as reflecting a consistent effect of methamidophos on learning and memory. In conclusion, administration of low doses of methamidophos to female and male Wistar rats for 16 weeks during early adulthood did not impair spatial working and reference memory in the Morris water escape task 33 and 55 weeks after cessation of treatment.     

Impairments of learning and memory following intracerebroventricular administration of AF64A in rats

Three types of learning and memory tests (Morris water maze, active and passive avoidance) were performed in rats following intracerebroventricular infusion of ethylcholine aziridium (AF64A). In Morris water maze, AF64A-treated rats showed the delayed latencies to find the platform from 6th day after the infusion. In pretrained rats, AF64A caused the significant delay of latency at 7th day, but not 8th day. In the active avoidance for the pre-trained rats, the escape latency was significantly delayed in AF64A-treatment. The percentages of avoidance in AF64A-treated rats were less increased than those in the control. Especially, the percentage of no response in the AF64A-treated rats was markedly increased in the first half trials. In the passive avoidance, AF64A-treated rats shortened the latency 1.5 h after the electronic shock, but not 24 h. AF64A also caused the pretrained rats to shorten the latency 7th day after the infusion, but not 8th day. These results indicate that AF64A might impair the learning and memory. However, these results indicate that the disturbed memory by AF64A might rapidly recover after the first retrain. Furthermore, these results suggest that AF64A may be a useful agent for the animal model of learning for spatial cognition.     

Effects of high-affinity GABAB receptor antagonists on active and passive avoidance responding in rodents with gamma-hydroxybutyrolactone-induced absence syndrome

RATIONALE: Absence seizures in man are behaviourally manifested as arrest and mild jerks mainly of facial muscles, associated in the electroencephalogram with synchronous spike and wave discharges. Gamma-hydroxybutyrolactone (GHBL) administration is currently used as an experimental model of absence seizures in rats and mice. OBJECTIVE: The aim of the present study was to examine the effects of three potent gamma-aminobutyric acid (GABA)B receptor antagonists CGP55845A, CGP62349 and CGP71982 (0.01 mg/kg) on the development of GHBL-induced absence epilepsy and in learning paradigms of active and passive avoidance tests in GHBL-treated mice and rats. METHODS: After 4 weeks of development of the absence syndrome, active and passive avoidance tests with negative reinforcement were performed. In both animal species, the absence syndrome was observed after 3 weeks of treatment in the saline group. RESULTS: The GABAB receptor antagonists CGP55845A and CGP62349 appeared to suppress the development of the absence syndrome to a greater degree in mice than in rats. CGP71982 suppressed it later than the other two antagonists (fifth week). In an active avoidance test in GHBL-treated mice, the GABAB antagonists had different effects - CGP62349 improved learning and memory retention to a greater extent than CGP55845A, whilst CGP71982 had no influence on it. In a passive avoidance test in GHBL-treated mice, the GABAB antagonists also had different effects - CGP71982 improved both learning and memory retrieval, whereas CGP55845A and CGP62349 had no effect. In the active avoidance test in GHBL-treated rats, the GABAB antagonist CGP55845A improved learning, whereas the other two, CGP62349 and CGP71982, had no effect. In the passive avoidance test the GHBL-treated rats showed an improvement in short memory retrieval. CGP55845A and CGP71982 improved this further, whilst CGP62349 had no effect. CONCLUSIONS: GHBL appeared to influence mice and rats in a different manner - rats learned the active avoidance task better than the GHBL-treated mice. The present study confirms previous data that GABAB antagonists suppress absence behaviour.     

