慢性应激对大鼠认知及脑脊液单胺类神经递质的影响

目的探讨慢性应激对大鼠脑单胺类神经递质以及认知功能影响的研究。方法75只SD大鼠随机分为对照组(25只)和慢性应激组(50只),后者以束缚浸水应激方式连续应激21天,每日记录大鼠体重及进食量并进行两组比较,三周后行水迷宫实验、大鼠脑单胺类神经递质测定。结果(1)应激组大鼠体重的增加、进食量较对照组明显减少(P<0.05);(2)水迷宫实验:应激组大鼠的游出时间较对照组明显增加(P<0.05),但错误次数无明显差异(P>0.05)。(3)大鼠脑脊液单胺类神经递质含量(ug/L):5-HT、5-HIAA及MHPG的含量应激组明显低于对照组(P<0.05),NA、DA及HVA在应激组均为升高,但无显著差异(P>0.05)。结论慢性束缚浸水应激三周使大鼠脑脊液中5-HT、5-HIAA及MHPG的含量降低,但对认知功能无明显影响。     

雌激素保护脑卒中后束缚应激大鼠作用与降钙素基因相关肽的相关性研究

目的:探讨雌激素保护脑卒中后束缚应激(PSR)大鼠作用与降钙素基因相关肽(CGRP)的相关性.方法:雌性SD 大鼠50只,经Open-Field实验评分后随机分成对照组、脑卒中组、束缚组、PSR组及雌激素治疗组,并建立相应模型.观察各组大鼠不同阶段行为学改变,并运用特异性放射免疫分析方法测定各组大鼠外周血,脊髓及前额叶的CGRP样免疫活性(CGRP-LI)物质,观察各组间CGRP-LI的改变.结果:与对照组比较,PSR大鼠Open-Field实验中水平和垂直得分明显减少,外周及中枢CGRP-LI含量明显降低;与PSR组比较,雌激素治疗组大鼠Open-Field实验中得分增加,外周血、脊髓及前额叶CGRP-LI含量较PSR组升高.结论:CGRP水平的上调可能是雌激素对PSR大鼠的保护作用之一.     

帕罗西汀对束缚应激与额叶皮质相关性的影响研究

目的：观察束缚应激对大鼠额叶皮质的影响,探讨帕罗西汀在防治束缚应激引起焦虑的作用机制。方法：复制大鼠束缚应激模型,分为束缚应激组、治疗组和保护组,另设对照组（不束缚应激）,每组均n=10。观察大鼠行为学改变、额叶皮质c-fos基因表达、5-羟色胺（5-HT）和血浆皮质酮含量的变化,观察帕罗西汀干预的影响。结果：与对照组比较,束缚应激组大鼠额叶皮质的c-fos表达显著增加,5-HT表达明显减少,血浆皮质酮含量明显升高;与束缚应激组比较,治疗组和保护组血浆皮质酮含量和额叶皮质c-fos表达明显减少,5-HT表达明显增加。结论：额叶皮质参与了束缚应激反应;帕罗西汀抑制额叶皮质的c-fos基因表达、减少血浆皮质酮含量和增加额叶皮质5-HT含量可能是其抗焦虑作用机制之一。     

