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1.
加味四逆散调控抑郁症大鼠海马BDNF、NR1表达及促进海马DG区神经再生的研究 总被引:1,自引:0,他引:1
目的研究加味四逆散对抑郁症大鼠海马BDNF、NR1表达的调控及促进海马DG区神经再生的效应及机制。方法建立慢性应激性抑郁症模型。采用荧光标记的免疫组化方法检测海马DG区NeuN、BrdU、脑源性神经营养因子(BDNF)、N-甲基-D-天冬氨酸受体1(NR1)的表达水平。原位杂交技术检测海马DG区BDNF表达水平。结果慢性应激能抑制海马DG前体细胞的增殖(P<0.01);抑郁症大鼠海马DG区BDNF表达明显下降(P<0.01),NR1的表达明显升高(P<0.01)。JWSNS和氟西汀能明显增加抑郁症大鼠海马DG单位面积中神经元数目和新增殖细胞量(P<0.01),增强海马DG区BDNF的表达(P<0.01)和降低NR1的表达(P<0.01)。结论 JWSNS能够促进抑郁症大鼠海马DG区神经细胞的增殖,并可能通过增强BDNF的表达和降低NR1的表达,促进海马DG区的神经再生。 相似文献
2.
《中国药理学与毒理学杂志》2019,(6)
目的探讨硫酸茯苓多糖(SP)是否通过调节α-氨基-3-羟基-5-甲基-4-异恶唑丙酸(AMPA)受体的表达而生产抗抑郁作用。方法实验设假手术组、抑郁症模型组、SP(25,50和100 mg·kg~(-1))剂量组及SP(100 mg·kg~(-1))+GYKI 52466(3 mg·kg~(-1))剂量组,每组12只。大鼠卵巢摘除加慢性不可预知性温和应激(CUMS)法诱导抑郁症动物模型。连续灌胃和腹腔注射给药21 d。糖水消耗、强迫游泳及敞箱试验观察大鼠行为变化。尼氏染色观察大鼠海马神经元病理变化。免疫组化法观察海马脑源性神经营养因子(BDNF)的表达。Western蛋白印迹法检测海马AMPA受体GluR1、磷酸化GluR1及c AMP反应元件结合蛋白(CREB)、p-CREB和BDNF蛋白表达。结果与模型组相比,SP各给药组大鼠强迫游泳不动时间明显降低而自发活动明显增加,同时糖水摄入量及糖水偏爱百分比明显升高(P<0.05,P<0.01),海马神经元损伤显著减轻,GluR1和GluR1磷酸化水平及p-CREB和BDNF表达均明显升高。但与SP(100 mg·kg~(-1))剂量组相比,SP+GYKI 52466组大鼠强迫游泳不动时间又明显增加而自发活动又明显减少,糖水摄入量及糖水偏爱百分比又明显降低,海马GluR1和p-GluR1及p-CREB和BDNF表达又明显降低(P<0.01)。结论 SP具有抗抑郁作用,其机制可能通过增强海马GluR1受体功能,进而上调海马p-CREB和BDNF蛋白表达有关。 相似文献
3.