Subchronic Inhalation Studies of Styrene in CD Rats and CD-1 Mice

Groups of 10 male and 10 female Charles River (CRL) CD (Sprague-Dawley-derived)rats were exposed to styrene vapor at 0, 200, 500, 1000, or1500 ppm 6 hr per day 5 days per week for 13 weeks. Styrenehad no effect on survival, hematology, or clinical chemistry.Males at 1500 ppm weighed 10% less after 13 weeks and malesand females at 1000 and 1500 ppm consumed more water than controls.Histopathologic changes were confined to the olfactory epitheliumof the nasal mucosa. Groups of 20 male and 20 female CRL CD-1and B6C3F1 mice were exposed to styrene vapor at 0, 15, 60,250, or 500 ppm 6 hr per day 5 days per week for 2 weeks. Mortalitywas observed in both CD-1 and B6C3F1 mice exposed to 250 or500 ppm; more female mice, but not males, died from exposureto 250 ppm than from 500 ppm. Groups of 10 male and 10 femaleCRL CD-1 mice were exposed to styrene vapors at 0, 50, 100,150, or 200 ppm 6 hr per day 5 days per week for 13 weeks. Twofemales exposed to 200 ppm died during the first week. Livertoxicity was evident in the decedents and in some female survivorsat 200 ppm. Changes were observed in the lungs of mice exposedto 100, 150, or 200 ppm and in the nasal passages of all treatmentgroups, those exposed to 50 ppm being less affected. Satellitegroups of 15 male rats and 30 male mice were exposed as describedabove for 2, 5, or 13 weeks for measurement of cell proliferation(BrdU labeling). No increase in cell proliferation was foundin liver of rats or mice or in cells of the bronchiolar or alveolarregion of the lung of rats. No increase in labeling index oftype II pneumocytes was seen in mouse lungs, while at 150 and200 ppm, an increased labeling index of Clara cells was seenafter 2 weeks and in occasional mice after 5 weeks. Large variationsin the labeling index among animals emphasize the need for largegroup sizes. For nasal tract effects, a NOAEL was not foundin CD-1 mice, but in CD rats, the NOAEL was 200 ppm. For othereffects, the NOAEL was 500 ppm in rats and 50 ppm in mice.     

Beneficial effects of resveratrol on scopolamine but not mecamylamine induced memory impairment in the passive avoidance and Morris water maze tests in rats

Resveratrol (3,5,4-trihydroxy-trans-stilbene), which is found in grapes and red wine has been shown to protect neuronal cells with its antioxidant activity, improve memory function in dementia and reverse acetylcholine esterase (AChE) activity. The aim of this study was to investigate the effect of resveratrol on emotional and spatial memory in naive rats, as well as on scopolamine- and mecamylamine-induced memory impairment in the passive avoidance and Morris water maze (MWM) tests. Resveratrol (12.5, 25 and 50 mg/kg), scopolamine (0.6 mg/kg) and mecamylamine (10 mg/kg) were administered to male Wistar rats. In the passive avoidance test, there was no significant difference in the first day latency between all groups, whereas scopolamine and mecamylamine significantly shortened the second day latency compared to the control group. Resveratrol reversed the effect of scopolamine at all doses used, but it had no effect on mecamylamine-induced memory impairment in the passive avoidance test. Both scopolamine and mecamylamine significantly decreased the time spent in the escape platform quadrant during the probe trial of the MWM test compared to the control group. Resveratrol reversed the effect of scopolamine at all doses, but did not change the effect of mecamylamine in the MWM test. There were no significant differences in the locomotor activities of any of the groups. In conclusion, we suggested that resveratrol had improving effects on learning and memory by acting on muscarinic cholinergic receptors and at least in part, may reverse AChE activity.     

方格星虫多糖对记忆障碍模型小鼠学习记忆能力的影响

目的观察方格星虫多糖(SNPS)对东莨菪碱所致小鼠学习记忆障碍的影响。方法 SNPS 3个剂量组100,200和400mg.kg-1每天小鼠灌胃给药1次,连续7天。采用东莨菪碱建立记忆获得障碍模型,再用Morris水迷宫法检测小鼠的学习记忆能力。测试结束后,分别检测血清中SOD活性和MDA含量。结果与模型组比较,SNPS能显著缩短逃避潜伏期和找到平台的时间,显著增加穿越原平台次数;SNPS能显著提高血清SOD活力,降低血清MDA含量。结论 SNPS能改善记忆获得障碍模型鼠的学习记忆能力,提高机体清除自由基、抗氧化能力。     

Sex-specific influence of exposure to bisphenol-A between adolescence and young adulthood on mouse behaviors

Bisphenol-A (BPA) is one of the most common environmental endocrine disrupters and has a wide range of effects on central nervous system. Adolescence is another important developmental period besides the early critical prenatal and neonatal periods. In the present study, we exposed mice to BPA (40, 400 μg/kg/d) between adolescence and young adulthood for 8 weeks and investigated its effects on the non-reproductive behaviors. In open field tests, rearing and grooming sex differences were abolished by BPA exposure. In the elevated plus maze test, the number of open arm entries, the time spent in open arms, and the number of unprotected head dips in the center area were reduced in males but increased in females by BPA at 40 or 400 μg/kg/d, thus eliminating or reversing sex differences in these behaviors. In the Morris water maze task, exposure to BPA at 40 μg/kg/d significantly extended the average escape pathlength to the hidden platform in males, but no significant influence was found in females; thus, the sex differences in spatial learning and memory were abolished. In the step-down test, the latency to step down from the platform 24 h after receiving a footshock was shortened by BPA exposure in males but not in females; thus, a sex difference was induced in passive avoidance memory in mice. These results suggest that long-term exposure to low levels of BPA between adolescence and young adulthood alters characteristic differences in certain non-reproductive behaviors of males and females, including exploration, anxiety, spatial learning and memory, and passive avoidance memory, although no obvious changes were found in the serum hormone levels or in the weights of reproductive organs.     

