抑郁模型大鼠中枢G蛋白的研究

目的 探讨抑郁模型人鼠中枢部分脑区Gαi蛋白的表达水平及其与部分抗抑郁剂作用机制的关系.方法 50只大鼠随机分为氨米帕明组、两酞普兰组、联合(碳酸锂加西酞普兰)干预组、生理盐水组、空白对照组,前4组接受慢件非顶见性应激制备为抑郁模型大鼠,并分别给予相应的干预措施;以强迫游泳试验评价药物疗效,利用免疫组织化学方法检测大鼠前额皮质、海马CA3、纹状体Gαi蛋白的表达.结果 实施干预4周后各组大鼠强迫游泳不动时间明硅延长,与末接受应激的空白对照组比较差异有统计学意义(F=2.61,P＜0.05),联合干预组强迫游泳不动时间于用药第1周恢复正常(F=4.58,P＜0.05),西肤普兰组于第2周恢复止常(F=4.33,P＜0.05),氯米帕明组于第3周恢复正常(F=2.86,P＜0.05);干预结束后,生理盐水组前额皮质、海马CA3区Gαi灰度值明显较空白对照组减少(F=2.75,P＜0.05;F=2.71,P＜0.05),药物干预后各组与空白对照组则无明显差异(P＞0.05);干预结束时,各组大鼠第4次强迫游泳小动时间和各脑区Gαi灰度值没有相关性(r=-0.28～0.495,P均大于O.05).结论 抑郁模型大鼠前额皮质、海马CA3 Gαi表达升高,恢复前额皮质、海马CA3的Gαi的表达可能是抗抑郁剂的作用靶点之一.     

慢性应激模型大鼠脑内5-HT1A受体表达分析

目的 探讨慢性不可预见性轻度应激(CUMS)模型大鼠各脑区(海马、中缝核、前额叶及纹状体)5-HT1A受体表达及与旷场行为变化的关系;西酞普兰对5-HT1A受体表达的影响.方法 将24只雄性SD大鼠随机分为3组(n=8):A组为对照组;B组为CUMS应激组;C组为CUMS应激+西酞普兰用药组(每天腹腔注射西酞普兰水溶液2 ml,10mg/kg).实验为期6周,通过旷场试验评价大鼠行为,6周后处死大鼠获取脑组织,采用Real-Time PCR检测各脑区5-HT1A mRNA表达水平,并分析其与矿场行为的相关性.结果 B组海马5-HT1A mRNA表达较A组有增高趋势(P=0.05),其余各脑区5-HT1A mRNA表达均差异无统计学意义(P＞0.05).海马5-HT1AmRNA表达大鼠移动次数、转身次数呈正相关,与总不动时间呈负相关;中缝核、纹状体5-HT1A mR-NA表达与中心移动距离呈正相关,纹状体5-HT1A mRNA表达与中心停留时间呈正相关(P均＜0.05).结论 慢性应激可能会引起海马5-HT1A受体表达增高;抗抑郁剂西酞普兰对5-HT1A受体表达无影响.5-HT1A mRNA表达与旷场行为变化有相关性.     

艾司西酞普兰与西酞普兰改善癫痫发作患者抑郁症状的对照研究

目的 探讨艾司西酞普兰与西酞普兰改善癫痫发作患者抑郁症状的效果.方法 将158例伴发抑郁症状的癫痫发作患者随机分为研究组(80例)和对照组(78例),研究组给予艾司西酞普兰系统治疗,对照组给予西酞普兰系统治疗,疗程均为4周.入组患者应用汉密尔顿抑郁量表(HAMD)与不良反应量表(TESS)在基线及治疗后第1、2、4周末分别评定疗效与不良反应.结果 与基线相比,研究组HAMD评分在第1周末即有显著性降低(P＜0.05),而对照组HAMD评分在第2周末才有显著性降低(P＜0.05).在治疗后的第1、2、4周末,研究组HAMD评分均低于对照组(P＜0.05).在治疗后的第4周末,研究组临床整体疗效优于对照组(P＜0.05).两组均未出现严重不良反应.结论 艾司西酞普兰和西酞普兰均可有效、安全地改善癫痫发作患者的抑郁症状,而艾司西酞普兰起效更快,疗效更好.     