目的 应用细胞内记录技术 ,研究 N- methyl- D- aspartate(NMDA)受体阻断剂 MK80 1对离体海马脑片 CA1区锥体细胞缺氧期间电生理的影响。方法 成年雄性 SD大鼠海马脑片随机分为单纯缺氧组 (Con组 ,n=1 0 )和 MK80 1组 (M组 ,n=1 0 )。Con组海马脑片给予 1 0分钟缺氧 ;而 M组的海马脑片在缺氧前 1 0分钟及 1 0分钟的缺氧期间分别应用 1 0 0 μmol/ L 的 MK80 1。所有脑片均给予 6 0分钟的复氧。应用细胞内记录技术记录海马 CA1区神经元缓慢去极化及快速去极化的时间、快速去极化的幅度。在复氧末 ,应用细胞内注入电流及经 Schaffer通路刺激 ,观察神经元对刺激的反应。结果 Con组海马 CA1区锥体神经元缓慢去极化速率为 (0 .2 2± 0 .0 5 ) m V/ s,显著高于 M组的 (0 .0 8± 0 .0 3) m V/ s (P<0 .0 5 ) ;NMDA受体阻断剂 MK80 1可以显著延迟神经元的快速去极化的时间 ,M组神经元的快速去极化时间为 (5 37± 1 39) s,显著高于 Con组的 (2 6 1± 2 6 ) s (P<0 .0 5 ) ;M组 CA1区神经元的快速去极化幅度为 (4± 1 3) m V,显著小于 Con组的 (5 3± 7) m V(P<0 .0 5 )。在复氧末 ,M组的 1 0例神经元中 ,9例神经元恢复对刺激的反应。结论 NMDA受体阻断剂可显著减轻神经元的缺氧性损伤 ,促进复氧后神经元功 相似文献
4.
目的:从基因水平探讨抑郁症模型大鼠海马区脑酪氨酸激酶受体B活性(TrkB)的变化。方法:SD♂大鼠,分为正常对照组,7,14,21 d不同时程慢性应激刺激组,运用敞箱实验(Open-Field-test)与糖水消耗量指标评定大鼠行为学改变,釆用免疫组织化学法检测TrkB蛋白表达,实时定量聚合酶链反应对TrkB进行定量分析。结果:实验前各组大鼠水平运动得分与垂直运动评分无差异,与正常对照组相比,7,14,21 d应激组水平﹑垂直运动得分均明显降低(P<0.05),各组间相比无明显差异(P>0.05)。14,21 d应激组其糖水偏爱度持续减少(P<0.05),免疫组织化学检测结果显示,7,21 d应激组海马区TrkB表达与正常对照组明显降低(P<0.05),7,21 d应激组TrkB的mRNA含量亦明显低于正常组。结论:提示不同时程慢性应激刺激海马的神经再生变化与TrkB的中介机制相关联。 相似文献
5.
目的研究中药复方加味四逆散(JWSNS)分时给药对慢性应激大鼠生物节律的影响。方法采用慢性不可预知轻度应激建立慢性应激大鼠模型。运用余弦节律分析法观察分析慢性应激大鼠昼夜体温节律、血清5-羟色胺(5-hydroxy tryptamine,5-HT)、褪黑素(melatonin,MT)、皮质酮(corticosterone,CORT)分泌及其节律的变化以及JWSNS的影响。血清5-HT、MT、CORT含量测定采用酶联免疫吸附试验。结果 JWSNS 3个给药组对模型大鼠体重增长缓慢现象没有抑制作用,但可以提高模型大鼠糖水偏爱度(P<0.01),表明JWSNS具有抗抑郁的效应。慢性应激使大鼠昼夜体温波动加剧,白昼体温更低,夜间体温更高,并且这种现象在谷值方面表现得更为明显。JWSNS酉时、卯酉分时给药对此现象具有抑制作用(P<0.05,P<0.01),且酉时给药表现为对峰值、谷值的双相调节作用,而卯酉分时给药则主要是作用于光时相,即对谷值(白昼)进行调节。慢性应激大鼠的体温节律出现延迟现象,主要表现为时相的推后,只有JWSNS卯时给药可以对体温节律延迟有抑制作用。慢性应激大鼠昼夜血清5-HT、MT、CORT含量波动幅度减小,分泌节律紊乱,主要表现为时相的大幅提前。JWSNS酉时和卯酉分时给药对大鼠血清5-HT水平低下具有抑制作用(P<0.01);JWSNS酉时给药对血清MT含量波动幅度的减小具有抑制作用(P<0.01),而JWSNS卯时给药和卯酉分时给药则对MT分泌节律紊乱具有抑制作用(P<0.01);JWSNS酉时和卯酉时给药可抑制CORT的升高,对血清CORT含量波动幅度的减小具有抑制作用(P<0.01)。结论 JWSNS卯时给药抗抑郁主要通过调节体温、激素以及神经递质分泌的节律,酉时给药抗抑郁主要通过调节激素和神经递质的分泌量,而卯酉分时给药则具有以上两方面的综合效应。 相似文献
6.