慢性应激对大鼠行为学及脑神经颗粒素水平的影响及药物防治

目的探讨慢性应激对大鼠外显行为学变化的影响,检测体内儿茶酚胺类物质及神经颗粒素(Neurogranin,Ng)表达的变化及三七皂苷Rg1的防治效果。方法成年雄性SD大鼠36只,随机分为对照组(CON)、模型组(CUS)、和治疗组(CUS-G),采用慢性不可预见性应激方法建立慢性应激动物模型;采用旷场试验检测行为学变化,运用Morris水迷宫实验进行学习记忆力测试,使用放射免疫法检测血浆、脑组织儿茶酚胺类含量,Western blot法检测皮质、海马、下丘脑Ng含量。结果 6 w慢性应激后,实验组大鼠在水平运动和垂直运动方面得分均明显低于对照组与药物组,均P0.05;水迷宫实验显示慢性应激后动物逃避潜伏期明显延长,而治疗组大鼠逃避潜伏期呈下降趋势(P0.05);血浆、脑组织去甲肾上腺素与多巴胺在对照组、实验组与药物组间无明显变化;慢性应激大鼠皮质、海马、下丘脑Ng含量水平皆与模型大鼠有差异(P0.05、P0.01、P0.05),治疗大鼠皮质、海马、下丘脑Ng含量亦皆与模型大鼠有差异(P0.01、P0.05、P0.05)。结论慢性应激研究领域,神经颗粒素的敏感性优于单胺类神经递质,可作为敏感指标加以观察;100 mg/kg剂量的三七皂苷Rg1能够抑制应激所致学习记忆功能紊乱,对应激所致外显行为有积极的调节作用,对脑内神经颗粒素表达水平降低趋势有较好抑制作用。     

可卡因成瘾大鼠脑立体定向核团毁损术前后形态学及单胺类神经递质的变化

目的研究可卡因成瘾大鼠脑形态学的变化及在脑立体定向核团毁损术前后单胺类神经递质的变化。方法采用普通SD大鼠作为实验动物,随机分为对照组、成瘾组、成瘾大鼠毁损伏核组、成瘾大鼠毁损海马组、成瘾大鼠毁损扣带回组、成瘾大鼠毁损伏核-海马-扣带回组。成瘾大鼠每天皮下注射溶解于0.2ml蒸馏水的盐酸可卡因15mg/kg,正常对照组每天皮下注射0.2ml蒸馏水,持续90 d。毁损组分别行不同部位的毁损,3 d后处死,采用高效液相色谱仪(HPLC)脑组织匀浆法检测纹状体的单胺类递质含量,同时观察比较正常、成瘾及毁损后大鼠不同脑区在光镜及电镜下形态学的改变。结果成瘾大鼠纹状体多巴胺含量较正常对照组升高(P<0.01)。毁损前后大鼠单胺类递质无明显变化。在成瘾大鼠的伏核、海马、扣带回观察到核固缩、间质水肿、纤维断裂及坏死。结论长期使用可卡因可以造成大鼠脑组织的损害及纹状体多巴胺含量升高。立体定向核团毁损术前后脑组织单胺类神经递质变化不明显。     

电针对慢性应激抑制模型大鼠脑单胺类神经递质的影响

目的 探讨电针刺百会，印堂穴对慢性应激抑郁模型大鼠脑内单胺类神经递质的影响及治疗抑郁症的机理。方法 将２４只Ｓｐｒａｇｕｅ－Ｄａｗｌｅｙ雄性大鼠随机分为对照组，抑郁模型组，抑制模型电针组和抑郁模型加阿米替林组，每组６只，用高效液相－电化学法测定大鼠脑内单胺类神经递质及其代谢产物的含量，比较含量的比值。结果 抑郁模型组大鼠脑皮层５－羟色胺（５－ＨＴ）／５－羟吲哚乙酸（５－ＨＩＡＡ），纹状体多巴胺（Ｄ     

星形胶质细胞在帕金森大鼠中的作用机制研究

目的观察移植星形胶质细胞后的PD大鼠行为学改变和单胺类神经递质含量的时空变化及相互关系,旨在分析星形胶质细胞在帕金森大鼠中的作用机制。方法偏侧两点法建立PD模型大鼠后,将星形胶质细胞移入PD大鼠纹状体中,2 w后对比PD组,观察行为学改变,检测单胺类神经递质(DA、DOPAC、HVA)含量变化。结果 PD+T2As组的行为学从第4周开始较PD组有显著改善(P 0. 01),单胺类神经递质(DA、DOPAC、HVA)含量与PD组比较第2周无明显区别(P0. 05),从第3周开始显著高于PD组(P 0. 01)。结论星形胶质细胞在一定程度上保护了受损的DA能神经细胞,对PD大鼠的黑质-纹状体通路具有修复作用。     