氟西汀干预对大鼠抑郁模型海马代谢的影响

目的探讨氟西汀干预对大鼠抑郁模型的海马代谢的影响。方法 45只SD大鼠随机分为正常对照组(n=15)以及抑郁组(n=30)。抑郁组又被分为干预亚组(n=15)及未干预亚组(n=15)。采用慢性不可预知应激及孤养的方法建立抑郁模型。在制模成功后不干预亚组大鼠腹腔注射生理盐水2.0 ml/d,干预亚组大鼠腹腔注射盐酸氟西汀溶液5.0 mg/(kg·d);均持续4周。于干预前后对各组大鼠进行氢质子磁共振波谱分析检查,并进行比较。结果抑郁组大鼠双侧海马N-乙酰天冬氨酸(NAA)/肌酸(Cr)及谷氨酸复合物(Glx)/Cr显著低于正常对照组,胆碱复合物(Cho)/Cr及肌醇(mI)/Cr显著高于正常对照组(P0.05~0.01)。干预亚组双侧海马的NAA/Cr及Glx/Cr显著高于未干预亚组双侧海马的Cho,ho/Cr及右侧海马的mI/Cr显著低于未干预亚组(P0.05~0.01)。与干预前比较,干预亚组干预后双侧海马NAA/Cr及Glx/Cr显著升高(均P0.05);未干预亚组双侧海马Cho/Cr及mI/Cr显著升高,NAA/Cr及Glx/Cr显著降低(均P0.05)。结论氟西汀能够改善海马神经细胞的谷氨酸循环及肌醇磷酸循环,恢复神经元及神经胶质细胞的功能。     

重复经颅磁刺激对抑郁模型大鼠行为学及海马BDNF表达的影响

目的探讨重复经颅磁刺激(repetitive transcranial magnetic stimulation,rTMS)对慢性应激抑郁模型大鼠行为学及海马脑源性神经营养因子(brain derived neurotrophic factor,BDNF)的影响,探讨rTMS抗抑郁作用的可能机制。方法 40只雄性SPF级Sprague-Dawley大鼠经过初次筛选后,随机分为造模组(n=30)和空白对照组(n=8),造模组应用孤养联合慢性不可预见性温和应激(chronic unpredictable mild stress,CUMS)方法建立大鼠抑郁模型,筛选造模成功的大鼠24只随机分为rTMS组、伪刺激组和抑郁对照组,每组8只,抑郁对照组不给予rTMS干预,rTMS组和伪刺激组分别接受10 Hz的rTMS刺激和伪刺激干预3周。分别于造模前、造模后和干预后进行体质量测量、蔗糖水消耗实验和旷场实验评估,在干预后,检测大鼠海马CA3区BDNF阳性染色的细胞数及海马BDNF m RNA的表达水平。结果造模后,rTMS组、伪刺激组和抑郁对照组大鼠的体质量减分率较空白对照组降低(P0.01),体质量增加缓慢(P0.01)。干预后,r TMS组大鼠体质量减分率、蔗糖水消耗量、旷场实验的水平运动评分以及垂直运动评分较伪刺激组和抑郁对照组均增高(均P0.05),与空白对照组差异并无统计学意义(均P0.05)。干预后,rTMS组大鼠海马CA3区BDNF阳性细胞数目较伪刺激组和抑郁对照组增加(P0.01),伪刺激组和抑郁对照组较空白对照组减少(P0.01);r TMS组大鼠海马BDNF m RNA的相对表达量较伪刺激组和抑郁对照组增多(P0.01),伪刺激组和抑郁对照组较空白对照组减少(P0.01)。结论 rTMS干预能够改善CUMS抑郁模型大鼠的抑郁样行为,可能与增加海马BDNF的表达导致海马神经元再生有关。     