Administration of midazolam in infancy does not affect learning and memory of adult mice

• 1 Midazolam is a common fast‐acting GABA_A receptor agonist. Recent data suggest that exposure to midazolam in early life may cause long‐term effects on brain function through stable epigenetic reprogramming. The aim of the present study was to determine whether the administration of midazolam to infant mice would affect their learning and memory in adulthood.
• 2 An open‐field test was conducted before and then 3, 24, 48 and 72 h after administration of midazolam (50 mg/kg, i.p.) to infant mice. Saline control mice received an equal volume of saline i.p. 3 h before the open‐field test. Total movements, total movement time, total movement distance and velocity were analysed. Novel object recognition (NOR), Morris water‐maze and passive avoidance tests were performed when the treated mice grew to adulthood (105 days of age).
• 3 The results of open‐field test showed that midazolam significantly reduced locomotor activity (total movements, total movement time, total movement distance and velocity) in infant mice 3 and 24 h after drug administration and that these effects had disappeared by 72 h after drug administration. The results of the water‐maze, NOR and passive avoidance tests in adulthood (at 105 days of age) indicated that administration of midazolam in infancy had no long‐term effects on the learning and memory behaviours of adult mice compared with the saline control.
• 4 Acute midazolam administration to infant mice affected spontaneous locomotor activity for approximately 2 days, but did not seem to have any significant impact on cognitive functioning that lasted into adulthood.

     

Repeated Neonatal Propofol Administration Induces Sex-Dependent Long-Term Impairments on Spatial and Recognition Memory in Rats

Propofol is an anesthetic agent that gained wide use because of its fast induction of anesthesia and rapid recovery post-anesthesia. However, previous studies have reported immediate neurodegeneration and long-term impairment in spatial learning and memory from repeated neonatal propofol administration in animals. Yet, none of those studies has explored the sex-specific long-term physical changes and behavioral alterations such as social (sociability and social preference), emotional (anxiety), and other cognitive functions (spatial working, recognition, and avoidance memory) after neonatal propofol treatment. Seven-day-old Wistar-Kyoto (WKY) rats underwent repeated daily intraperitoneal injections of propofol or normal saline for 7 days. Starting fourth week of age and onwards, rats were subjected to behavior tests including open-field, elevated-plus-maze, Y-maze, 3-chamber social interaction, novel-object-recognition, passive-avoidance, and rotarod. Rats were sacrificed at 9 weeks and hippocampal protein expressions were analyzed by Western blot. Results revealed long-term body weight gain alterations in the growing rats and sex-specific impairments in spatial (female) and recognition (male) learning and memory paradigms. A markedly decreased expression of hippocampal NMDA receptor GluN1 subunit in female- and increased expression of AMPA GluR1 subunit protein expression in male rats were also found. Other aspects of behaviors such as locomotor activity and coordination, anxiety, sociability, social preference and avoidance learning and memory were not generally affected. These results suggest that neonatal repeated propofol administration disrupts normal growth and some aspects of neurodevelopment in rats in a sex-specific manner.     

Repeated toluene exposure and changes of response latency in shock avoidance learning

Behavioral effects of repeated exposure to toluene were investigated. After 1, 3, and 6 weeks exposure to toluene at 1000 and 2000 ppm, all rats received shock avoidance training. Toluene-exposed rats could acquire shock avoidance learning and there was no significant difference between exposed rats and control rats. Analyzing response latencies (RLs) of avoidance responses, control rats shifted them to a longer RL and at last they learned to perform avoidance responses with specific RLs (3-4 sec). However, rats exposed to 1000 ppm toluene for 1 week and to 2000 ppm toluene for 1 week and 3 weeks, did not learn to respond with specific RLs. Rats exposed to 1000 ppm and 2000 ppm toluene for 6 weeks did not shift to longer RLs. It was suggested that repeated exposure to toluene vapor ranging up to 2000 ppm had no influence on the acquisition of shock avoidance learning, but caused some functional impairments of higher nervous functions.     