酸枣仁汤对抑郁模型大鼠海马Wnt-1 基因和蛋白 表达的影响

目的 观察酸枣仁汤对抑郁模型大鼠海马Wnt-1 基因和蛋白表达的影响。方法 制作慢 性轻度不可预见性应激抑郁大鼠模型，实验分成对照组、模型组、氟西汀组、酸枣仁汤低、中、高剂量 组，分别采用酸枣仁汤和氟西汀治疗抑郁模型大鼠，测定其体重、糖水消耗、旷场实验行为活动前后得 分变化情况，以及Western blot 和Real-time PCR 分别检测大鼠海马中Wnt-1 蛋白和基因的表达情况。结 果 抑郁模型大鼠体重增长速度减慢，糖水消耗和旷场实验行为活动得分减少，海马内Wnt-1 蛋白和基 因表达也减少；酸枣仁汤治疗后，大鼠体重增长明显，糖水消耗量明显增多，旷场实验行为活动得分也 增加明显，Wnt-1 蛋白和基因表达上调。结论 酸枣仁汤可增加大鼠抑郁模型海马Wnt-1 基因和蛋白的 表达，减少神经元细胞凋亡，具有抗抑郁作用。     

脑梗死后遗症大鼠模型脑组织ATP、ADP及单胺类神经递质含量的变化

目的 研究脑梗死后遗症大鼠模型脑组织ATP、ADP及单胺类神经递质含量的变化。方法 建立脑梗死后遗症大鼠模型，用高效液相色谱（HPLC）法测定大鼠脑组织ATP、ADP及单胺类神经递质含量。结果 刺激组（SG）毛发相对黯淡无光、卷曲，精神萎靡，惊恐，消瘦，肢体无力，摄食减少，饮水减少，手术伤口愈合迟缓，符合中医脑梗死后遗症征候。正常组（NG）大鼠脑组织ATP、ADP含量显著高于SG组、术后不刺激组（SG）（P〈0．01），同时NSG组大鼠脑组织ATP、ADP含量显著高于SG组（P〈0．05）。SG组大鼠脑组织NE、DA和5-HT含量显著低于NG组（P〈0．01），NSG组（P〈0．05）；NSG组大鼠脑组织DA含量显著低于NG组（P〈0．05）。结论 脑梗死后遗症大鼠由于能量代谢障碍而出现脑组织的ATP、ADP含量降低，并且伴有大脑释放单胺类递质增加及脑细胞内的单胺类递质含量减少，单胺类递质分泌增加又加重了脑组织的损伤，加剧ATP、ADP等能量物质代谢障碍，形成恶性循环。     

帕罗西汀对慢性不可预见应激大鼠惊跳反射和弱刺激抑制影响的初步研究

目的 探讨慢性不可预见应激大鼠的听觉惊跳反射和弱刺激抑制变化情况以及帕罗西汀对其的影响.方法 将24只大鼠按随机数字表法分为阴性对照组(8只)、慢性不可预见应激组(8只)和帕罗西汀组(8只).阴性对照组:静养21 d后给予蒸馏水灌胃;慢性不可预见应激组:先给予慢性不可预见应激21d后再给予蒸馏水灌胃21 d;帕罗西汀组:先给予慢性不可预见应激21 d后再给予帕罗西汀灌胃21 d.3组大鼠均接受体质量测量、自发活动、糖水偏好、惊跳反射和弱刺激抑制测试.结果 (1)慢性不可预见应激组大鼠体质量[(380.50±22.23)g]、10 min旷场自发活动[ (5765.57 ±2942.28) mm]、糖水摄入量[(19.09 ±7.16) ml/kg]均低于阴性对照组[(426.38±33.73)g、(12 272.15±2343.02) mm(42.58±11.68) ml/kg,P＜0.01];帕罗西汀组体质量[ (353.62 ±29.37)g]低于阴性对照组(P＜0.01).(2)惊跳反射实验结果3组大鼠之间差异无统计学意义(P＞0.05).(3)慢性不可预见应激组大鼠弱刺激抑制[( 30.50±14.84)％]小于阴性对照组和帕罗西汀组[ (57.80±13.32)％、(42.32±15.82)％],帕罗西汀组弱刺激抑制小于阴性对照组,差异均有统计学意义(P ＜0.01);82 dB时的弱刺激抑制高于70、64、58 dB时的弱刺激抑制(P＜0.01);76 dB时的弱刺激抑制高于64、58 dB时的弱刺激抑制(P ＜0.01);70 dB时的弱刺激抑制高于58 dB时的弱刺激抑制(P＜0.05).结论 随着弱刺激强度增加,弱刺激抑制逐渐增加;慢性不可预见应激大鼠存在弱刺激抑制的缺失,帕罗西汀能够缓解这一状况.     

