Dose-dependent effects of repeated ketamine administration on muscarinic acetylcholine receptors in the mouse forebrain

To study the effects of repeated ketamine administration (0: saline, 12.5, 25, and 50 mg·kg⁻¹ every 3 days for a total of five times, subcutaneously) on the central muscarinic acetylcholine receptors (mAchRs), receptor binding assays of mAchR were carried out in the forebrain of mice, using [³H]quinuclidinyl benzilate ([³H]QNB) as a ligand. We also examined whether repeated ketamine administration could modify the sensitivity to scopolamine (0.5 mg·kg⁻¹) (a muscarinic antagonist). Repeated ketamine administration produced a significant increase in the receptor density values (Bmax) for [³H]QNB (1520±51 fmol·mg protein⁻¹ for the control group, 1650±43 for the 12.5 mg·kg⁻¹ group, 1966±70 for the 25 mg·kg⁻¹ group and 2064±125 for the 50 mg·kg⁻¹ group) (P<0.05, when the 25 mg·kg⁻¹ and 50 mg·kg⁻¹ groups were compared to the control group) without any change in apparent affinity. Repeated ketamine reduced scopolamine-induced hyperlocomotion at 50 mg·kg⁻¹ (P<0.05). We conclude that repeated ketamine administration produces up-regulation of mAchRs, which is probably associated with the altered Ach transmission of the central nervous system.     

东莨菪碱对大鼠离体室旁核神经元单位放电的影响

目的 为对东莨菪碱抗休克的机制作进一步分析，观察其对大鼠离体下丘脑室旁核神经元活动的影响。方法与结果 在２５个大鼠下丘脑薄片上，用玻璃微电极记录了５５个室旁核神经元自发放电。其放电活动可分非周期型和周期型两类。当灌流含东莨菪碱（１０＾－７ｍｏｌ／Ｌ，３ｍｉｎ）的人工脑脊液后，在３２个非周期型放电单位中呈现增频反应的有５个（１５．６％），减频反应的１２个（３７．５％），１５个无反应（４６．９％）；７     

The effects of d-cycloserine, a partial agonist at the glycine binding site, on spatial learning and working memory in scopolamine-treated rats

Summary The present study investigated the effect of d-cycloserine, a partial agonist at the glycine binding site on NMDA receptor complex, on the performance of scopolamine-treated adult rats in a water maze task assessing spatial learning and in a delayed non-matching to position task assessing working memory in a spatial context. In the spatial learning task, scopolamine (0.4 mg/kg, i.p.) impaired acquisition (increased escape latency and distance) and increased swimming speed of rats. D-cycloserine (1.0 mg/kg, i.p.) reversed the deficits in acquisition performance but not the increases in behavioral activity. In the working memory task, scopolamine (0.2 mg/kg, i.p.) produced deficits on nonmnemonic rather than on mnemonic performance factors; scopolamine delay-independently decreased the percent correct responses and reduced behavioral activity of rats. D-cycloserine (1.0, 3.0 and 10 mg/kg, i.p.) did not reverse these performance deficits. When administered alone, the moderate to higher doses of d-cycloserine had no effects on working memory but the lower dose produced slight deficits in mnemonic performance factors; the 1.0 mg/kg dose delay-dependently decreased the percent correct responses without affecting behavioral activity of rats. In the water maze task, d-cycloserine had no effects on acquisition performance or behavioral activity of rats. These results suggest that acute, systemic administration of d-cycloserine does not improve spatial learning or working memory. However, at appropriate doses this agent may be efficacious in disease states of central cholinergic hypofunction since 1.0 mg/kg d-cycloserine was able to reverse the scopolamine-induced deficits in acquisition.     

Role of cholinergic inputs to the medial preoptic area in regulation of sleep–wakefulness and body temperature in freely moving rats

The medial preoptico-anterior hypothalamic area receives adrenergic as well as cholinergic inputs. Independent studies showed that both these inputs influence sleep, wakefulness and body temperature. The role of the adrenergic inputs was studied earlier. The role of cholinergic inputs is reported here. The cholinergic agonist, carbachol, and antagonist, scopolamine, were injected into this area during the day and the night in freely moving rats and the effects on sleep–wakefulness and body temperature studied. It was observed that carbachol induced wakefulness accompanied by a fall in body temperature while scopolamine induced an opposite effect, i.e. sleep accompanied by an increase in body temperature. This suggested that the cholinergic input into the medial preoptic area is spontaneously active in regulating sleep–wakefulness and body temperature and this regulation is mediated through muscarinic receptors present in this area. The results also suggest that, contrary to the action of adrenergic inputs (which have a dissociated effect on sleep–wakefulness and body temperature), the cholinergic input is unlikely to have a dissociated effect on those functions. © 1997 Elsevier Science B.V. All rights reserved.     

