人疱疹病毒增强谷氨酸神经毒性作用

人疱疹病毒(HVH,0.2 ml/mouse ip)加重谷氨酸单钠(MSG,2.5 g·kg~(-1)sc)对下丘脑弓状核的损毁,同时,下丘脑和脊髓的线粒体膜结合钙明显降低。Fura-2单细胞检测表明,MSG既可引起胞外Ca_(2 )内流,又可促进胞内钙库释放Ca~(2 ),使胞内Ca~(2 )超载,最终导致细胞死亡。结果提示,MSG可引起胞内Ca~(2 )超载而破坏神经元排空或封存Ca~(2 )的能力,从而损伤细胞。而HVH可增强上述损伤效应。     

β-内啡肽对谷氨酸神经毒性作用的影响

采用形态学观察、β-内啡肽(β-End)放射免疫测定及单细胞内游离钙浓度——[Ca²⁺]i检测等方法,观察了β-End对谷氨酸单钠(MSG)诱发神经元损伤的影响,分析了可能的作用机制。结果表明,β-End可以明显加重MSG诱发的下丘脑弓状核神经元的损伤;β-End和MSG诱发的[Ca²⁺]i增高可被维拉帕米部分逆转。另外,吗啡可以进一步加剧MSG诱导的各脑区β-End含量的变化。提示β-End可以明显地加剧MSG的神经毒性作用,其机制与MSG能诱发脑内β-End的含量的增多及β-End可进一步破坏MSG引起的胞内钙稳态失衡有关。     

青风藤对吗啡成瘾小鼠学习与记忆能力的影响

目的：研究青风藤对吗啡成瘾小鼠学习与记忆能力的影响及可能机制。方法：通过Y-迷宫观察青风藤对吗啡成瘾小鼠学习与记忆能力的影响,观察海马形态研究青风藤对海马CA1区神经元的影响。结果：青风藤治疗组与吗啡戒断组小鼠的分辨学习及记忆保持能力有显著差异．小鼠海马CA1区神经元细胞数差异显著。结论：青风藤对吗啡戒断小鼠的分辨学习及记忆保持能力有极大提高．对吗啡戒断致小鼠海马CA1区神经元的损伤有一定的治疗作用。     

成瘾物质引起腹侧被盖区多巴胺神经元及其投射脑区伏隔核多巴胺神经递质的实时动力学变化

目的 阐明不同成瘾性物质(甲基苯丙胺、可卡因和吗啡)引起的腹侧被盖区多巴胺神经元及其投射脑区伏隔核内多巴胺递质的实时动力学变化。方法 将携带多巴胺神经递质荧光探针和携带酪氨酸羟化酶钙启动子钙指示剂蛋白病毒分别注射在小鼠伏隔核和腹侧被盖区，每个脑区各28只。小鼠分为生理盐水组、甲基苯丙胺(1 mg·kg^-1,ip)组、可卡因(10 mg·kg^-1,ip)组和吗啡(10 mg·kg^-1,sc)组，给药后，立即采用光纤记录系统监测2 h内多巴胺神经递质和多巴胺能神经元的实时动力学变化，包括多巴胺神经递质荧光变化曲线下面积(AUC)，曲线极值及达极值的潜伏时间，多巴胺能神经元钙离子信号变化AUC，曲线最高值或最低值及达极值的潜伏时间和作用持续时间。结果 ip给予甲基苯丙胺(1 mg·kg^-1)和可卡因(10 mg·kg^-1)均会引起多巴胺能神经元的Ca²⁺信号快速而持续地下降，而sc给予吗啡(10 mg·kg^-1)引起多巴胺能神经元的Ca     