西酞普兰联合心理干预对抑郁症患者症状及认知功能的疗效

目的观察草酸艾司西酞普兰联合心理干预治疗对抑郁症患者的临床疗效及认知功能的影响。方法选取2014年6月到2016年12月我院收治的64例抑郁症患者,随机分成两组,其中对照组32例采用草酸艾司西酞普兰治疗,研究组32例在药物治疗基础上联合心理干预,为期2个月。观察对比两组患者治疗前后抑郁焦虑改善情况及认知功能改变。结果两组患者治疗前焦虑抑郁及认知功能评分组间差异不明显(P0.05)。治疗后两组患者抑郁、焦虑评分均降低,认知功能相关评分均升高,差异具有统计学意义(P0.05);且与对照组比较,治疗后研究组焦虑抑郁情绪及认知功能改善程度更明显(P0.05)。结论草酸艾司西酞普兰联合心理干预能更有效的改善抑郁症患者的焦虑抑郁情绪及认知症状,值得临床推广应用。     

雷公藤多甙对致痫大鼠学习记忆及海马Ng和PKC表达的影响

目的研究雷公藤多甙(TWP)在戊四氮(PTZ)所致癫痫大鼠学习记忆障碍中的干预作用及可能机制,探讨神经颗粒素(Ng)和蛋白激酶C(PKC)在癫痫大鼠海马组织中的表达的影响。方法通过水迷宫及Y迷宫筛选方式挑选学习记忆功能正常的SD大鼠90只,随机分为PTZ致痫组、TWP低剂量组(TWP1)、TWP高剂量组(TWP2)、正常对照组,采用戊四氮(PTZ)腹腔注射慢性点燃癫痫。用水迷宫和Y迷宫对4组大鼠进行学习记忆能力检测,运用实时荧光定量PCR及酶联免疫吸附法分别检测其海马组织Ng和PKC基因mRNA及相应蛋白的表达水平。结果与PTZ组相比,TWP干预组大鼠在水迷宫中提高,其学习记忆能力接近NC组(P0.05);而4组逃避潜伏期差异无统计学意义(P0.05)。在Y迷宫TWP干预组错误反应次数比PTZ组明显减少(P0.05),其行为能力接近NC组(P0.05);但4组在全天总反应时间上的差异无统计学意义(P0.05)。经TWP干预后大鼠海马Ng和PKC基因mRNA及相应蛋白的表达上调,与PTZ组比较,差异具有统计学意义(P0.05),上调水平与NC组接近(P0.05);而TWP1和TWP2两组之间的差异无统计学意义(P0.05)。结论 TWP可有效改善PTZ所致癫痫大鼠的学习记忆能力,这与上调大鼠海马组织Ng及PKC表达水平密切相关。     

西酞普兰和阿米替林治疗脑卒中后抑郁临床对照观察

目的:比较西酞普兰与阿米替林治疗脑卒中后抑郁的疗效和安全性。方法:41例脑卒中后抑郁患者,随机分两组,分别用西酞普兰和阿米替林治疗6周。采用汉密尔顿抑郁量表(HAMD)、抑郁自评量表(SDS)和副反应量表(TESS)于治疗前和治疗1、2、4、6周末分别评定疗效和不良反应。结果:两组治疗后各周HAMD和SDS评分均较治疗前下降(P均<0.05);其中治疗后1周末,西酞普兰组评分下降较阿米替林组更明显,两组比较差异有显著性(P<0.05),但治疗2~6周末比较,差异均无显著性(P均>0.05);西酞普兰组不良反应较阿米替林组少而轻。结论:西酞普兰治疗脑卒中后抑郁疗效与阿米替林相当,但起效较快,安全性高,不良反应轻微。     

西酞普兰联合认知行为干预对58例脑卒中后抑郁焦虑患者与生活质量的影响分析

目的观察西酞普兰与认知行为干预疗法联合对脑卒中后抑郁焦虑情绪者及生活质量的改善效果。方法采用随机数字表法将116例脑卒中后抑郁患者进行分组,治疗组实施西酞普兰联合认知行为干预,对照组给予西酞普兰治疗,观察连续治疗2个月末抑郁、焦虑、生活质量改善情况。结果 2组均能够降低治疗后SDS评分和SAS评分,但治疗组降低治疗后SDS评分和SAS评分幅度明显大于对照组,P0.05;2组治疗方案均能够提高生活质量评分,但治疗组提高生活质量评分明显高于对照组,P0.05。结论西酞普兰具有降低机体对去肾上腺素和多巴胺摄取等作用,配合认知行为干预疗法能够显著改善脑卒中后抑郁者焦虑情绪及生活质量效果,联合治疗效果显著,值得临床对作用机制继续探讨。     

