学习和记忆中的中枢烟碱受体亚型

目的：观察不同的中枢烟碱受体亚型在学习、记忆中的作用。方法：小鼠被动回避性反应试验，包括跳台试验和避暗试验，产海马脑片ＣＡＩ区长时程突触增强（ＬＴＰ）效应。结果：六烃季铵（Ｃ６）和Ｋａｐｐａ－银环蛇毒素（ｋ－ＢＴＸ）明显抑制小鼠被动回 获得，且ｋ－ＢＴＸ的作用有量效关系。ｋ－ＢＴＸ １μｍｏｌ。Ｌ＾－１抑制大鼠海马脑片ＣＡ１区ＬＴＰ形成（Ｐ〈０．０５），但不影响正常突触传递，也不影响ＬＴＰ维持。结     

学习和记忆中的中枢烟碱受体亚型

目的:观察不同的中枢烟碱受体亚型在学习、记忆中的作用。方法:小鼠被动回避性反应试验,包括跳台试验和避暗试验,大鼠海马脑片CA1区长时程突触增强(LTP)效应。结果:六烃季铵(C_6)和Kappa-银环蛇毒素(κ-BTX)明显抑制小鼠被动回避条件反应的获得,且κ-BTX的作用有量效关系。κ-BTX 1μmol·L~(-1)抑制大鼠海马脑片CA1区LTP形成(P<0.05),但不影响正常突触传递,也不影响LTP维持。结论:中枢烟碱受体与学习记忆有关,对κ-BTX敏感的中枢烟碱受体亚型在学习记忆中起重要作用。     

莨菪类生物碱对18,28及38日龄小鼠的行为和记忆障碍作用

比较阿托品（Ａｔｒ），东莨菪碱（Ｓｃｏ），樟柳碱（ＡＴ３）和山莨菪碱（Ａｎｉ）对小鼠行为及记忆损伤作用。方法：行为和记忆实验用开阔和回避反应法。脑Ｍ受体用［＾３Ｈ］ＱＮＢ测定。结果：Ａｔｒ，Ｓｃｏ和ＡＴ３增加小鼠走动行为２６％－４２％，降低站忆。４个药物均能妨碍回避反应。小鼠１８日龄额叶皮层和海马［＾３Ｈ］ＱＮＢ结合位点数少于３８日龄７％－２３％。结论：１）莨菪类生物碱对小鼠行为和记忆障碍的作用随     

Belladonna alkaloids-induced behavioral changes and amnesia on open-field and step-through in 18-,28-, and38-day-old mice

目的：比较阿托品（Ａｔｒ），东莨菪碱（Ｓｃｏ），樟柳碱（ＡＴ３）和山莨菪碱（Ａｎｉ）对小鼠行为及记忆损伤作用．方法：行为和记忆实验用开阔和回避反应法．脑Ｍ受体用［３Ｈ］ＱＮＢ测定．结果：Ａｔｒ，Ｓｃｏ和ＡＴ３增加小鼠走动行为２６％－４２％，降低站立，修饰，排便行为５０％－１００％，并抑制开阔记忆．４个药物均能妨碍回避反应．小鼠１８日龄额叶皮层和海马［３Ｈ］ＱＮＢ结合位点数少于３８日龄７％－２３％．结论：１）莨菪类生物碱对小鼠行为和记忆障碍的作用随其日龄增加而减弱．２）Ｓｃｏ对幼年小鼠的行为及记忆障碍作用的最小有效量分别是Ａｔｒ，ＡＴ３和Ａｎｉ的１／１０，１／１００和１／１０００．     

SNK法及Kruskal-Wallis H检验法研究尼莫地平对小鼠开场行为和学习记忆的影响

采用Ｙ－迷宫分辨学习和一次被动回避反应两种行为模型,利用小鼠海马内微注射技术,检测了钙通道拮抗剂尼莫地平的中枢效应,并观察了开场行为,利用ＳＮＫ法及Ｋｒｕｓｋａｌ－ＷａｌｉｓＨ检验法处理实验数据,结果表明,海马内钙离子水平升高会破坏小鼠的分辨学习能力及一次被动回避反应的记忆保持。尼莫地平本身对正常小鼠的分辨学习无明显影响,但可促进小鼠一次被动回避反应的记忆保持,并可对抗海马内Ｃａ２＋水平升高引起的小鼠分辨学习障碍及记忆保持的破坏。     