目的观察哇巴因预处理对模拟缺血大鼠海马神经元损伤的保护作用及其机制。方法采用原代培养的大鼠海马神经元,以全细胞膜片钳方法记录海马神经元NMDA电流(INMDA)。采用无糖无氧的方法模拟缺血灌流,建立神经元的体外急性缺血模型,观察模拟缺血对低浓度哇巴因预处理的海马神经元NMDA电流的影响。结果模拟缺血显著激活INMDA,低浓度哇巴因预处理可阻断模拟缺血对神经元INMDA的激活。结论模拟缺血可促进NMDA通道开放。哇巴因预处理能保护神经元抵抗由NMDA受体诱导的兴奋性神经毒性,此神经保护机制与哇巴因阻断缺血对NMDA受体的过度激活、缓解神经元Ca2+超载密切相关。 相似文献
7.
潘群皖 《中国药物依赖性杂志》2009,18(6):463-466
目的:记录海洛因慢性给药戒断期大鼠离体海马脑片和海洛因急性灌流正常大鼠离体海马脑片生物电活动,观察其特征性变化。方法:制作海洛因慢性给药戒断大鼠模型及其海马离体脑片,正常组大鼠海马脑片用两种浓度海洛因急性灌流,分别记录海马CA1区神经元的电活动。结果:慢性给药戒断状态:大鼠海马CA1神经元的被动电学性质与各组比较差异无显著性,但锋电位的半幅时程、10%-90%衰减时间显著缩短(P<0.05,P<0.01);给予1.6-2.0nA胞内电流刺激时,放电频率较对照组增加(P<0.01);CA1区神经元兴奋性突触后电位(EPSP)幅值显著增强(P<0.01)。急性灌流用药:0.3mmol.L-1海洛因灌流,使膜电位和阈值绝对值减小(P<0.05,P<0.01),锋电位的半幅时程、10%-90%衰减时间显著延长(P<0.05,P<0.01);膜斜率电阻增大(P<0.01),EPSP幅值显著下降(P<0.01)。结论:海洛因急、慢性给药状态下,大鼠海马CA1区生物电特性存在着明显的差别。 相似文献
8.
谷氨酸损伤大鼠皮层神经元及抑制钙/钙调蛋白依赖性蛋白激酶Ⅱ活性 总被引:3,自引:0,他引:3
利用原代培养的大鼠胎鼠皮层神经元 ,采用乳酸脱氢酶 (LDH)测定和32 P参入方法 ,研究谷氨酸 (Glu)对皮层神经元损伤 ,钙 /钙调蛋白依赖性蛋白激酶 (Ca MK )活性的影响及其机理 .Glu(50- 1 0 0 0μmol· L-1)作用 1 0 min,导致皮层神经元Ca MK 活性立即明显下降 ,神经元形态及 LDH释放早期无明显改变 ,2 4 h时 LDH释放显著增加 ,神经元损伤 .N-甲基 - D-天冬氨酸 (NMDA)受体拮抗剂地佐环平 (MK- 80 1 )明显降低 LDH释放 ,保护Ca MK 活性 ,而非 NMDA受体拮抗剂 6,7-二硝基喹口恶啉二酮 (DNQX)无保护作用 .去除胞外 Ca2 +可明显保护 Ca MK 活性 .Ca MK 抑制剂 KN- 62可明显拮抗 Ca MK 活性下降 ,部分保护神经元损伤 .结果提示 ,Glu兴奋毒引起皮层神经元迟发性损伤和 Ca MK 活性早期明显下降 ,主要由 NMDA受体介导和胞外 Ca2 +内流增加有关 . 相似文献
9.