西酞普兰与文拉法辛治疗精神分裂症后抑郁的对照研究

目的 比较西酞普兰与文拉法辛治疗精神分裂症后抑郁症状的疗效和安全性.方法 50例精神分裂症后抑郁患者随机分为2组,分别用西酞普兰和文拉法辛治疗6周.采用汉密尔顿抑郁量表(HAMD),简明精神病量表(BPRS)和副反应评定量表(TESS)于治疗前和治疗1、2、4、6周末分别评定疗效和不良反应.结果 2组治疗后HAMD和 BPRS评分均较治疗前下降(P＜0.01),2组疗效无显著性差异(P＞0.05),2组不良反应发生率无显著性差异(P＞0.05).结论 西酞普兰与文拉法辛治疗精神分裂症后抑郁疗效相当,安全性高,不良反应轻微.     

西酞普兰对慢性应激大鼠行为及脑内ERK1/2磷酸化水平的影响

目的：探讨西酞普兰能否预防或减弱慢性应激的不良反应及其可能的作用机制。方法：对SpragueDawley大鼠，随机分为正常对照（NC）组，束缚应激（RS）组和西酞普兰预处理（CP）组。RS组大鼠每日束缚6h，连续21d。利用Morris水迷宫观察大鼠的空间记忆能力，运用免疫组织化学方法观察脑内细胞外信号调节激酶（extracellular signal-regulated kinase1／2，ERK1／2）磷酸化（p-ERK1／2）水平的改变。结果：RS组大鼠的Morris水迷宫试验目标象限活动时间和穿越站台次数比NC组大鼠显著减少（P〈0．05）；CP组大鼠的上述指标较RS组大鼠明显改善（P〈0．05）。RS组大鼠的前额皮质、杏仁内侧核以及杏仁皮质后内侧核中p-ERK1／2阳性细胞数均较NC组显著减少（P〈0．05）；而CP组大鼠以上各脑区中p-ERK1／2阳性细胞数均较RS组明显增多（P〈0．05）。结论：慢性束缚应激后大鼠的空间记忆明显受损；应激前和应激期间给予西酞普兰处理，能明显缓解应激对大鼠造成的记忆损伤，增加脑内ERK信号传导通路的活化。     

The effect of citalopram on chronic stress-induced depressive-like behavior in rats through GSK3β/β-catenin activation in the medial prefrontal cortex

Antidepressant treatments enhance synaptic connectivity in stress-sensitive brain regions such as the medial prefrontal cortex (mPFC). The mPFC plays a key role in controlling cognition and emotion. While several signaling pathways are involved in this enhancement process, the exact mechanisms are not fully established. In the present study, we evaluated the role of the glycogen synthase kinase 3β (GSK3β)/β-catenin signaling pathway in the antidepressant effect of citalopram in rats exposed to forced swim stress. The acute stress group received the classic, two-day variant of the forced swimming test (FST), whereas the chronic stress group received swim stress for 14 consecutive days. We found that rats exposed to acute swim stress showed depressive-like behaviors and expressed normal GSK3β and β-catenin levels in the mPFC. Chronic swim stress, also induced a significant behavior changes but was associated with decreased levels of phosphorylated GSK3β and β-catenin in the rat's mPFC. Chronic citalopram treatment alleviated these behavioral changes in chronically stressed rats and normalized the downregulation of GSK3β/β-catenin signaling. Our results suggest that GSK3β/β-catenin signaling plays an important role in chronic but not acute stress-related depression and contributes, at least in part, to the antidepressant effects of citalopram in distinct brain regions associated with mood regulation.     