Cryogenic lesions induce a mast cell-dependent increase in cerebral cortical histamine levels in the mouse

Unilateral cryogenic lesions of the brain were produced in mice by applying the face of the brass rod cooled in liquid nitrogen to the exposed parietal bone. As a result of the cryogenic lesion, the mast cells in the dura mater underlying the parietal bone were disrupted. This disruption of dural mast cells was accompanied by a significant increase in the histamine content within the cryogenically injured cerebral cortex. However, when similar lesions were produced in mice which are deficient or lacking in mast cells, this increase in cerebral cortical histamine did not occur. Thus, the cryolesion-induced elevation of cerebral cortical histamine apparently depends on the release of histamine from mast cells located near the injured cerebral cortex. The significance and role(s) of the lesion-induced elevation of this potent biogenic amine and putative neurotransmitter is presently unknown, but may involve alteration of the blood-brain barrier, vasomotor activity of the cerebrovasculature and/or other sequelae to brain injury.     

卒中后抑郁大鼠模型的建立及评估

目的 建立卒中后抑郁（poststroke depression，PSD）有效动物模型。方法 大脑中动脉闭塞（MCAO）制备大鼠局灶脑缺血模型，加以慢性不可预见的温和刺激结合孤养建立PSD模型并予氟西汀干预。分为对照组、卒中组、抑郁组、PSD组和PSD+氟西汀组。分别采用糖水消耗试验、旷野试验（open-field test，OFT)、强迫游泳评估大鼠快感缺失、活动减少、行为绝望等行为。结果 应激14 d时，与对照组及卒中组相比，PSD组体重增长幅度显著降低（P<0.05），经氟西汀干预后体重增长幅度明显增加（P<0.01）。PSD组水平得分在应激第7天时与对照组相比显著降低（P<0.05）；到应激14 d时，PSD组与对照组及卒中组相比水平得分进一步下降（P<0.01），并持续到应激18 d（P<0.01）。PSD组垂直得分在应激14 d时与对照组、卒中组相比均显著下降（P<0.05或P<0.01），强迫游泳的不动时间明显延长（P<0.05）；而氟西汀干预后水平得分与垂直得分均显著增加（P<0.05或P<0.01），不动时间明显缩短（P<0.01）。结论 PSD模型大鼠较充分而持续表现快感缺乏、活动减少等“抑郁”核心症状，可操作性和重复性较好，是研究PSD较为理想的大鼠模型。氟西汀能改善PSD模型大鼠行为学异常。     

Biological aspects of the link between smoking and depression

A link between smoking and depressive symptoms has been described in the literature for over a decade. The neurotransmitter systems affected by cigarette smoke mirror the neurotransmitter pathways thought to be involved in the biological mechanisms of depression. Cigarette smoke contains several psychoactive chemicals; nicotine is the best studied among these and is widely accepted to be the addictive substance in tobacco. Nicotine binds to nicotinic receptors in the brain, augmenting the release of numerous neurotransmitters, including dopamine, serotonin, norepinephrine, acetylcholine, gamma-aminobutyric acid, and glutamate. Cigarette smoke has other psychoactive properties apart from nicotinic receptor stimulation. For example, it inhibits monoamine oxidase (the enzyme responsible for breaking down the biogenic amine neurotransmitters norepinephrine, serotonin, and dopamine) in the brain. Various antidepressants act through modulation of the biogenic amine neurotransmitter pathways. That the neural substrates modified by both smoking and antidepressant drugs overlap has relevance to smoking cessation. The use of antidepressants as adjuvants to smoking-cessation treatment can enhance cessation success rates. Understanding the neurobiological mechanisms underlying the association between smoking and depression may improve physicians' ability to assist smokers in their efforts to quit and will contribute to a more thorough comprehension of both the biology of addiction and the etiology of depression.     