目的:观察逍遥散对抑郁症模型的干预作用,初步揭示逍遥散治疗抑郁症的作用机制。方法:采用慢性应激的方法复制抑郁症大鼠模型,灌胃给予逍遥散,进行观察大鼠行为学改变,测试糖水消耗量,测定海马TNF-α和c-fos的表达。结果:逍遥散及阳性药氯丙咪嗪可增加模型大鼠体重增长速度、糖水消耗及行为学运动得分,并降低大鼠海马TNF-α和c-fos的表达。结论:逍遥散能够抗抑郁,其机制可能是调节免疫系统功能,并抑制海马神经元细胞凋亡,从而减少脑损伤。 相似文献
10.
目的研究氟西汀与噻萘普汀对慢性应激抑郁模型大鼠海马胱天蛋白酶-9(Caspase-9)表达的影响。方法将大鼠随机分为抑郁模型组、氟西汀组、噻萘普汀组和对照组。模型组、氟西汀组和噻萘普汀组给予21d的应激刺激,此期间对照组正常饲养,刺激期间氟西汀组每天灌胃氟西汀(10mg/kg),噻萘普汀组每天灌胃噻萘普汀(50mg/kg),模型组和对照组每天灌胃等体积的生理盐水。行为学检测应用开场法和液体消耗实验。采用Western blot法检测各组大鼠海马Caspase-9的表达情况。结果模型组水平穿越格数、竖立次数、修饰次数、糖水消耗百分比均显著低于对照组(P<0.01)。氟西汀组水平穿越格数、竖立次数、修饰次数和糖水消耗百分比均高于模型组(P<0.05)。噻萘普汀组糖水消耗百分比高于模型组(P<0.05),水平穿越格数、竖立次数和修饰次数也高于模型组,但差异无统计学意义。慢性应激后模型组大鼠海马Caspase-9的表达水平显著高于对照组(P<0.01);氟西汀组大鼠海马Caspase-9的表达水平低于模型组(P<0.01),高于对照组(P<0.05);噻萘普汀组大鼠海马Caspase-9的表达水平低于模型组(P<0.01),高于对照组(P<0.01)。结论氟西汀和噻萘普汀2种抗抑郁药物均可以逆转慢性应激抑郁模型大鼠海马中Caspase-9表达的升高。 相似文献
11.
Effects of MK801 and neuroleptics on prepulse inhibition: re-examination in two strains of rats 总被引:3,自引:0,他引:3
Disruption of prepulse inhibition (PPI) induced by NMDA receptor antagonists, such as MK801, has been used as an animal model of positive and negative symptoms of schizophrenia. Previous studies suggested that atypical, but not typical, neuroleptics can selectively restore MK801-induced PPI disruption and that such selectivity may depend on strain differences. The present study re-examined PPI disruption by systemic MK801 in Wistar (WS) and Sprague-Dawley (SD) strains, and addressed the issue whether clozapine (atypical), compared to haloperidol (typical), effectively antagonizes MK801-induced PPI disruption. In addition, we tested the effects of bilateral microinfusion of MK801 into the ventral hippocampus in WS. Systemic MK801 disrupted PPI in both strains. Neither clozapine nor haloperidol antagonized MK801-induced PPI in either strain. Our clozapine data do not agree with previous reports of clozapine's ability to antagonize MK801-induced PPI disruption. Similar to previous results with SD, MK801 infusion into the ventral hippocampus failed to affect PPI in WS. In our view, the selective ability of atypical neuroleptics to restore PPI disruption by NMDA antagonists, and to serve as a tool for identifying possible atypical neuroleptics, requires further examination. PPI disruption with systemic MK801 may be due to the blockade of NMDA receptors in multiple brain sites. 相似文献
12.