Effects of acute citalopram on the expression of conditioned freezing in naive versus chronic citalopram-treated rats

An acute challenge with selective serotonin (5-HT) reuptake inhibitors (SSRIs) reduces the conditioned freezing in rats, a model of anxiety. The increase in the 5-HT levels in the nerve terminal induced by SSRIs is closely related to its pharmacological effects. Clinically, SSRIs exert an anxiolytic effect after chronic treatment. The effects of repeated treatment with citalopram on conditioned freezing in rats were examined in the present study. Acute citalopram (10 mg/kg) reduced freezing at a short post-training interval (1 day) significantly. While the effect of citalopram (10 mg/kg) on freezing was diminished by prolonging the interval between conditioning and the exposure to conditioned fear stress, repeated citalopram (10 mg/kg) injection twice daily for 7 days restored the inhibitory effect of acute challenge of citalopram (10 mg/kg) on freezing. By prolonging the period between conditioning and exposure to conditioned fear stress, this model may have a more precise predictive validity of anxiety disorder as an animal model.     

西酞普兰对慢性应激大鼠海马CA1和CA3区神经细胞B细胞淋巴瘤/白血病-2及Bcl相关蛋白表达与凋亡的影响

目的 探讨西酞普兰对慢性应激大鼠海马CA1、CA3神经细胞B细胞淋巴瘤/白血病-2(Bcl-2)、Bcl相关蛋白(Bax)表达和凋亡的影响.方法 40只雄性Sprague-Dawley大鼠随机分为对照组、应激组(生理盐水灌胃)、处理1～3组[分别以不同剂量(1 mg·kg-1·d-1、4 nag·kg-1·d-1、8 mg·kg-1·d-1)氢溴酸西酞普兰灌胃],每组8只.采用强迫游泳制造慢性应激模型,用大鼠悬尾实验、力竭实验进行行为学观察,免疫组织化学检测Bel-2、Bax表达水平.脱氧核糖核苷酸末端转移酶介导的缺口末端标记法检测细胞凋亡.尼康图像分析软件测量分析Bcl-2、Bax阳性表达、凋亡阳性细胞数量及积分吸光度值.结果 应激组静止不动时间[(279±53)s]长于对照组[(182±35)s]及处理1～3组[(200±71)s,(159±59)s,(165±54)s];挣扎次数[(20±3)次]少于对照组[(24±3)次]及处理1～3组[(37±16)次,(32±10)次,(24±4)次];力竭时间[(38.3±5.1)min]长于对照组[(22.9±1.8)min]、短于处理1～3组[(54.4±2.9)min,(69.3±17.6)min,(46.4±4.0)min];差异均有统计学意义(P<0.05或0.01).与对照组比较,应激组CA1、CA3神经细胞Bcl-2表达变弱、Bax表达增强、凋亡细胞增多,差异均有统计学意义(P<0.05或0.01).与应激组比较,处理1～3组Bcl-2表达增强、Bax表达变弱、凋亡细胞减少,差异均有统计学意义(P<0.05或0.01).处理组1～3组的部分Bcl-2/Bax表达、凋亡阳性细胞数量与对照组的差异有统计学意义(P<0.05),但IA值的差异均无统计学意义(P均>0.05).结论 慢性应激可影响大鼠海马CAI、CA3神经细胞Bcl-2、Bax表达水平,促进细胞凋亡;西酞普兰可影响慢性应激大鼠海马CAI、CA3神经细胞Bcl-2、Bax表达水平,拈抗细胞凋亡.     

Action of selective serotonin reuptake inhibitor on aggressive behavior in adult rat submitted to the neonatal malnutrition

The effect of the malnutrition during suckling on the aggressiveness was investigated in adult rats treated or not with citalopram, a selective serotonin reuptake inhibitor (SSRI). The animals were divided into two groups according to the diet used: nourished group - the rats received the control diet with 23% protein during the life; and malnourished group - the rats had its mothers submitted to diet with 7.8% protein during suckling. At 120 days of age, each group was sub-divided according to the treatment: acute - consisting a single i.p. injection of saline solution or 20-mg/Kg citalopram; chronic - consisting the single injections (1 per day during 14 days) of saline or 20 mg/Kg citalopram. The acute or chronic treatment with SSRI reduces aggressive response in nourished rats, but not in malnourished ones. Thus, the malnutrition during the critical period of brain development seems to induce durable alterations in the function of the serotoninergic neurotransmission     

