Long-term oestradiol treatment enhances hippocampal synaptic plasticity that is dependent on muscarinic acetylcholine receptors in ovariectomised female rats

Short-term oestradiol treatment modulates hippocampus-dependent memory and synaptic plasticity in the hippocampus. Long-term oestradiol treatment can also enhance hippocampus- dependent memory, although the effects of long-term oestradiol treatment on synaptic plasticity are unknown. We investigated the effects of long-term oestradiol treatment on synaptic plasticity at the Schaeffer Collateral/CA1 synapse in 8-month-old female rats. In addition, we determined the role of endogenous activation of muscarinic acetylcholine receptors (mAChRs) in synaptic transmission and plasticity using scopolamine (1 μm), an antagonist of mAChRs. Hippocampus slices from ovariectomised rats that were treated with oestradiol-containing capsules for 5 months were compared with slices from ovariectomised rats that received cholesterol-containing capsules. Unexpectedly, scopolamine application significantly increased the baseline field excitatory postsynaptic potentials (fEPSP) and decreased paired pulse facilitation (PPF) in slices from cholesterol-treated rats. Baseline fEPSPs and PPF were not significantly modulated in slices from oestradiol-treated rats by scopolamine. Slices from oestradiol-treated rats showed enhanced long-term potentiation relative to slices from cholesterol-treated rats. Scopolamine significantly reduced the magnitude of plasticity in slices from oestradiol-treated rats. Taken together, these results suggest that mAChRs have a significant effect on baseline synaptic transmission through a decrease in the probability of glutamate release in slices from cholesterol-treated rats. Long-term oestradiol treatment blocks this effect and enhances theta-burst stimulation-induced synaptic plasticity in the middle-aged female rat, and this effect is mediated by activation of mAChRs.     

Neuroprotection of N-benzylcinnamide on scopolamine-induced cholinergic dysfunction in human SH-SY5Y neuroblastoma cells

Alzheimer's disease, a progressive neurodegenerative disease, affects learning and memory resulting from cholinergic dysfunction. Scopolamine has been employed to induce Alzheimer's disease-like pathology in vivo and in vitro through alteration of cholinergic system. N-benzylcinnamide(PT-3), purified from Piper submultinerve, has been shown to exhibit neuroprotective properties against amyloid-β-induced neuronal toxicity in rat cortical primary cell culture and to improve spatial learning and memory of aged rats through alleviating oxidative stress. We proposed a hypothesis that PT3 has a neuroprotective effect against scopolamine-induced cholinergic dysfunction. PT-3(125–200 n M) pretreatment was performed in human neuroblastoma SH-SY5 Y cell line following scopolamine induction. PT-3(125–200 n M) inhibited scopolamine(2 m M)-induced generation of reactive oxygen species, cellular apoptosis, upregulation of acetylcholinesterase activity, downregulation of choline acetyltransferase level, and activation of p38 and JNK signalling pathways. These findings revealed the underlying mechanisms of scopolamine-induced Alzheimer's disease-like cellular dysfunctions, which provide evidence for developing drugs for the treatment of this debilitating disease.     

东莨菪碱和毒扁豆碱对吗啡处理大鼠Morris水迷宫空间学习能力的影响

目的:研究吗啡及胆碱能系统的药物对大鼠空间学习能力的影响 方法:应用Morris水迷宫学习程序研究吗啡处理大鼠的空间学习能力及其在东莨菪碱和毒扁豆碱作用下的变化.结果:高剂量吗啡(10mg/kg)和低剂量吗啡(3mg/kg)对大鼠学习能力的影响差异有显著性;东莨菪碱(3mg/kg)和吗啡(10mg/kg)联合给药,可以使吗啡时学习能力的损害进一步加重;毒扁豆碱(0.1mg/kg)可以改善吗啡所致的学习能力损害,但不能完全逆转.结论:吗啡损害大鼠空间学习能力,已存在量-效关系;胆碱能系统与吗啡处理大鼠空间学习能力关系密切,有可能影响成瘾的发生及治疗.     