This study was conducted to assess the involvement of N-methyl-d-aspartate (NMDA) and γ-aminobutyric acid (GABA) receptor systems, located in specific limbic brain regions, in the discriminative
stimulus effects of ethanol. Male Long-Evans rats were trained to discriminate between intraperitoneal (IP) injections of
ethanol (1 g/kg) and saline on a two-lever drug discrimination task. The rats were then implanted with bilateral injector
guides aimed at the nucleus accumbens core (AcbC), prelimbic cortex (PrLC), hippocampus area CA1 (CA1), or extended amygdala
(i.e., at the border of the central and basolateral nuclei). Infusions of the non-competitive NMDA antagonist MK 801 in the
AcbC or CA1 resulted in dose-dependent full substitution for IP ethanol. MK 801 infusion in the PrLC or amygdala failed to
substitute for ethanol. Injection of the competitive NMDA antagonist CPP in the AcbC also failed to substitute for ethanol.
Co-infusion of MK 801 in the hippocampus potentiated the effects of MK 801 in the AcbC, whereas NMDA infusion in the hippocampus
attenuated the ability of MK 801 in the AcbC to substitute for ethanol. The direct GABAA agonist muscimol resulted in dose-dependent full substitution for IP ethanol when it was injected into the AcbC or amygdala,
but failed to substitute when administered in the PrLC. Co-infusion of MK 801, but not CPP, potentiated the effects of muscimol
in the AcbC. These results demonstrate that ethanol’s discriminative stimulus function is mediated centrally by NMDA and GABAA receptors located in specific limbic brain regions. The data also suggest that the discriminative stimulus effects of ethanol
are mediated by interactions between ionotropic GABAA and NMDA receptors in the nucleus accumbens, and by interactions among brain regions.
Received: 2 December 1997 / Final version: 24 January 1998 相似文献
13.
W H Lunn D D Schoepp D O Calligaro R T Vasileff L J Heinz C R Salhoff P J O'Malley 《Journal of medicinal chemistry》1992,35(24):4608-4612
At physiological pH, the spatial arrangement of the three charges of DL-tetrazol-5-ylglycine (5) could be viewed as similar to those found in certain conformations of the two excitatory amino acids (EAAs)--aspartic and glutamic acids. Given significant binding to one or more EAA receptors, 5 would offer unique modeling and perhaps biological opportunities. We have previously shown it to be the most potent NMDA agonist known, with a unique and marked in vitro neutrotoxicity at depolarizing concentrations. Now we report the details required for its synthesis, together with its potency and efficacy in two assays of functional activation of the NMDA receptor, namely agonist-influenced [3H]MK801 binding and agonist-induced release of the neurotransmitter [3H]-norepinephrine from brain slices. In both these assays DL-tetrazol-5-ylglycine proved to be more potent and efficacious than NMDA and cis-methanoglutamate. It was more potent than, and equally efficacious to, L-glutamate in [3H]MK801 binding. The structural features of 5 may well reflect optimal agonist interaction at the NMDA receptor site. (We considered the possibility that some decarboxylation of DL-tetrazol-5-ylglycine may have occurred during testing. This would give 5-(aminomethyl)tetrazole (13), the tetrazole acid analog of glycine; and glycine is involved in NMDA receptor activation. Compound 13 does not affect [3H]glycine binding at the strychnine-insensitive glycine binding site, and [3H]MK801 binding studies showed that the (aminomethyl)-tetrazole, even if is formed, would probably have no effect on the activity of tetrazol-5-ylglycine at the NMDA receptor. 相似文献
14.