A Sonic Hedgehog (SH) Fusion Protein Corrects Multifocal Defects In Experimental Diabetic Neuropathy

Although increased protein kinase C (PKC) activity has been invoked in the pathogenesis of diabetic retinopathy, nephropathy and macroangiopathy, the role of PKC in neuropathy remains unclear. We reported that total PKC activity in sciatic nerves of STZ-induced diabetic rats was not altered compared with that of normal rats, and that PKC-β inhibitor, LY-333531 (LY) ameliorated neural dysfunction and reduced endoneurial blood flow without affecting PKC activity, suggesting that this effect of LY would be mediated through its action on endoneurial microvasculature. In this study, effect of LY on diabetic neuropathy was investigated in Otsuka Long-Evans Tokushima fatty (OLETF) rats, an animal model of type 2 diabetes. Three-month-old male OLETF rats and Long-Evans Tokushima Otsuka (LETO) rats as normal control rats were divided into 5 groups as follows: 1) LETO control, 2) OLETF control, 3) LY (1 mg/kg/day)-treated OLETF, 4) sucrose-fed OLETF, and 5) sucrose-fed OLETF treated with LY. After 21-month treatment, motor nerve conduction velocity (MNCV) in tail nerves, sciatic nerve blood flow (SNBF) and protein expression of phosphorylated PKC in sciatic nerves were measured. 1) MNCV : OLETF rats demonstrated a significant delay in MNCV, which was enhanced by sucrose feeding, and these deficits were prevented by LY. 2) SNBF : reduced SNBF in OLETF and sucrose-fed OLETF rats was ameliorated by LY. 3) PKC : phosphorylated PKC expression was decreased in OLETF rats, which was more prominent in sucrose-fed OLETF rats. Treatment with LY increased phosphorylated PKC expression in both groups of OLETF rats. These observations suggest that diabetes with long duration and poor glycemic control decreases phosphorylated PKC in nerve tissues, which would contribute to the development of diabetic neuropathy, and that PKC-β inhibition would be beneficial for the prevention of this neuropathy.     

Effects of fenfluramine and antidepressants on protein kinase C activity in rat cortical synaptoneurosomes

Fenfluramine releases serotonin (5-HT) via the 5-HT transporter (SERT). Previous work has shown that amphetamine increases particulate protein kinase C (PKC) activity in striatal synaptoneurosomes. The increased PKC activity is linked to the outward transport of dopamine, and when release is diminished, the inward transport of amphetamine inhibits PKC instead. Since there is homology among monoamine transporters, this study was undertaken to determine if D-fenfluramine has similar effects on PKC. The role of 5-HT receptors and endogenous 5-HT were also examined. Naive rats and rats pretreated with p-chlorophenylalanine (PCPA), a 5-HT synthesis inhibitor, were sacrificed. Cortical synaptoneurosomes were prepared and incubated with fenfluramine. PKC activity was determined by thiophosphorylation of endogenous substrates. It was found that 5-HT, D/L-fenfluramine, and D-fenfluramine increased PKC activity in a time- and dose-dependent manner. The 5-HT-mediated increase in PKC activity was attenuated by pretreatment with the 5-HT(2) antagonist ketanserin, but not with the SERT inhibitor fluoxetine. The D-fenfluramine-induced increase in PKC activity was completely prevented, however, by pretreatment with SERT inhibitors and partially with ketanserin. It was also attenuated by pretreatment with PCPA, resulting in a dose-dependent inhibition of PKC instead. Thus, when 5-HT release was diminished the uptake of D-fenfluramine inhibited PKC. Similar effects have been observed with amphetamine. Unlike D-fenfluramine, the D/L-fenfluramine-induced increase in PKC activity was partially resistant to PCPA pretreatment but was attenuated with bupropion, a dopamine transporter (DAT) inhibitor. SERT inhibitors (sertraline, paroxetine, citalopram, and fluoxetine) also increased PKC activity. Nefazodone and bupropion increased PKC activity, but mirtazapine was relatively inactive. The SERT inhibitor-induced increase in PKC was unaffected by pretreatment with PCPA but was inhibited by calcium. Similar effects on PKC activity have been observed with DAT inhibitors. These results, showing that D-fenfluramine altered PKC activity similar to D-amphetamine, suggest that the topographic homology between DAT and SERT may extend to their effects on PKC activity.     