Antidepressant-like effects of paeoniflorin on post-stroke depression in a rat model

ABSTRACT

Background: Post-stroke depression (PSD) is one of the most prevalent emotional disorders after stroke and often results in poor outcomes. However, the underlying physiopathologic mechanism and effective treatment of PSD remain poorly elucidated.

Objective: To investigate whether paeoniflorin has antidepressant-like activity in a rat model of PSD.

Methods: Rats were randomly divided into four groups: sham-operated control (Sham), PSD, paeoniflorin (with PSD) and fluoxetine group(with PSD). PSD was developed by the right middle cerebral artery occlusion followed 21 days chronic unpredictable mild stress combined (CUMS) with raised alone. Tests of sucrose preference and open field were used to assess the depression-like behavior. Neurological function was evaluated by neurological deficit score and beam balance test. Expression of phosphorylated CREB (p-CREB) and brain-derived neurotrophic factor (BDNF) in the CA1 region of the hippocampal complex was evaluated by western blot and immunofluorescence.

Results: Te depressive-like behaviors markedly improved after paeoniflorin and fluoxetine treatment. Furthermore, paeoniflorin treatment significantly increased BDNF and p-CREB expression in the CA1 region.

Conclusions: Observed results suggested that paeoniflorin could ameliorate the symptoms and improve the functional capability of PSD rats, similar to the effect of fluoxetine.

Abbreviations: PSD: post-stroke depression; CUMS: chronic unpredictable mild stress stimulation; MCAO: middle cerebral artery occlusion; OFT: open field test; SPT: sucrose preference test, NDS: neurological deficit score, BBT: beam balance test; BDNF: brain-derived neurotrophic factor protein; p-CREB: phosphorylated Cyclic-AMP responsive element binding protein     

卒中后抑郁患者的认知功能、自主神经功能及血浆单胺类神经递质水平的相关性

目的探讨卒中后抑郁(PSD)患者认知功能、自主神经功能与血浆单胺类神经递质水平的相关性。方法对33例PSD患者(PSD组)和33名健康对照者(正常对照组)进行事件相关电位(ERP)、交感神经皮肤反应(SSR)和血浆单胺类神经递质水平的测定;对检测结果进行Pearson多元相关分析。结果与正常对照组比较,PSD组ERP(P300、N400、CNV及MMN)、SSR各波潜伏期明显延长(均P<0.01),波幅明显下降(均P<0.01);血浆单胺类神经递质水平明显降低(均P<0.01)。PSD组各项指标间均具有相关性(P<0.05～0.01)。结论PSD患者血浆单胺类神经递质水平降低与其认知功能及自主神经功能障碍相关。     

Validation of a fluorescence-based high-throughput assay for the measurement of neurotransmitter transporter uptake activity

Pre-synaptic dopamine, norepinephrine and serotonin transporters (DAT, NET and SERT) terminate synaptic catecholamine transmission through reuptake of released neurotransmitter. Common approaches for studying these transporters involve radiolabeled substrates or inhibitors which, however, have several limitations. In this study we have used a novel neurotransmitter transporter uptake assay kit. The assay employs a fluorescent substrate that mimics the biogenic amine neurotransmitters and is taken up by the cell through the specific transporters, resulting in increased fluorescence intensity. In order to validate the assay, a variety of reference and proprietary neurotransmitter transporter ligands from a number of chemical and pharmacological classes were tested. The ability of these compounds to inhibit the selective transporter-mediated uptake demonstrated a similar rank order of potency and IC(50) values close to those obtained in radiolabeled neurotransmitter uptake assays. The described assay enables monitoring of dynamic transport activity of DAT, NET and SERT and is amenable for high-throughput screening and compound characterization.     