A role for N-methyl-D-aspartate (NMDA)-type glutamate receptors in mediating the dopaminergic regulation of neurotensin (NT) systems was observed in extrapyramidal and limbic structures. Blockade of the NMDA receptor with the non-competitive antagonist, MK801, prevented increases in striatal and nigral levels of NT following both single and multiple administrations of methamphetamine. Significant attenuation of the methamphetamine-induced changes in the striatal NT system were observed with MK801 doses as low as 0.01 mg/kg per dose. In contrast, administration of NMDA caused significant increases in both striatal and nigral NT. The NMDA-induced increase in striatal NT content, like that caused by methamphetamine, was blocked by MK801. The NT system associated with the nucleus accumbens responded in a similar manner in that MK801 (0.1 mg/kg per dose) totally blocked the methamphetamine-induced increases and NMDA administration elevated the NT levels in this structure. Since the methamphetamine-related changes in NT content have been previously shown to be due to increased activity at dopamine D1 receptors, these results strongly suggest that NMDA receptors play an important role in mediating the dopamine D1 regulation of neurotensin systems. Interestingly, the presence of MK801 had no impact on sulpiride-mediated changes in striatal NT levels, suggesting that the NMDA receptor is not linked with the dopamine D2 receptor regulation of NT pathways. 相似文献
15.
Ambuja S Bale Meredith D Jackson Quentin Todd Krantz Vernon A Benignus Philip J Bushnell Timothy J Shafer William K Boyes 《Toxicological sciences》2007,98(1):159-166
Acute exposure to toluene and other volatile organic solvents results in neurotoxicity characterized by nervous system depression, cognitive and motor impairment, and alterations in visual function. In vitro, toluene disrupts the function of N-methyl-D-aspartate (NMDA)-glutamate receptors, indicating that effects on NMDA receptor function may contribute to toluene neurotoxicity. NMDA-glutamate receptors are widely present in the visual system and contribute to pattern-elicited visual-evoked potentials (VEPs) in rodents, a measure that is altered by toluene exposure. The present study tested the hypothesis that effects on NMDA receptors contribute to toluene-induced alterations in pattern-elicited VEPs. Prior to examining the effects of NMDA receptor agonists and antagonists on toluene-exposed animals, a dose-range study was conducted to determine the optimal dose for NMDA (agonist) and MK801 (antagonist). Dose levels of 2.5 mg/kg NMDA and 0.1 mg/kg MK801 were selected from these initial studies. In the second study, Long-Evans rats were exposed to toluene by inhalation, and VEPs were measured during toluene exposure in the presence or absence of NMDA or MK801. Pattern-elicited VEPs were collected by exposing rats to a sinusoidal pattern modulated at a temporal frequency of 4.55 Hz. Following collection of baseline VEPs, rats were injected with either saline, NMDA (2.5 mg/kg, ip), or MK801 (0.1 mg/kg, ip) and 10 min later were exposed to air or toluene (2000 ppm). VEP amplitudes were calculated for 1x (F1) and 2x stimulus frequency (F2). The F2 amplitude was reduced by approximately 60, 60, and 50% in the toluene-exposed groups (TOL): SALINE/TOL (n = 11), NMDA/TOL (2.5 mg/kg; n = 13), and NMDA/TOL (10 mg/kg, n = 11), respectively. Thus, NMDA (2.5 and 10 mg/kg) did not significantly affect toluene-mediated F2 amplitude effects. Administration of 0.1 mg/kg MK801 prior to toluene exposure blocked the F2 amplitude decreases caused by toluene (n = 9). However, when 0.1 mg/kg MK801 was administered 20 min after the onset of toluene exposure, toluene-mediated F2 amplitude decreases persisted despite the challenge by MK801. These data support the hypothesis that acute actions of toluene on pattern-elicited VEPs involve NMDA receptors. 相似文献
16.