Autoreceptors remain functional after prolonged treatment with a serotonin reuptake inhibitor

Serotonin (5-hydroxytryptamine, 5-HT) autoreceptors may desensitize during prolonged administration of antidepressant drugs. If autoreceptors desensitize, their inhibitory influence on extracellular 5-HT should be attenuated. To test this hypothesis, the selective serotonin reuptake inhibitor (SSRI) citalopram (10 mg kg(-1), s.c., b.i.d.) or saline was administered for 14 days to rats. After a 24-h washout period, rats were anesthetized, and implanted with dialysis probes for determination of 5-HT in the frontal cortex (FCx) and dorsal hippocampus (DH). In response to citalopram (5 mg kg(-1), s.c.) challenge, there were moderate increases in 5-HT in the FCx and DH of both the chronic citalopram and saline pretreatment groups. After subsequent administration of the 5-HT(1A/1B) autoreceptor antagonist, (-)-penbutolol, there were further increases in 5-HT in the FCx and DH of the saline pretreatment group. Moreover, contrary to the expected effect if autoreceptors were desensitized, the potentiation produced by (-)-penbutolol was greater in the FCx and DH of the chronic citalopram group as compared to rats pretreated with saline. These results suggest that autoreceptors still restrain the increase in 5-HT produced by an SSRI after prolonged administration.     

Memory impairment induced by chronic intracerebroventricular infusion of beta-amyloid (1-40) involves downregulation of protein kinase C

Signaling pathways underlying the cognitive deficit of the Alzheimer's disease (AD) are not completely understood. Protein kinase C (PKC), a major neuronal protein plays a critical role in cellular signal transduction and it is known to be subjected to modulation in AD. We showed previously that, chronic infusion of beta-amyloid (1-40) into rat cerebroventricle leads to deficit in spatial and non-spatial memory formation. As an attempt to identify the cellular correlates of the memory deficit, in the present study we investigated the PKC activation in different brain areas. Chronic infusion of beta-amyloid (1-40) for 14 days into the rat cerebroventricle decreased the activity of soluble protein kinase C (PKC) in the hippocampus. Subcellular translocation of PKC to membrane fraction in hippocampal slices of rats treated with beta-amyloid (1-40) was completely abolished under acute stimulation with 0.5 microM phorbol-dibutyrate (PDBu). We also reported a decreased affinity (k(D)) for PDBu binding in the hippocampus, cerebral cortex and striatum. The total number of binding sites for PDBu (B(max)) was increased, in the three brain areas analyzed on the day 14, but the changes were not statistically significant. Our data indicate that chronic accumulation of beta-amyloid (1-40) into the rat brain reduced activation of PKC, effect that would substantially contribute to the memory deficit found in these animals.     

慢性脑缺血大鼠海马PARP、MDA的表达及阿魏酸钠的抗氧化作用

目的研究慢性脑缺血大鼠海马聚腺苷二磷酸核糖聚合酶(PARP)的表达,并探讨阿魏酸钠在慢性脑缺血所致的氧化应激性损伤中的作用。方法28只成年大鼠用于实验,10只采用双侧颈总动脉结扎制备大鼠慢性脑缺血模型,10只在颈总动脉结扎后给立即予阿魏酸钠腹腔注射,另8只为假手术组。2月后取大鼠海马,采用硫代巴比妥酸法检测丙二醛(MDA)含量,用免疫印迹的方法检测PARP蛋白的表达量。结果慢性脑缺血大鼠海马MDA及PARP蛋白含量明显增多,而经阿魏酸钠治疗后,MDA含量下降,PARP表达下调。结论慢性脑缺血可诱导内源性氧化应激使自由基增多,产生脂质过氧化损伤作用,并导致DNA链的断裂,激活PARP的表达;阿魏酸钠可减少MDA和PARP的生成,在慢性脑缺血氧化应激中起保护作用。