褪黑素抗吗啡戒断反应及其对中脑导水管周围灰质β-内啡肽的影响

目的:观察褪黑素(MEL)抗小鼠吗啡依赖戒断反应与其对脑内中脑导水管周围灰质(PAG)中β-内啡肽(β-EP)影响之间的关系,以探讨MEL抗戒断反应的中枢机制。方法:采用剂量递增法连续皮下注射(sc)吗啡建立小鼠吗啡依赖模型,sc纳洛酮催促戒断,以小鼠体重下降和戒断跳跃次数为指标观察MEL抗小鼠吗啡依赖戒断反应的效应;采用放射免疫分析法,检测小鼠中脑导水管周围灰质β-EP含量。结果:(1)连续8d腹腔注射(ip)10,20,40mg.kg-1的MEL能剂量依赖性地抑制吗啡依赖小鼠的戒断症状;(2)吗啡依赖组小鼠脑内PAG中β-EP含量明显低于生理盐水对照组;(3)连续8dip20mg.kg-1MEL的小鼠,其PAG中β-EP含量明显高于吗啡依赖组小鼠。结论:MEL可减弱小鼠吗啡依赖戒断反应,这种效应可能与其增加脑内PAG中β-EP的含量有关。     

可乐定镇痛与中枢Ca~(2+)的关系

用大鼠甩尾法和放射配基结合实验,探讨了可乐定镇痛与中枢Ca~(2+)的关系。CaCl_2(1μmol/rat,icv)和EGTA(0.2μmol/rat,icv)分别拮抗和增强可乐定(1mg/kg,sc)的镇痛。戊脉安(0.1μmol/rat,icy)对可乐定(1 mg/kg,sc)镇痛无明显影响,但可部分翻转CaCl_2对可乐定镇痛的拮抗。CaCl_2(1×10~(-3)mol)对[~3H]-可乐定结合无明显抑制。结果表明可乐定镇痛与脑室周围组织中Ca~(2+)浓度变化密切相关,Ca~(2+)至少部分需经对戊脉安敏感的钙通道进入细胞内方可拮抗可乐定镇痛。推沦:可乐定镇痛与神经元内Ca~(2+)有关。     

加味参附汤戒毒治疗作用的实验研究

目的观察中药复方制剂加味参附汤 (MSFD)的戒毒治疗作用并探讨其机理。方法连续剂量递增腹腔注射吗啡造成吗啡依赖小鼠及大鼠模型 ,灌胃给予不同剂量MSFD后观察上述模型动物在戒断后第 2d、第 6d由纳洛酮引起的催促戒断反应 ,测定吗啡依赖小鼠在戒断后第 6d的免疫功能指标及吗啡依赖大鼠在戒断后第 2d、第 6d下丘脑内NA、5 HT、DA的含量、戒断后第 6d下丘脑内 β 内啡肽 ( β End)、亮氨酸脑啡肽 (Leu Enk)和强啡肽 (Dyn)的含量及下丘脑弓状核中阿黑皮素原 (POMC)mRNA的表达情况。结果MSFD能明显抑制吗啡依赖小鼠及大鼠戒断后第 2d、第 6d的催促戒断反应 ,MSFD联合丁丙诺啡治疗疗效增强。戒断后第 6d ,吗啡依赖小鼠出现脾脏和胸腺萎缩 ,巨噬细胞功能、外周血T淋巴细胞总数及对PHA的增殖反应、脾T淋巴细胞CD+ 4百分率及CD+ 4/CD+ 8比值下降 ,MSFD能不同程度地减轻上述改变 ,丁丙诺啡治疗作用不显著。吗啡依赖大鼠戒断后第 2d、第 6d下丘脑内NA、5 HT含量增多 ,DA含量减少 ,戒断后第 6d下丘脑内β End、Leu Enk含量及弓状核内POMCmRNA表达减少 ,下丘脑内Dyn含量增多 ;MSFD能促进上述改变趋向正常 ,但对Dyn含量无显著影响 ;MSFD联合丁丙诺啡治疗 ,能减少丁丙诺啡对单胺类神经递质及内阿片肽的影响 ,加速?     