The importance of the autonomic nervous system in health and disease*

Baroreceptor control of the circulation is now generally thought to be concerned only with short term buffering of changes in arterial pressure, rather than with long term setting of pressure levels. This paper reviews evidence to the contrary, which suggests that impairment of the baroreflex, either by local changes in the carotid sinus or by environmental or genetic influences working through cortical modulation of the reflex gain, may have an important influence on long term arterial pressure. Further interest in the baroreflex has been revived by the demonstration in several large studies that autonomic control, measured either by baroreflex sensitivity (BRS) or heart rate variability (HRV), is a powerful independent prognostic factor, which adds to other clinical measures of risk stratification in patients with left ventricular damage, or who have survived a myocardial infarction. The inter-relationships are complex, poorly understood, and subject to many confounding factors. Nevertheless, BRS and HRV are promising techniques. Further understanding holds out the hope of new therapeutic approaches to these patients.     

山莨菪碱治疗麻醉剂依赖性

阿片成瘾者２５０例（男性２２２例，女性２８例，年龄３０±ｓ５ａ）应用山莨菪碱０．５－２ｍｇ／（ｋｇ·ｄ），分２－３次加入１０％葡萄糖２５０ｍＬ或５％葡萄糖生理盐水５００ｍＬ静脉滴注；东莨菪碱０．０２－０．０３ｍｇ／ｋｇ加入１０％葡萄糖２５０ｍＬ静脉滴注１次，必要时对重患者追加１次，疗程５－７ｄ。结果戒断症状均有改善（Ｐ＜０．０１），２７例需加用羟丁酸钠。不良反应轻，可作为阿片瘾者的脱瘾药物。＊Ｐ＜０．０１。碱确能解除阿片药物戒断症状。其对阿片戒断症状缓解时间在治疗４－５ｄ后，强烈觅药渴求也随之逐渐消失。１５０例（６０％）要求进食，１７５例（７０％）仍需借助安眠药睡眠。另６５例（２６％）戒断症状阵发性发作，每次持续０．５－１ｈ，症状轻重不一，轻者流泪、全身弥漫性疼痛，重者焦躁不安、心中猫抓虫咬样难受，甚至想自残，可配合艾司唑仑３－４ｍｇ／ｄ，ｐｏ或氯硝西泮６－１０ｍｇ／ｄ，ｐｏ；也可用氯硝西泮１－２ｍｇ／次，ｉｍ，每日２－３次；针刺胃俞、脾俞、中脘、足三里、印堂、太阳、百会、内关、合谷、命门、夹脊和肾俞穴位，根据临床症状任选其中３－５个穴位进行治疗或心理治疗能快速减轻患者戒断症状。治程中２７例（１０．８％）重?     

党参总碱对东莨菪碱引起小鼠记忆障碍和脑内乙酰胆碱及胆碱乙酰化酶的作用

用跳台法观察到党参总碱(DSA)能改善东莨菪碱(Scop)引起的记忆障碍,并能对抗Scop所致小鼠脑内乙酰胆碱(ACh)浓度下降及胆碱乙酰化酶(ChAT)活性的降低。体外实验发现当在反应液中加入DSA后,ChAT生成ACh的量增加。     

Effects of low-dose transdermal scopolamine on autonomic cardiovascular control in healthy young subjects