Blockade of Prefronto-cortical α1-Adrenergic Receptors Prevents Locomotor Hyperactivity Induced by Subcortical D-Amphetamine Injection

The stimulation of cortical dopaminergic D1 receptors can counteract the increased locomotor activity evoked by D-amphetamine application in the nucleus accumbens (Vezina et al., Eur. J. Neurosci., 3 , 1001–1007, 1991). Moreover, an α1 antagonist, prazosin, prevents the locomotor hyperactivity induced by electrolytic lesions of the ventral tegmental area (Trovero et al., Neuroscience, 47 , 69–76, 1992). Attempts were thus made to see whether blockade of α1-adrenergic receptors in the rat prefrontal cortex could reduce nucleus accumbens D-amphetamine-evoked locomotor activity. Rats implanted chronically and bilaterally with cannulae into the medial prefrontal cortex and the nucleus accumbens were used for this purpose and locomotor activity was monitored in circular corridors. Preliminary experiments indicated that intraperitoneal injection of prazosin (0.06 mg/kg) reduces the locomotor hyperactivity induced by the peripheral administration of D-amphetamine (0.75 mg/kg). This effect of prazosin was not observed when locomotor hyperactivity was obtained by an intraperitoneal injection of scopolamine (0.8 mg/kg). Bilateral nucleus accumbens injections of D-amphetamine (4.0 nmol/side) markedly increased locomotor activity, as estimated in a 30 min period. Prior (20 min) bilateral injections of either prazosin or WB-4101 (0.16 pmol) into the medial prefrontal cortex abolished the nucleus accumbens D-amphetamine-evoked response. The recovery of the nucleus accumbens D-amphetamine-evoked response was closely dependent on the amount of prazosin used, very prolonged inhibitory effects of the drug being seen with a high amount (>4 days with 160 pmol). In contrast, whatever the amount of WB-4101 used (0.16–160 pmol), recovery occurred within 3 days. It is suggested that the blockade of cortical d-adrenergic receptors facilitates locally dopaminergic D1 transmission. This latter effect may counteract the increased locomotor activity induced by the application of D-amphetamine into the nucleus accumbens.     

Age-dependent effects of scopolamine on avoidance,locomotor activity,and rearing

In Experiment 1, 15-, 17-, 21-, 36- and 90-day-old rats were injected with either physiological saline or 0.5, 1.0, 4.0, 8.0, 16.0 or 32.0 mg/kg of scopolamine (an anticholinergic). Immediately after the injection, shuttle crossings during adaptation were recorded for 8 min, and then the rats were given a single session of 100 two-way avoidance trials. In all ages, scopolamine increased two-way avoidance and intertrial responses throughout training and avoidance and intertrial responses were positively correlated, suggesting that increased avoidance was due, in part, to increased locomotor activity. In addition, scopolamine increased locomotor activity at an earlier age in a stressful situation, i.e. during the intertrial interval, than in a less stressful environment, i.e. during adaptation. In Experiment 2, photocell crossings and rearing were examined in 15-, 17-, 21-, 36-, 90- and 275-day-old rats injected with saline or 0.5, 1.0, 4.0, 8.0 or 16.0 mg/kg of scopolamine hydrobromide. Scopolamine increased photocell crossings in rats 21 days of age and older but did not increase rearing until 36 days of age. Scopolamine also had different behavioral effects in the three oldest ages. Thus, cholinergic involvement in these behaviors changes from at least 15 to 275 days of age. Methylscopolamine, which does not cross the blood-brain barrier, did not alter the behaviors examined in Experiments 1 and 2, suggesting that development of cholinergic neurons in the CNS is responsible for the agedependent behavioral effects of scopolamine.     

Central cholinergic interactions in somato-vegetative reflexes

In cats lightly anaesthetized with urethane (600 mg/kg, i.p.), electrical stimulation of the sciatic nerve elicited frequency-dependent pressor reflexes and contractions of the nictitating membrane. Administration of oxotremorine (0.2 mg/kg, i.v.) or physostigmine (0.5 mg/kg, i.p.) resulted in depression of the pressor reflexes. At the same time, physostigmine enhanced the reflex contractions of the nictitating membrane, while oxotremorine induced sustained contraction of the latter. All these effects were antagonized by the tertiary amine scopolamine, but not by the quaternary atropine methylbromi.The results point to a role of central cholinergic mechanisms in the integration of somato-vegetative reflexes, and give evidence that the sympathetic driving of different effectors is not uniformly organized by the central nervous system.     

Scopolamine does not restore normal conditioned avoidance performance in raclopride-treated rats