作用于中枢神经系统的药物

对早老性痴呆症治疗有两种新战略：烟碱（N）激动剂和选择性毒草碱（M）M1受体激动剂。抗早老性痴呆药如WarnerLambert公司的他克林（tacrine）和Hoechst公司的维那克林（velnacrine）促进中枢乙酸胆碱介导活性，抑制乙酸胆碱酯酶。Abbott公司开发了烟碱衍生物ABT—418，选择性作用于某些N受体亚型，处在Ⅰ期临床试验初期。烟碱可促进动物学习记忆，流行病学资料提示早老性痴呆和吸烟呈负相关；烟碱减轻早老性痴呆激动和焦虑症状；烟碱有许多亚型受体，可能将有益作用和副作用（如胃肠道紊乱和高血压）分开。动物研究中ABT－418有增强…     

芦丁复合物对兔实验性脑梗塞血浆中TXB_2、6－Keto－PGF_（1α）的影响

通过建立兔大脑中动脉阻塞局灶性脑缺血实验模型，测定缺血后及经芦丁复合物治疗后血浆中ＴＸＢ_２、６－Ｋｅｔｏ－ＰＧＦ_（１α）含量。结果发现ＴＸＢ_２在脑梗塞后明显增高，而６－Ｋｅｔｏ－ＰＧＦ_（１α）含量降低，经芦丁复合物治疗后ＴＸＢ_２减少，６－Ｋｅｔｏ－ＰＧＦ_（１α）增高，与缺血组比较有显著性差异（Ｐ＜０．０ｌ）。提示芦丁复合物有明显的调节ＴＸＢ_２／６－Ｋｅｔｏ－ＴＧＦ_（１α）平衡，减轻缺血性脑损伤的作用。     

新化合物三环哌酯的抗N和M胆碱受体作用

三环哌酯盐酸盐（ＴＣＰＮ·ＨＣｌ）和碘甲烷盐（ＴＣＰＮ·ＣＨ₃Ｉ）为新化学实体。本文以烟碱诱发小鼠惊厥，豚鼠回肠收缩为评价中枢和外周神经元性Ｎ受体功能的指标，以槟榔碱诱发小鼠震颤为评价中枢Ｍ受体功能的指标，并在肌细胞上进一步观察药物对Ｎ受体离子通道的影响。结果表明，ＴＣＰＮ·ＨＣｌ使烟碱诱发小鼠惊厥的量效曲线平行右移；并对抗槟榔碱诱发小鼠震颤的作用，也可对抗烟碱诱发回肠收缩，阻断神经肌肉接头处自发微终板电流，并优先阻断开放时间长、电流强度大的Ｎ受体离子通道。提示ＴＣＰＮ·ＨＣｌ有强效抗中枢Ｎ和Ｍ受体作用。     

孕鼠血浆一氧化氮减少与内皮素、血栓素、前列环素的关系

本文研究一氧化氮减少对孕鼠血浆内皮素（ＥＴ）、血栓素Ｂ２（ＴＸＢ２）、６－酮－前列腺素Ｆ１α（６－ｋｅｔｏ－ＰＧＦ１α）等血管活性因子的影响。结果显示妊娠大鼠血浆ＥＴ、ＴＸＢ２、６－ｋｅｔｏ－ＰＧＦ１α均升高，ＴＸＢ２／６－ｋｅｔｏ－ＰＧＦ１α比值降低，未妊娠大鼠血浆ＥＴ升高，６－ｋｅｔｏ－ＰＧＦ１α降低，ＴＸＢ２无显著变化，ＴＸＢ２／６－ｋｅｔｏ－ＰＧＦ１α比值升高。说明孕鼠体内一氧化氮减少时，ＥＴ及ＴＸＢ２上升，血管收缩，而作为代偿和保护机制，６－ｋｅｔｏ－ＰＧＦ１α升高，ＴＸＢ２比值降低。未妊娠大鼠无此代偿效应。     

丁基苯酞对局部脑缺血大鼠记忆障碍的影响

观察了丁基苯酞（ＮＢＰ）对局部脑缺血大鼠记忆障碍的影响．用穿梭箱进行学习记忆获得性训练，以主动回避反应潜伏期和次数以及逃避反应潜伏期为指标，评价大脑中动脉阻断（ＭＣＡＯ）后记忆保持的能力．结果表明：假手术组的记忆功能与正常组没有显著差别，而缺血对照组大鼠主动回避反应次数减少６０％，主动回避和逃避反应潜伏期分别较缺血前延长４．２±１．６和４．１±３．３ｓ．给ＮＢＰ３０和１００ｍｇｋｇ－１后主动回避反应的次数明显提高，主动回避反应潜伏期明显缩短，与缺血对照组比较均有非常明显的差别．表明ＮＢＰ对局部脑缺血引起的记忆障碍有明显改善作用．     

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.     