We studied how posture influences the effects of transdermal scopolamine on autonomic cardiovascular regulation in a randomized, double-blind, placebo-controlled crossover study of 10 healthy young volunteers. We recorded the electrocardiogram and auscultatory sphygmomanometric and continuous non-invasive finger arterial pressure (Finapres device) to obtain signals for the beat-by-beat R–R interval and systolic, mean and diastolic pressures. R–R interval and arterial pressure variabilities were characterized by power spectral analysis. Scopolamine increased the mean R–R intervals and reduced arterial pressure in both the supine and the standing positions, but did not affect blood pressure variability. Scopolamine increased the total variability of R–R interval and its mid- (0·07–0·15 Hz) and high- (0·15–0·40 Hz) frequency band power in the standing position during controlled breathing at 0·25 Hz. In the supine position, scopolamine did not affect R–R interval variability. In the deep breathing test, scopolamine increased the maximal expiratory–inspiratory R–R interval ratio. This study showed that low-dose scopolamine increases vagal cardiac inhibition in both supine and standing positions in healthy volunteers. However, scopolamine increases heart rate variability only in the standing position during partial vagal withdrawal. The study also demonstrates that transdermal scopolamine decreases blood pressure in healthy young subjects.     

Cholinergic and dopaminergic agents which inhibit a passive avoidance response attenuate the paradigm-specific increases in NCAM sialylation state

Summary The influence of cholinergic and dopaminergic agents on the acquisition of a passive avoidance response in the rat is demonstrated. Trifluoperazine (0.12 mg/kg), a dopamine antagonist, inhibited task acquisition when present during training or later, during consolidation, at the 10–12 h posttraining period and at no other intervening time point. Induction of amnesia was dose-dependent and was not apparent when the dose exceeded 0.12 mg/ kg. This effect appears to be due to an increase in dopamine release through presynaptic receptor antagonism as similar results could be obtained by the administration of apomorphine (0.5 mg/kg), a dopamine agonist, and this effect could be antagonized by the D 1 receptor selective antagonist SCH-23390. Scopolamine (0.15 mg/kg), a muscarinic antagonist, impaired acquisition of the passive avoidance response when administered during training and, separately, at the 6 h post-training period. This could not be attributed to presynaptic antagonism as oxotremorine (0.2 mg/kg), a muscarinic agonist, had no amnesic action. Administration of apomorphine or scopolamine during training and at the appropriate post-training period prevented subsequent paradigm-specific increases of neural cell adhesion molecule sialylation state in hippocampal immunoprecipitates obtained at 24 h after task acquisition and 4 h following intraventricular infusion of the labelled sialic acid precursor — N-acetyl-D-mannosamine. Oxotremorine alone did not influence neural cell adhesion molecule sialylation state. These observations provide further evidence of a regulatory role for neural cell adhesion molecule sialylation state in information storage processes.Abbreviations NCAM neural cell adhesion molecule - RSA relative specific activity - SDS-PAGE sodium dodecyl sulphate polyacrylamide gel electrophoresis - TCA trichloroacetic acid - TFP trifluoperazine     

Pharmacological evidence of cholinergic involvement in adult hippocampal neurogenesis in rats

In adult hippocampus, neural progenitor cells give rise to neurons throughout life, and the neurogenesis is modulated by various intrinsic and extrinsic factors. Recent reports showed that lesion of septal cholinergic nuclei projecting to hippocampus suppressed the survival of newborn cells in the dentate gyrus (DG) of hippocampus. Here, we studied whether pharmacological treatment to activate or inhibit the cholinergic system could modulate adult hippocampal neurogenesis. 5'-Bromo-2'-deoxyuridine (BrdU) was injected to label dividing cells before the drug treatment. Immunohistochemical analysis was performed in normal rats chronically treated with an acetylcholinesterase inhibitor donepezil or a muscarinic acetylcholine receptor blocker scopolamine for four weeks. Donepezil increased, but scopolamine decreased, the number of BrdU-positive cells in the DG as compared with the control. Neither drug altered the percentage of BrdU-positive cells that were also positive for a neuronal marker neuronal nuclei, nor net population of proliferative cells labeled with proliferating cell nuclear antigen. We also found that donepezil enhanced, and scopolamine suppressed, the expression level of phosphorylated cAMP response element binding protein (CREB), which is related to cell survival, in the DG. These results indicate that donepezil enhances and scopolamine suppresses the survival of newborn cells in the DG via CREB signaling without affecting neural progenitor cell proliferation and the neuronal differentiation. This is the first evidence that pharmacological manipulation of the cholinergic system can modulate adult hippocampal neurogenesis.