葡萄籽原花青素对学习记忆的影响

目的　研究葡萄籽原花青素对学习记忆和对血液、脑组织过氧化脂质的影响。方法　通过对小鼠scD 半乳糖 6周 ,制备小鼠衰老模型 ,同时 po葡萄籽原花青素 ,分别采用跳台法、Y型迷宫法测试小鼠的学习记忆能力 ,并测定小鼠血液和脑组织的过氧化脂质 ;正常小鼠 po给予葡萄籽原花青素 ,连续 19d ,采用Morris水迷宫法测试小鼠的学习记忆能力。结果　葡萄籽原花青素对D 半乳糖处理小鼠在跳台法的测试中 ,延长潜伏期 ,减少 5min内错误总数 ;在Y型迷路的测试中 ,能减少错误反应次数 ;并能降低小鼠血液和脑组织中过氧化脂质 ;葡萄籽原花青素对正常小鼠在Morris水迷宫法测试中 ,对小鼠定位航行SPL无明显影响 ,对休息30d后的小鼠空间搜索的CPT和CPP均有提高作用。结论　葡萄籽原花青素能改善D 半乳糖所致衰老小鼠的学习记忆能力 ;能明显增强正常小鼠信息的保持和再现能力。作用机制可能与其能降低血液和脑组织中过氧化脂质有关。     

A 13-week vapor inhalation study of 3,3-dimethyl-2-butanol in Sprague-Dawley rats

Four groups of male and female Sprague-Dawley rats were exposed for 13 weeks to 3,3-dimethyl-2-butanol (PA) at concentrations of 0.00, 0.20, 1.00 or 5.00 mg/l (1 mg/l = 240 ppm). Exposures were for 6 hr per day, 5 days per week with sacrifices at 7 and 13 weeks of exposure, and at 4 weeks after exposure. The test animals were evaluated for abnormalities in physiology, behaviour, clinical laboratory parameters, and gross and microscopic morphology. No abnormalities were detected in electrocardiograms, respiratory indices, spontaneous activity, passive avoidance activity and open-field behaviour. Clinical signs related to PA exposure included alopecia, ataxia and lacrimation. There were no biologically significant between-group differences in body-weights during the study. The clinical laboratory data demonstrated a 30% increase in serum cholesterol and bilirubin at 7 weeks in high-dose males and an increase in urea nitrogen in intermediate and high-dose males at 13 weeks. There were no abnormalities in hematologic or coagulation parameters. At necropsy there were no significant gross abnormalities; however, examination of organ weights revealed enlarged kidneys in high-dose male rats at 13 weeks, enlarged ovaries in high-dose female rats at 13 weeks, and microscopic study of tissue sections revealed minimal to mild renal tubular injury in high and possibly intermediate dose males at several sacrifices. These findings suggest that the primary target organ of PA, when given by inhalation, is the kidney in male rats and possibly the ovary in female rats. The renal changes in the high-dose males were not fully reversible during the recovery period.(ABSTRACT TRUNCATED AT 250 WORDS)     

Memory retention test performance in mice: Improvement by chronic oral cholinergic drug treatment

Mice consumed solutions containing 0, 0.025, 0.050 or 0.075 mg/ml of arecoline hydrobromide (ARE) one week prior to training (T-maze, footshock, active avoidance) and a total of two weeks prior to testing memory retention. The mean daily doses of ARE were estimated to be 0, 157, 302, or 500 μg per mouse, respectively. An inverted-U dose-response curve was obtained; the best retention test performance was by the group receiving 0.050 mg/ml of ARE. Measures of activity and weight taken over the experiment indicated no significant differences between ARE groups and the control group; thus no apparent toxicity. Separate groups of mice consumed 0 or 0.050 mg/ml of ARE for one week, then were trained to a criterion of 5 avoidances in 6 training trials. There were no significant differences in trials to first avoidance response or to criterion. Thus the enhanced retention test performance of the 0.050 mg/ml ARE group reflected improved memory processing rather than better learning.     

