Blood alcohol level and caloric intake in the gravid rat as a function of diurnal period, trimester, and vehicle

Blood ethanol levels, caloric intake and weight gain were monitored over the 21-day gestational period in the gravid Sprague-Dawley rat as a function of the administration of ethanol in either a liquid diet (Ensure) or an aqueous saccharin solution. The mean daily percentage of ethanol consumed (38% vs 31%), and g/Kg of ethanol consumed (11.9 vs 9.7 g/Kg) were higher for the liquid diet group than the aqueous solution group. Ethanol consumption varied by the trimester in the Ensure but not in the saccharin solution rats. Proportional maternal weight gain, live litter size, and live litter weight did not vary as a function of the method of ethanol administration. Both groups exhibited significant diurnal periodicity in ethanol consumption, and the greatest caloric intake during the second trimester. The implications of these results for ethanol administration in gravid rats is discussed.     

石杉碱类似物异香兰石杉碱甲对胆碱酯酶的抑制作用和东莨菪碱导致的记忆障碍的影响(英文)

目的:研究石杉碱类似物异香兰石杉碱甲(IVHA)对胆碱酯酶的抑制作用和东莨菪碱导致的记忆障碍的影响.方法:乙酰胆碱酯酶和丁酰胆碱酯酶活力用Ellman比色法测定.抑制常数K_i值抑制机制用Lineweaver和Burk的双倒数作图法测定.行为测试用八臂迷宫装置.结果:IVHA的抗AChE作用稍弱于Hup-A.它对红细胞膜AChE的IC_(50)为0.11 μmol·L~(-1).作用强于Phys和Gal.属混合型抑制剂,K_i值为32 nmol·L~(-1).不同于异氟磷,与AChE为可逆性结合.ip给与IVHA0.2 mg·kg~(-1)翻转东莨菪碱导致的八臂迷宫记忆障碍.结论:IVHA是一个新的强效可逆胆减酯酶抑制剂,值得进一步研究.     

Grooming behavior induced by ACTH involves cerebral cholinergic neurons and muscarinic receptors

The grooming behavior induced by intracerebroventricular administration of ACTH was specifically antagonized by the muscarinic receptor antagonists, atropine and scopolamine. The antagonism occurred in a dose-dependent manner with an ED50 of 0.2 mg/kg (i.p.) for atropine, and 0.03 mg/kg (i.p.) for scopolamine. Neither methylscopolamine nor methylatropine, injected intraperitoneally affected grooming induced by ACTH (except for a small inhibition at the largest dose of methylscopolamine), but pronounced inhibition occurred when these drugs were administered intracerebroventricularly. The grooming induced by ACTH was also inhibited by prior intracerebroventricular administration of hemicholinium-3, a cholinergic antagonist that acts presynaptically by inhibiting the uptake of choline and hence, the synthesis of acetylcholine. These data suggest a role for cholinergic neurons and muscarinic receptors in the CNS in grooming behavior induced by ACTH.     

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.     

垂体后叶素对东莨菪碱致小鼠认知功能障碍的影响

目的 观察垂体后叶素对东莨菪碱致小鼠认知功能障碍的影响.方法 健康昆明种小鼠48只,随机分为4组：正常组（Con组）、东莨菪碱组（Sco组）、东莨菪碱＋垂体后叶素大剂量组（Sco＋Pit 30 U/kg组）、东莨菪碱＋垂体后叶素小剂量组（Sco＋Pit 3.0 U/kg组）,每组12只.腹腔注射东莨菪碱1 mg/kg制备认知功能障碍模型,用跳台和避暗实验观察垂体后叶素对东莨菪碱致小鼠认知功能障碍的影响.结果 与Con组相比,Sco组小鼠在跳台实验与避暗实验中的潜伏期均缩短,错误次数均增加（P〈0.05）;与Sco组相比,Sco＋Pit组小鼠在跳台实验与避暗实验中的潜伏期均延长,错误次数均减少（P〈0.05）.结论 垂体后叶素可减轻东莨菪碱致小鼠认知功能障碍.     