吗啡增强谷氨酸单钠神经毒性及其作用机制

用皮层神经细胞体外培养、形态学观察、单个神经细胞内游离钙检测及乳酸脱氢酶(LDH)测定等方法,观察了吗啡对谷氨酸单钠(MSG)神经毒性增强作用以及纳洛酮对吗啡作用的逆转,分析了其可能的作用机制。结果表明:吗啡能显著增强的MSG的细胞毒作用.纳络酮可逆转这种增强作用,细胞内Ca²⁺超载可能是兴奋性神经毒素引起神经元死亡的共同病理学机制。     

中缝背核参与大鼠吗啡依赖和戒断的形成机制研究

目的观察大鼠脑内神经核団中缝背核(DRN)在一氧化氮(NO)介导的吗啡依赖和戒断形成的作用机制。方法雄性成年SD大鼠随机分为5组:戒断组(腹腔注射吗啡+纳洛酮);依赖组(注射吗啡+生理盐水);生理盐水组(注射生理盐水);纳洛酮组(注射生理盐水+纳洛酮);抑制剂组(注射吗啡加NOS抑制剂+纳洛酮)。戒断组和依赖组,用剂量递增法经腹腔注射吗啡10～100mg.kg-1,每天3次,连续5天,建立吗啡依赖与戒断模型,并进行行为学观测与评分后,用神经元型一氧化氮合酶(nNOS)免疫组织化学标记,计数各组动物相同层面脑片上nNOS标记细胞的表达情况。结果戒断组,戒断症状及总评分较对照组和依赖组均差异显著(P<0.01);NOS抑制剂组,戒断症状评分较戒断组明显降低(P<0.05)。于中缝背核相应区域计数到部分nNOS标记神经元,生理盐水组及纳洛酮组比较无显著性差异;而依赖组与戒断组,其神经元计数明显增加(P<0.05);而NOS抑制剂组,神经元数量较戒断组明显减少(P<0.05)。结论脑内中缝背核可能通过一氧化氮信号通路参与了大鼠吗啡依赖与戒断的形成。     

吗啡依赖对小鼠海马内一氧化氮合酶阳性神经元的影响

目的·· :探讨吗啡依赖对小鼠海马不同亚区一氧化氮合酶(NOS)活性的影响。方法·· :以剂量递增法皮下注射吗啡建立吗啡依赖小鼠模型 ,采用还原型辅酶Ⅱ -黄递酶(NADPH -d)组织化学法显示吗啡依赖组、纳洛酮催促戒断组和正常对照组小鼠海马CA1区、CA3区和齿状回NOS阳性神经元。结果·· :与对照组相比 ,吗啡依赖组和纳洛酮催促戒断组海马CA1区和齿状回NOS阳性神经元的数目均明显减少 (P<0.01) ,纳洛酮催促戒断组更为明显 ,而在CA3区无明显改变。结论·· :吗啡依赖和纳洛酮催促戒断小鼠海马CA1区和齿状回NOS活性降低 ,提示NO合成的能力下降 ,戒断期下降更明显。这些变化可能是吗啡依赖造成学习记忆功能下降的原因之一。     

Glutamate and aspartate impair memory retention and damage hypothalamic neurons in adult mice

We examined the effects of systemic administration of monosodium glutamate (MSG) or aspartate (ASP) on the memory retention and neuronal damage in the brains of adult mice. Compared with the control mice, a single intraperitoneal injection of either 4.0 mg/g MSG or 0.5 mg/g ASP after acquisition trial significantly shortened the response latency in the passive avoidance test, accompanying by the transient weight loss. Histopathological analysis of the brains of these mice revealed that neurons in the arcuate nucleus of hypothalamus were damaged markedly by MSG (4.0 mg/g) or ASP (0.5 mg/g). Other brain areas including cerebral cortex and hippocampus did not show any pathological changes. These findings suggest that systemic administration of MSG or ASP could impair memory retention and damage hypothalamic neurons in adult mice.     

Studies on brain lesion by administration of monosodium L-glutamate to mice. I. Brain lesions in infant mice caused by administration of monosodium L-glutamate

Light-microscopic examination was performed on the brain lesions induced by monosodium L-glutamate (MSG) in neonatal and infant mice of ICR strain. Lesions characterized as cytoplasmic balooning, chromatin clumping, pyknosis and karyorrhexis of neurons were recognized in the arcuate nucleus (AN), subfornical organ, preoptic area, area postrema and cerebral cortex. The most vulnerable region was the AN in which the region near the root of the median eminence was easily damaged. The changes in the AN were severest in 7-day-old mice, but only slight in 20-day-old mice. Thresholds of inducing AN lesions in 10-day-old mice after intraperitoneal injection and force-tube feeding were 0.4 and 0.7-0.8 g/kg body weight, respectively. The threshold of retinal changes was about 2.5-fold that of AN in force-tube feeding. In neonatal mice injected daily with 4 g MSG/kg body weight, the neurons of the AN disappeared almost completely by the 4th day of intraperitoneal administration.     