石菖蒲水提取物SIPI-SCPd改善动物学习记忆的研究

目的研究石菖蒲水提取物SIPI-SCPd是否有改善动物学习记忆的作用。方法将70,35,17.5和8.75 mg/kg的SIPI-SCPd分别连续给予ICR小鼠口服2周或Wistar大鼠口服4周,采用跳台法或避暗法观察其对东莨菪碱、NaNO2及45%乙醇诱导的小鼠记忆损伤(记忆获得障碍,记忆巩固不良,记忆再现障碍)模型的影响,以及采用Morris水迷宫法观察SIPI-SCPd对由东莨菪碱所致大鼠记忆障碍的影响。并观察受试小鼠脑内乙酰胆碱酯酶活力的变化。结果 70,35,17.5 mg/kg的SIPI-SCPd均能延长记忆获得障碍、记忆巩固不良和记忆再现障碍模型小鼠跳下平台或进入暗室的潜伏期;并能改善由东莨菪碱所致的大鼠空间记忆障碍。SIPI-SCPd对乙酰胆碱酯酶的活性没有影响。结论 SIPI-SCPd对几种药物诱导的记忆障碍模型动物的学习记忆功能均有一定的改善作用,且该作用与乙酰胆碱酯酶的活性无关。     

Effect of CDP-choline on learning and memory processes in rodents.

The effects of cytidine (5') diphosphocholine (CDP-choline) on learning and memory were studied using conditioned reflex methods for passive avoidance and active avoidance with punishment reinforcement (step-through, step-down, shuttle box and maze), for active avoidance with alimentary reinforcement (staircase maze), and the Morris water maze. The majority of experiments involved comparative studies of the nootropic drugs meclofenoxate and/or piracetam. CDP-choline was administered orally, in some of the experiments also intraperitoneally, at doses of 10-500 mg/kg body weight once or twice daily for 5 or 7 days. In separate cases only single doses were administered. Trainings started one hour after the last dose of the drugs. Retention tests were given 3 h, 24 h, 7 days or 10 days after training. The results obtained with the different methods document CDP-choline's ability to improve learning and memory in rats and mice. No essential differences in the effects of CDP-choline were established upon oral and intraperitoneal administration of the drug. The learning- and memory-facilitating effects of CDP-choline were similar to those of meclofenoxate and piracetam. The results of the present study permit us to define CDP-choline as a substance capable of improving cognitive levels.     

Inhibitory Effects of Eucommia ulmoides Oliv. Bark on Scopolamine-Induced Learning and Memory Deficits in Mice

Eucommia ulmoides Oliv. Bark (EUE) is commonly used for the treatment of hypertension, rheumatoid arthritis, lumbago, and ischialgia as well as to promote longevity. In this study, we tested the effects of EUE aqueous extract in graded doses to protect and enhance cognition in scopolamine-induced learning and memory impairments in mice. EUE significantly improved the impairment of short-term or working memory induced by scopolamine in the Y-maze and significantly reversed learning and memory deficits in mice as measured by the passive avoidance and Morris water maze tests. One day after the last trial session of the Morris water maze test (probe trial session), EUE dramatically increased the latency time in the target quadrant in a dose-dependent manner. Furthermore, EUE significantly inhibited acetylcholinesterase (AChE) and thiobarbituric acid reactive substance (TBARS) activities in the hippocampus and frontal cortex in a dose-dependent manner. EUE also markedly increased brain-derived neurotrophic factor (BDNF) and phosphorylation of cAMP element binding protein (CREB) in the hippocampus of scopolamine-induced mice. Based on these findings, we suggest that EUE may be useful for the treatment of cognitive deficits, and that the beneficial effects of EUE are mediated, in part, by cholinergic signaling enhancement and/or protection.     

纳洛酮对慢性酒精中毒学习记忆障碍大鼠脑内阿片肽含量的影响

目的：研究慢性酒精中毒对大鼠空间学习记忆的影响、脑区内阿片肽含量的变化，及其阿片受体拮抗剂纳洛酮的治疗作用。方法：3周龄雄性SD大鼠分为4组：给A、B组大鼠自由饮用由含6％逐渐递增至15％（v／v）的乙醇水溶液8周，建立慢性酒精中毒模型，而C、D组自由饮水；8周后B、D大鼠连续10天腹腔注射纳洛酮，A、C组腹腔注射生理盐水；然后用Morris水迷宫训练方法，比较四组大鼠的空间学习记忆能力的差异；采用放射免疫法测定下丘脑、海马、纹状体和前额皮质每克组织中β内啡肽（β-EP：pendorphin）和强啡肽A（DynA：dynophine草药A）的含量。结果：在Morris水迷宫隐匿平台训练中，有多个时段A组动物的逃避潜伏期较正常对照组C长（P〈0．01或P〈0．05），其中纳洛酮治疗后B组比A组明显缩短（P〈0．05）。大鼠慢性酒精摄入后下丘脑、海马和纹状体内的β-EP水平较正常对照组出现不同程度的升高（P〈0．01或P〈0.05或P〈0．001），而海马、纹状体和前额皮质内的DynA水平却出现下降；而给予纳洛酮处理后，能部分或完全逆转脑区内β-EP和DynA含量的变化并改善大鼠学习记忆的行为学成绩（P〈0．05）。结论：酒精损害了大鼠的学习记忆能力，其机制可能与学习相关脑区内的β-EP和DynA水平的变化有关；纳洛酮逆转其部分脑区内阿片肽水平的变化，从而对学习记忆障碍有一定的改善作用。     