Effects of concurrent manipulations of nicotinic and muscarinic receptors on spatial and passive avoidance learning

The present study investigates the effects of concurrent manipulations of nicotinic and muscarinic cholinergic receptors on spatial and passive avoidance learning/retention in rats. Daily pretraining test injections of combinations of the subthreshold doses of muscarinic (scopolamine 0.3 mg/kg) and nicotinic (mecamylamine 2.5 mg/kg or 10 mg/kg) antagonists impaired acquisition of the water-maze task (WM). Drug-induced deficits were also observed during the retention trial: the groups injected with scopolamine 0.3 mg/kg, mecamylamine 10 mg/kg and scopolamine 0.3 mg/kg in combination with mecamylamine 2.5 mg/kg showed reduced spatial bias compared with controls. Single preretention test injections of the combination of subthreshold doses of mecamylamine (10 mg/kg) and scopolamine (0.8 mg/kg) impaired memory retrieval in WM. Combined pretraining injections of subthreshold doses of scopolamine (1.0 mg/kg) and mecamylamine (10 mg/kg) induced a severe passive avoidance impairment comparable to 2.0 mg/kg of scopolamine. However, preretention test injections did not impair passive avoidance retention. Either single or combined injections of hexamethonium (5.0 mg/kg, SC) and methylscopolamine (1.0 mg/kg) did not impair either passive avoidance or water-maze performance. The present results suggest that 1) nicotinic and muscarinic systems jointly modulate performance in spatial and avoidance learning tasks and 2) cholinergic antagonists affect acquisition functions more effectively than retention ability. These findings may be relevant to the clinical disorders, like Alzheimer's disease, which are associated with a loss of both cholinergic neurons and nicotinic receptors.     

Oxiracetam prevents mecamylamine-induced impairment of active, but not passive, avoidance learning in mice

The nicotinic antagonist mecamylamine (2.5 and 5 mg/kg/IP) depressed both active (shuttle-box) and passive (step-through) avoidance learning in mice of the DBA/2 strain. The nootropic drug oxiracetam (50 and 100 mg/kg/IP) improved acquisition in the multitrial active avoidance test, but had no effect on one-trial passive avoidance learning. When the two drugs were combined, oxiracetam did not counteract mecamylamine-induced impairment of passive avoidance learning, even if it maintained a facilitating action on shuttle-box avoidance acquisition in mice receiving the nicotinic receptor blocker. Prevention of mecamylamine-induced shuttle-box avoidance depression by oxiracetam indicates that central nicotinic mechanisms are probably involved in the improving effects exerted by nootropic drugs on learning.     

Nicotinic potentiation of glutamatergic synapses in the prefrontal cortex: New insight into the analysis of the role of nicotinic receptors in cognitive functions

In contrast with the now well-recognized effects of nicotine in promoting learning and memory, little is known about the functional and pharmacological properties of putative nicotinic acetylcholine receptors located in neocortical areas involved in cognitive functions. Recent electrophysiological experiments using intracellular recordings in the rat prefrontal cortex in vitro have revealed that nicotine selectively enhances the amplitude of excitatory postsynaptic potentials mediated by glutamate in pyramidal cells. The effect was blocked by the specific nicotinic antagonists neuronal bungarotoxin and dihydro-β-erythroidine. Several arguments suggest that the potentiation of excitatory potentials by nicotine is due to the activation of presynaptic nicotinic receptors located on glutamatergic afferent terminals. Thus the control by nicotinic receptors of the effectiveness of excitatory inputs to the prefrontal cortex might influence significantly the processing of information in this area. The possibility of a functional cooperation between nicotinic and glutamatergic systems in the neocortex provides an integrative mechanism for the involvement of both neurotransmitter systems in synaptic plasticity underlying memory processes. © 1994 Wiley-Liss, Inc.     

Effects of the antidepressant drug moclobemide on learning and memory in rats

Moclobemide is a well known drug with antidepressant action. The aim of this study was to investigate the effects of moclobemide on learning and memory processes in Sprague Dawley rats. Over a 5-day period, learning sessions with 30 trials per day and memory retention tests were performed. The conditioned responses (avoidances), the unconditioned responses (escapes) and the intertrial crossings were observed. An active avoidance test was carried out using a shuttle box. Two passive avoidance tests were used: step-through (using a light chamber) and step-down (using a platform). In the step-through passive avoidance test, the learning and retention sessions consisted of three trials each and the latency of reaction times (the rat remaining in the light chamber for more than 180 sec) was used as criterion. In the step-down passive avoidance test, learning and retention sessions consisted of two trials and the latency of reaction times (the rat remaining on the platform for 60 sec) was used as criterion. In the active avoidance tests, moclobemide dose-dependently increased the number of avoidances during learning sessions and maintained this number in memory retention tests. Moclobemide did not alter the number of escapes, but did increase motor activity. In the passive avoidance tests, moclobemide also increased the latency of reaction times in learning and short memory retrieval tests. These findings suggest that moclobemide improves learning and memory processes in active and passive avoidance tests and has a cognition-enhancing effect.     