谷氨酸单钠对成年小鼠的神经毒性作用

［３Ｈ］谷氨酸（Ｃｌｕ）ｓｃ后的不同时程，柱层析分离血清中［３Ｈ］Ｇｌｕ，液闪测定，发现随代谢时程的延长［３Ｈ］Ｇｌｕ的量明显降低。外周组织中［３Ｈ］Ｇｌｕ含量的变化与血清中的类似，而神经组织则不同。非标记谷氨酸单钠ｓｃ以剂量依赖方式损伤成年小鼠的分辨学习能力。引起特征性神经元退变，降低下丘脑和脊髓的线粒体膜结合钙水平。结果表明，４．０ｍｇ·ｇ－１谷氨酸单钠可以透过血脑屏障对成年动物产生神经毒性作用。其作用机理可能与细胞内Ｃａ２＋超载，线粒体封存或排空Ｃａ２＋的能力失常。最终导致神经元损伤甚至死亡有关。     

Monosodium glutamate and analgesia induced by morphine. Test-specific effects

Neonatal administration of monosodium glutamate (MSG) destroyed perikarya in the arcuate nucleus and median eminence, including those that contain met-enkephalin and beta-endorphin and it increased the density of opiate receptors in the midbrain. Treatment with glutamate decreased the analgesic response on the jump test following a 10 mg/kg dose of morphine, yet increased the analgesic response on the hot-plate test following 1 mg/kg dose of morphine. The present study demonstrated that changes in morphine-induced analgesia induced by glutamate varied as functions of the pain test and of gender. While males treated with glutamate displayed attenuated analgesia induced by morphine (2.5-15 mg/kg) on the jump test, jump thresholds of females treated with glutamate were potentiated after a 10 mg/kg dose of morphine and attenuated after a 15 mg/kg dose of morphine, relative to controls. In contrast, analgesia on the hot-plate test was potentiated in animals of both genders treated with glutamate after all doses of morphine. Changes in tolerance to morphine induced by glutamate also depended on the pain test and gender. While the peak analgesic response on the jump test did not occur until the fifth injection of morphine in all rats treated with glutamate, tolerance on the jump test was subsequently retarded in males treated with glutamate and accelerated in glutamate-treated females. Tolerance on the hot-palate test appeared not to be consistently affected by treatment with glutamate. Morphine-induced hyperthermia was initially decreased in rats treated with glutamate, but subsequently decreased in glutamate-treated males and increased in glutamate-treated females.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pyroglutamate kinetics and neurotoxicity studies in mice

Plasma and brain kinetics of L-glutamic (GA) and L-pyroglutamic (PY) acids were studied after oral administration of monosodium glutamate (MSG) or pyroglutamate to adult mice. Oral MSG (0.5 g/kg) increased plasma GA and PY levels 4.5 and 1.8 times, respectively. A small increase in brain PY (1.3 times the basal level) but not in brain GA, was observed. Oral administration of pyroglutamate (0.5 g/kg) increased plasma PY levels 56 times in adult mice and 69 times in infant mice. No lesions in the arcuate nucleus of the hypothalamus were observed when pyroglutamate was administered orally to infant mice at doses of 2 and 4 g/kg.     