Summary. Several studies have shown antagonism by anticholinergics of antipsychotic-induced suppression of conditioned avoidance behavior, as well as of catalepsy, in rats. These observations provide pharmacological evidence for these behaviors mediated via nigro-striatal dopaminergic projections, as well as known dopaminergic-cholinergic interactions in the neostriatum. The objective of the present study was to examine the quality of behavioral change produced by scopolamine (0.25–1.00 mg kg⁻¹ s.c.) on conditioned avoidance behavior, by itself, and in combination with raclopride (0.1 mg kg⁻¹ s.c.) in the rat. Adult male Wistar rats were trained to perform a conditioned avoidance response requiring a brightness discrimination. A two-way avoidance shuttle-box was used with the modification that there were two passages in the partition separating the two compartments of the shuttle-box. In order to make a correct avoidance in the response to white noise conditioned stimulus, the rat had to take background light into consideration. Correct passage under dim background conditions was to the left and, with increased background lights, to the right. A weak, intermittent, electric shock (≈0.2 mA) was used as unconditioned stimulus. Scopolamine by itself (0.25–1.00 mg kg⁻¹ s.c.) disrupted the visual discrimination without affecting avoidance performance. As expected, raclopride (0.1 mg kg⁻¹ s.c.) produced a suppression of conditioned avoidance behavior. A dose of 1.00 mg kg⁻¹ of scopolamine was needed to restore raclopride-induced suppression of conditioned avoidance behavior. Thus, restoration of the avoidance behavior by scopolamine treatment was not possible at doses that allow normal performance of the visual discrimination. It is concluded that anticholinergics do not restore normal behavior after neuroleptic-induced suppression of conditioned avoidance behavior. Received July 21, 2000; accepted November 20, 2000     

Steroid structure and pharmacological properties determine the anti-amnesic effects of pregnenolone sulphate in the passive avoidance task in rats

Pregnenolone sulphate (PREGS) has generated interest as one of the most potent memory-enhancing neurosteroids to be examined in rodent learning studies, with particular importance in the ageing process. The mechanism by which this endogenous steroid enhances memory formation is hypothesized to involve actions on glutamatergic and GABAergic systems. This hypothesis stems from findings that PREGS is a potent positive modulator of N-methyl-d-aspartate receptors (NMDARs) and a negative modulator of gamma-aminobutyric acid(A) receptors (GABA(A)Rs). Moreover, PREGS is able to reverse the amnesic-like effects of NMDAR and GABA(A)R ligands. To investigate this hypothesis, the present study in rats examined the memory-altering abilities of structural analogs of PREGS, which differ in their modulation of NMDAR and/or GABA(A)R function. The analogs tested were: 11-ketopregnenolone sulphate (an agent that is inactive at GABA(A)Rs and NMDARs), epipregnanolone ([3beta-hydroxy-5beta-pregnan-20-one] sulphate, an inhibitor of both GABA(A)Rs and NMDARs), and a newly synthesized (-) PREGS enantiomer (which is identical to PREGS in effects on GABA(A)Rs and NMDARs). The memory-enhancing effects of PREGS and its analogs were tested in the passive avoidance task using the model of scopolamine-induced amnesia. Both PREGS and its (-) enantiomer blocked the effects of scopolamine. The results show that, unlike PREGS, 11-ketopregnenolone sulphate and epipregnanolone sulphate failed to block the effect of scopolamine, suggesting that altering the modulation of NMDA receptors diminishes the memory-enhancing effects of PREGS. Moreover, enantioselectivity was demonstrated by the ability of natural PREGS to be an order of magnitude more effective than its synthetic enantiomer in reversing scopolamine-induced amnesia. These results identify a novel neuropharmacological site for the modulation of memory processes by neuroactive steroids.     

麻醉前应用长托宁与东莨菪碱对心率与血压的影响

目的:了解盐酸戊乙奎醚和东莨菪碱能否造成对心率和血压的改变及程度.方法:10～79岁手术病人80例,随机分为盐酸戊乙奎醚组和东莨菪碱组各40例.进手术室后肌注盐酸戊乙奎醚(0.3～0.8mg)或东莨菪碱(0.2～0.3mg).记录入室即刻、注射后15和30min三个时点的心率和血压,并以基础值为参考.结果:肌注盐酸戊乙奎醚患者的心率和血压有轻度变化,但无显著性差异(P>0.05);东莨菪碱组患者心率明显增加,有显著性差异(P<0.05).结论:盐酸戊乙奎醚不增加心率.除心动过缓和心脏束支传导阻滞的病人外,可安全用于麻醉前给药.     

101果汁澄清剂在中药液澄清中的应用

对含生药量不同的中药复方煎液（简称原液），加入101果汁澄清剂不同比例及加与不加滑石粉对所处理的药液在沉淀和过滤速度、溶液颜色及溶液稳定性等方面进行比较实验。结果证明原液含生药量1：1．5－2．0（V：W）为宜．原液中加5％101果汁澄清剂量以8％为佳，加入量少．沉淀和过滤速度慢．颜色深；加101果汁澄清剂量后再加入0．5％滑石粉，可加快絮状物凝聚成大颗粒沉淀而迅速沉降、并起助滤作用，经此法处理的溶液稳定性好。