Memory-enhancing effect of a cerulein analogue following peripheral administration in the rat

Our previous studies demonstrated that cerulein (CER) has a potent preventive action on amnesia induced by electroconvulsive shock, administration of scopolamine, puromycin, anisomycin, NMDA receptor antagonists, and protein kinase C inhibitors. The present study was aimed at finding more effective CER analogues which could enhance memory processes. Five CER analogues were synthesized and the potencies in passive and active avoidance responses and in the Morris water pool test were examined in the rat. Among the preparations, des-Gln²-[Leu⁵, Nle⁸]-CER was found to possess particularly potent effects on memory acquisition and/or storage. The effects were apparent in less than 1 μg/kg single subcutaneous (s.c.) injection for at least 120 hr in passive avoidance response and 15 days in active avoidance response. Memory impairments induced by scopolamine and puromycin were well improved in passive avoidance response. In the Morris water maze test, disordered behaviors caused by scopolamine and protein kinase C inhibitor were totally restored to the normal state by s.c. injection of this CER analogue. © 1992 Wiley-Liss, Inc.     

Chronic phosphatidylserine treatment improves spatial memory and passive avoidance in aged rats

Learning/memory deficits in senescent animals are widely used as a tool to evaluate the therapeutic potential of agents for treatment of age-associated cognitive dysfunction. As assessed in the Morris water maze test, aged (21–24 months) rats showed a variable loss of spatial memory. Aged non-impaired rats performed as well as young subjects, while aged impaired rats exhibited a severe and persistent place-navigation, deficit. Passive avoidance retention was similarly affected in the two aged subpopulations. Chronic oral administration of phosphatidylserine (50 mg/kg/day for up to 12 weeks), a pharmacologically active phospholipid, was found to improve both the spatial memory and the passive avoidance retention of aged impaired rats. Results are discussed with reference to the phosphatidylserine-induced improvement of age-associated deterioration of brain functions in rats.We are grieved to record the unexpected, death of Professor L. Valzelli. He was a scientist of merit and a great humanitarian     

Dose‐specific improvements in memory‐related task performance by rats and aged monkeys administered the nicotinic‐cholinergic antagonist mecamylamine

The centrally acting nicotinic‐cholinergic antagonist mecamylamine (mec) is well documented to produce amnestic effects in animals and humans. However, in certain circumstances the compound has enhanced performance of some memory‐related tasks in animals and further investigation of this paradoxical effect is warranted. The present study was designed to determine under what conditions mec would enhance memory‐task performance in rats and aged nonhuman primates. Mec (various doses) or saline was administered IP to rats tested in the Morris Water Maze (MWM), to rats trained to perform a delayed stimulus discrimination task (DSDT), and IM to aged rhesus monkeys (average age 24.6 years) trained to perform a delayed matching to sample task (DMTS). In rats, mec 1.0 mg/kg improved location of the hidden platform on day 1 of the MWM, but inhibited learning in subsequent trials, while several μg/kg doses improved DSDT accuracy. Further, some μg/kg doses of mec also improved accuracy in aged monkeys in DMTS at both 10 min and 24 h after administration. Mec had no effect on swim speeds in the MWM, response latencies in the DSDT, or on choice or response latencies in the DMTS task. Collectively, the results indicate that some doses of mec can mimic certain memory‐enhancing effects produced by nicotinic‐acetylcholine receptor agonists. It is not clear whether mec is acting as a partial agonist in this regard, or whether low‐level nicotinic antagonism produces a cellular response that is in some way analogous to nicotine‐induced receptor desensitization. Drug Dev. Res. 47:127–136, 1999. © 1999 Wiley‐Liss, Inc.