Acute effects of a low‐dose atropine/scopolamine mixture as a food contaminant in human volunteers

To verify the assumptions in our previous risk assessment of an atropine/scopolamine mixture in buckwheat flour, we performed a randomized, double‐blind, placebo‐controlled cross‐over study in 20 healthy, adult volunteers. The volunteers ingested a traditional Slovenian buckwheat meal, made of boiled buckwheat flour to which alkaloids were added. In addition to the placebo they ingested 0.12/0.10, 0.37/0.29, 1.22/0.95, 3.58/2.81 and 12.10/9.50 µg kg^–1 body mass (BM) of the atropine/scopolamine mixture. The changes in body temperature, heart rate, salivary and sweat secretion, pupil size, near‐point vision and subjective symptoms were recorded regularly for 4 h after the ingestion. Decreased salivary and sweat secretion, increased heart rate and pupil size and reduced near‐point vision accompanied by characteristic subjective symptoms were observed at 12.10/9.50 µg kg^–1 BM. At doses of 0.37/0.29 and 1.22/0.95 µg kg^–1 BM, a significant decrease in the heart rate was noted, which we consider to be a critical effect of a low‐dose exposure to the atropine/scopolamine mixture. Although this did not have any clinical relevance in our subjects, it may have serious implications if it occurred in people with pre‐existent cardiac conditions or those on medications that may cause bradycardia. No significant changes in the observed end points were noted at 0.12/0.10 µg kg^–1 BM. We estimate that the NOAEL (No Observed Adverse Effect Level) for the atropine/scopolamine mixture lies between the lower two administered doses. Applying the uncertainty factor of 10, we propose a new provisional Acute Reference Doses (ARfDs) of the mixture, i.e. 0.01 µg kg^–1 BM for each alkaloid, and a further refinement using higher‐tier approaches. Copyright © 2012 John Wiley & Sons, Ltd.     

Determination of anti‐convulsant and life‐preserving capacities of three types of auto‐injector therapies against soman intoxication in rats

More effective countermeasures against nerve‐agent poisoning are needed, because current ones do not protect sufficiently, particularly the central nervous system (CNS). The purpose of the present study was to make a comparison of the antidotal capabilities of atropine/obidoxime/diazepam (termed the obidoxime regimen), atropine/HI‐6 (1‐[([4‐(aminocarbonyl)pyridinio]methoxy)methyl]‐2‐[(hydroxyimino)methyl]pyridinium)/avizafone (termed the HI‐6 regimen), and scopolamine/HI‐6/physostigmine (termed the physostigmine regimen) against various doses of soman (2, 3, 4 x LD₅₀). The results showed that each regimen administered twice (1 min and 5 min after exposure) effectively prevented or terminated epileptiform activity within 10 min. However, the regimens differed markedly in life‐saving properties with the physostigmine regimen ranking highest followed in descending order by the HI‐6 and obidoxime regimens. Pretreatment with pyridostigmine increased the potency of the HI‐6 regimen, but not the obidoxime regimen. The latter regimen administered thrice (1 min, 5 min, and 9 min after exposure) did not compensate for the insufficiency. In half of the rats that lived for 7 days, neuropathology was unexpectedly observed predominantly in the left hemisphere unrelated to whether they seized or not. Local glutamatergic excitotoxic activity may occur even if manifest toxic signs are absent. The physostigmine regimen has excellent antidotal capacity, but the very narrow therapeutic window (< 10 min) makes it unsuitable for use in the field. The HI‐6 regimen appears to constitute an efficacious therapy against lower doses of soman (2 and 3 x LD₅₀). Copyright © 2012 John Wiley & Sons, Ltd.     

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.     

Scopolamine model of dementia: electroencephalogram findings and cognitive performance

Background

Memory and cognitive functions are known to decline with advancing age. Studies have suggested that this may be due to a decrease in cholinergic function in the brains of elderly people. This review aims to assess studies documented in the literature dealing with the ‘scopolamine model’ of dementia.

Methods

Sources included MedLine searches from the last 10 years (search for ‘scopolamine model’, ‘dementia’, ‘electroencephalogram’, ‘cognition’) and references from original and review articles. The aim was to include human and animal studies occupying the cholinergic hypothesis in cognitive dysfunction. Electroencephalographic (EEG) and cognition findings were considered.

Results

Scopolamine influences delta, theta, alpha and beta activity in EEG and partially mimics the EEG changes found in patients with senile dementia or dementia of the Alzheimer type. Effects on different cognitive functions have been extensively documented.

Conclusion

Scopolamine produces similar memory deficits seen in the elderly, but the drug cannot induce the full range of deficits seen in patients with Alzheimer's disease. Various aspects of memory were unaffected by scopolamine administration. Memory improvements in elderly subjects can be achieved after cholinergic stimulation.

     

鹿茸多肽对轻度认知功能障碍大鼠学习记忆能力的改善作用及其调节Keap1/Nrf2 /HO-1信号通路的机制

观察鹿茸多肽（VAP）对轻度认知功能障碍（MCI）模型大鼠学习和记忆能力及海马组织中KELCH状ECH相关蛋白1 （Keap1）/核因子E2相关因子2（Nrf2）/血红素氧合酶1（HO-1）信号通路相关蛋白表达的影响,并探讨其作用机制。