脑卒中后抑郁大鼠海马齿状回5-羟色胺1A受体的表达

目的 观察脑卒中后抑郁(PSD)大鼠海马齿状回5-羟色胺1A(5-HT1A)受体的表达.方法 将SD雄性大鼠分为正常对照组、卒中组、应激抑郁对照组和PSD组,每组6只.应用左侧大脑中动脉阻塞(MCAO)联合不可预见的慢性温和应激(CMS)刺激及孤养法建立PSD大鼠模型,采用荧光实时定量聚合酶链反应和Western印迹法检测并比较各组大鼠CMS第19天和第28天齿状回5-HT1A受体(mRNA)和蛋白表达水平.结果 (1)CMS第19天,PSD组5-HT1A受体mRNA表达(O.012±0.001)低于正常对照组(0.361±0.010)和卒中组(0.039±0.002;P＜0.001);其5-HT1A受体蛋白表达(0.400±0.030)低于正常组(1.320±0.060)和卒中组(0.610±0.060;均P＜0.001).(2)CMS第28天,PSD组5-HT1A受体mRNA(0.013±0.001)低于正常对照组(0.336±0.011)、卒中组(0.063±0.006;均P＜0.001);其5-HT1A受体蛋白表达(0.080±0.020)低于正常组(0.620 ±0.030)、卒中组(0.260±0.040)和应激抑郁组(0.320±0.020;均P＜0.001).结论 PsD大鼠海马齿状回5-HT1A受体表达水平降低,此改变可能是PSD发病的分子机制之一.     

Novel antidepressants and the biogenic amine hypothesis of depression. The case for iprindole and mianserin.

The introduction of two tricyclic compounds (iprindole and mianserin) that are reported to have antidepressant properties but to be relatively devoid of effects on central amine neurotransmitter systems has raised questions about the amine hypothesis of depression and about the mechanism of action of tricyclics in general. In view of the importance of these questions, a critical review of both the clinical and pharmacological profiles of iprindole and mianserin was undertaken. Iprindole is a relatively weak inhibitor of both norepinephrine (NE) and serotonin, whereas mianserin possesses at least modest potency as an inhibitor of NE uptake. However, the evidence is as yet insufficient to prove the superiority of iprindole over placebo in the treatment of those depressions characterized by endogenous symptoms. In considering the pharmacological profiles of these two drugs together with their clinical profiles, the data are not inconsistent with the hypothesized role of biogenic amines in major depression.     

Anesthetic propofol normalized the increased release of glutamate and γ-amino butyric acid in hippocampus after paradoxical sleep deprivation in rats

Objective: Multiple lines of evidence suggest that general anesthesia helps the recovery from sleep deprivation. However, little is known about the underlying neurochemical mechanisms. In the current study, we investigated the effect of anesthetic propofol on the release of glutamate (Glu) and γ-amino butyric acid (GABA) in the hippocampal CA1 region of rat with 24 h-paradoxical sleep deprivation (PSD).

Methods: A guide cannula for microdialysis was inserted into the CA1 region of hippocampus in rats. At six days after cannula implantation, rats received 24 h-PSD by using the platform–water tank method. The rats were then subjected to natural sleep or propofol anesthesia (100 mg/kg, i.p.), respectively, after 24-h PSD. Microdialysis samples from hippocampus were collected before and at the end of PSD, and also at 1, 3, 6, and 8 h post-PSD. The concentrations of Glu and GABA in collected samples were determined by using high performance liquid chromatography.

Results: The current study showed that 24 h-PSD significantly increased the release of Glu and GABA in the hippocampus in rats. In both natural sleep and propofol anesthesia groups, the upregulated Glu and GABA levels after PSD gradually decreased and returned to the baseline level by 8 h post-PSD.

Conclusion: Our data indicate that propofol anesthesia promotes the restoration of disturbed excitatory and inhibitory neurotransmitter release in the hippocampus after PSD, similar to the beneficial effects of natural sleep. This finding suggests that propofol anesthesia may be a viable pharmacotherapeutic strategy for the treatment of certain sleep disorders that share similar mechanisms with PSD.