DOPAMINERGIC PROJECTION TO THE CENTRAL AMYGDALA MEDIATES THE FACILITATORY EFFECT OF CCK-8US AND CAERULEIN ON MEMORY IN RATS

The involvement of dopaminergic projection to the central amygdala in the facilitatory effect of cholecystokinin unsulphated octapeptide (CCK-8US) and caerulein (CER) on memory motivated affectively was investigated in male rats. CCK-8US and CER were administered subcutaneously at the doses of 10 micrograms kg-1and 0.5 microgram kg-1, respectively, immediately after a single learning trial in a passive avoidance situation, after bilateral 6-OHDA lesions to the central amygdala. Bilateral 6-OHDA lesions to the central amygdala totally abolished the facilitatory effect of CCK-8US and CER on retention of passive avoidance behaviour evaluated 24 h after the learning trial. These results may indicate that the facilitatory effect of CCK-8US and CER on memory motivated affectively is mediated by dopaminergic projection from ventral tegmental area to the central amygdala.     

CR 2249: a New Putative Memory Enhancer. Behavioural Studies on Learning and Memory in Rats and Mice

The effects of S-4-amino-5-[4,4-dimethylcyclohexyl)amino]-5-oxopentanoic acid (CR 2249), a new entity selected from a new series of glutamic acid derivatives, has been investigated in different paradigms for screening nootropics. CR 2249 ameliorated the memory retention deficit produced by scopolamine in step-through-type passive avoidance in rats and by electroconvulsive shock in step-down-type passive avoidance in mice. CR 2249 was also capable of improving performance in behavioural tests of learning and memory in the absence of cholinergic hypofunction or cognitive deficit. The activity was determined using different passive and active avoidance behavioural test procedures on rats. CR 2249 was active only when given 45 min before training and did not show any effect when administered immediately after the learning training or before the retention trial. No changes in the general behaviour or motor activity of the animals were observed, indicating that CR 2249 effects cannot be attributed to sensory-motor deficit. Microdialysis experiments have shown that CR 2249 significantly increased noradrenaline release in the hippocampus of freely moving rats and reduced 3,4-dihydroxyphenylglycol efflux. These effects have led us to hypothesize that CR 2249 memory effect might be mediated by a direct or indirect action on noradrenergic transmission. These behavioural results suggest that this new agent has clinical application in memory disorders.     

Somatostatin and SMS 201-995 reverse the impairment of cognitive functions induced by cysteamine depletion of brain somatostatin

The involvement of somatostatin in the organization of cognitive functions was studied. We assessed changes in learning and memory processes by studying the effects of cysteamine, a compound that decreases somatostatin-like immunoreactivity in the brain, somatostatin and the potent somatostatin analogue, SMS 201-995, on active avoidance behaviour, assessed with a shuttle box apparatus, or on passive avoidance behaviour. Cysteamine induced a loss of the conditioned active avoidance response acquired after 3 weeks of daily trials. The effect was observed 2 h (-29%) and 4 h (-51%) after cysteamine treatment (300 mg/kg s.c.) and disappeared after 24 h. Intracerebroventricular administration of somatostatin or SMS 201-995 to cysteamine-treated rats significantly reversed the cysteamine effects on the conditioned avoidance responses. Similar results were obtained on passive avoidance behaviour. We also investigated the effect of cysteamine treatment on brain somatostatin-sensitive adenylate cyclase. We observed that adenylate cyclase activity in the frontal cortex of cysteamine-pretreated animals was more sensitive to inhibition by the SRIF analogue, SMS 201-995, than it was in control animals. This effect was observed at concentrations of SMS 201-995 that were ineffective in control tissue. These results show that disruption of somatostatinergic transmission affects cognitive functions of rats.     

Cholinergic modulation of memory in rats

Central cholinergic systems have long been implicated in the modulation of learning and memory processes in animals and man. Drugs that affect the central cholinergic system have been found either to enhance or to hinder performance in tests of learning and memory. Few studies have evaluated the effects of different cholinergic drugs within a single experimental paradigm and with a relatively wide dose range. The studies reported here investigated the effects of cholinergic drugs with diverse modes of action on the retention of a passive avoidance response. Physostigmine, arecoline, oxotremorine, nicotine, and 4-aminopyridine were administered IP immediately following the acquisition of a one-trial passive avoidance task. All of the drugs were found to enhance 72-h retention of passive avoidance; however, the effective doses were different for each of the drugs studied.