Consequences of monosodium glutamate or goldthioglucose arcuate nucleus lesions on ethanol-induced locomotion

It has been suggested that the endogenous opioid system, especially beta-endorphins, may play an important role in the behavioral effects of ethanol. The main site of beta-endorphin synthesis in the brain is the hypothalamic arcuate nucleus (ARC). In the present study, we used the neurotoxins monosodium glutamate (MSG) or goldthioglucose (GTG) to produce a selective ARC lesion and to assess its effects on the locomotion observed after ethanol administration. The results show that MSG or GTG pre-treatment produces a blockade of the increased locomotion produced by the injection of low and moderate doses of ethanol (0.5 and 1.5 g/kg, respectively). These effects were observed in the absence of any change in blood ethanol levels. On the other hand, MSG (but not GTG) pre-treatment enhanced the locomotor depression produced by higher doses of this alcohol (2.5 g/kg). Finally, caffeine (10 mg/kg)-induced locomotion was unaffected by the aforementioned neurotoxic agents. Thus, taken together, the present results suggest that MSG and GTG administration produce a blockade of the stimulating effects of ethanol on locomotion in mice and thus provides further support for a role of the ARC in the behavioral effects observed after ethanol administration.     

Neonatal monosodium glutamate lesions alter neurosensitivity to ethanol in adult mice

A number of studies have indicated a relationship between brain peptide activity and sensitivity to the behavioral effects of ethanol. Specifically, it has been suggested that ethanol effects are mediated by changes in the endogenous opioid peptides derived from the proopiomelanocortin (POMC) precursor. Most cell bodies containing brain POMC-derived peptides are found in the arcuate nucleus of the hypothalamus. Neonatal administration of monosodium glutamate (MSG) has been reported to destroy cell bodies of the arcuate nucleus. We treated WSC strain mice on postnatal Day 4 with a single SC injection of 4 mg/g MSG or saline. When adult, MSG and control mice were challenged with an IP injection of ethanol and its effect on body temperature, open field activity, or duration of loss of righting reflex was assessed. Blood ethanol concentration (BEC) was measured and the hypothalamic content of beta-endorphin like immunoreactivity (beta-EP) was determined by radioimmunoassay. beta-EP was markedly reduced in both females and males by MSG treatment. MSG-treated animals of both sexes showed significantly less ethanol-induced hypothermia than controls. BEC was higher in MSG-treated animals of both sexes than in controls, so the differences were not due to ethanol pharmacokinetics. beta-EP was generally lower in males. Duration of righting reflex was prolonged in MSG treated animals, and the reduction in open field activity was potentiated. These latter effects may be in part attributable to the higher BECs achieved in lesioned animals. These data suggest that beta-EP cell bodies in the arcuate nucleus of the hypothalamus mediate neurosensitivity to some effects of ethanol in mice, but further experiments will be necessary to implicate beta-EP specifically.     

谷氨酸单钠损毁弓状核对雌性大鼠骨组织形态计量学的实验研究

目的 观测EPO治疗大鼠面神经损伤后对面神经核神经元凋亡的的影响,探讨EPO促进神经再生与修复的机理.方法 96只SD大鼠随机分成4组.利用神经卡压法损伤面神经,每组在术后第7d,14d,21d和28d四个时间点取材,尼氏染色和免疫组织化学方法对面神经核神经元进行染色并定量分析.结果 经EPO治疗后,大鼠面神经核内凋亡抑制基因Bcl-2明显增多,细胞凋亡明显减少,EPO组明显优于对照组(P<0.01).结论 EPO有效提高周围神经损伤后的神经核内凋亡抑制基因的含量的表达,减少神经元凋亡,促进神经的再生与神经功能的恢复.     

Morphine conditioned reward is inhibited by MPEP,the mGluR5 antagonist

In the present study we examined the effect of MPEP [2-methyl-6-(phenylethynyl)-pyridine] a potent, selective and systemically active metabotropic glutamate receptor (mGluR) type I (subtype mGluR5) antagonist on conditioned morphine reward in mice. In an unbiased version of conditioned place preference (CPP) paradigm, single conditioning with 10 mg/kg of morphine produced reliable place preference. MPEP at 30, but not 10 mg/kg significantly inhibited the acquisition as well as expression of morphine-induced CPP, but it neither produced place preference or aversion, nor affected locomotor activity of mice. Effects of MPEP on learning and memory were studied in the elevated plus maze model of spatial learning. In contrast to 0.1 mg/kg of MK-801, which inhibited the acquisition of this task, 30 mg/kg of MPEP affected neither learning nor memory retrieval. These data suggest that mGluR5 may be involved in conditioned morphine reward.