Differential effects of MK801 and lorazepam on heart rate variability in adolescent rhesus monkeys (macaca mulatta) 总被引:3,自引:0,他引:3
Previous research shows that ketamine significantly alters cardiac signal regulation in rhesus monkeys, however relatively little is known about the mechanism for this effect. In the study reported here the relative contributions of NMDA receptor activation on cardiac signal dynamics were determined by administering a specific NMDA antagonist, MK801, to rhesus monkeys. The general effects of sedation were assessed by measuring cardiac response to lorazepam, a sedative drug without direct NMDA receptor activity. Electrocardiographic signal dynamics were examined before and after I.V. administration of either MK801 (0.16 mg/kg) or lorazepam (0.48 mg/kg). Inter-beat interval time series data were analyzed in the frequency domain after Fourier transform, and a nonlinear measure of autocorrelation, the Hurst exponent (H), was derived. After MK801 administration, log [HF /Total power] increased post-infusion (M = 1.11, SD = 0.45) compared with pre-infusion values [M = -0.19, SD = 0.32, F(1,4) = 19.49, P = 0.01] while H decreased, mean pre versus post 0.52+/-S.D. 0.10 versus 0.01+/- 0.05, P = 0.0002. Lorazepam administration did not significantly alter heart rate variability measures obtained in the frequency or nonlinear domains. To our knowledge, this is the first study that has defined the effects of peripherally administered MK801 on cardiovascular dynamics in primates and establishes that peripheral administration of NMDA antagonists result in large increases the high-frequency components of cardiac rhythm and increased heart rate variability compatible with MK801-associated increases in parasympathetic outflow. 相似文献
17.
Lidocaine increases phosphorylation of focal adhesion kinase in rat hippocampal slices 总被引:3,自引:0,他引:3
Dahmani S Reynaud C Tesnière A Rouelle D Desmonts JM Mantz J 《European journal of pharmacology》2004,489(1-2):55-58
We examined the effect of lidocaine on phosphorylation of the tyrosine kinase focal adhesion kinase (PP125FAK) in rat hippocampal slices by immunoblotting with both antiphosphotyrosine and specific anti-PP125FAK antibodies in the presence of tetrodotoxin (1 microM). Lidocaine induced a concentration-related increase in tyrosine phosphorylation of the 125-kDa band corresponding to PP125FAK phosphorylation (EC50 value=0.39+/-0.09 microM, maximal effect=169+/-28% of control, P<0.001). This effect was sensitive to neither the N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (MK 801, 10 microM) nor the inhibitor of the ryanodine receptor dantrolene (30 microM). In contrast, it was completely blocked by the protein kinase C (PKC) inhibitors chelerythrin, bisindolylmaleimide I (GF 109203X) and bisindolylmaleimide IX (RO-318220, 10 microM). We conclude that lidocaine increases phosphorylation of the tyrosine kinase PP125FAK in the rat hippocampus by a tetrotoxin (TTX)-insensitive mechanism which involves activation of PKC. 相似文献
18.
Anni‐Maija Lindn Jussi Visnen Markus Storvik Merja Lakso Esa R. Korpi Garry Wong Eero Castrn 《Basic & clinical pharmacology & toxicology》2001,88(2):98-105
Abstract: N‐methyl‐D‐aspartate (NMDA) receptor function appears to be under complex control during physiological and pharmacological states. We have investigated the effects of acute administration of uncompetitive NMDA receptor antagonists on mRNA levels of NMDA receptor subunits and on molecules known to cluster or phosphorylate the receptor utilizing in situ hybridization on rat brain sections. A high dose (5 mg/kg; 4 hr) of dizocilpine (MK‐801) decreased mRNA levels of NMDA receptor subunits NR2C and NR2B in the entorhinal and parietal cortices, respectively. MK‐801 increased mRNA levels of synapse‐associated protein‐90/postsynaptic density‐95 (SAP90/PSD‐95) and a γ‐isoform of protein kinase C (PKCγ) in cortical regions. Synapse‐associated protein‐97 (SAP97) mRNA levels were increased in the entorhinal cortex layer III after MK‐801 or after relatively high doses of other uncompetitive NMDA receptor antagonists: phencyclidine (15 mg/kg; 6 hr) and memantine (50 mg/kg; 6 hr). Memantine also increased SAP97 mRNA expression in other cortical regions, but this effect was not observed with MK‐801 or phencyclidine. NMDA receptor uncompetitive antagonists alter the expression of multiple receptor components and such events may ultimately play a role in adaptation or toxic responses. 相似文献
19.
In this study, we investigated the effects of both N-methyl D-aspartate (NMDA) and MK-801 on WIN55,212-2(WIN)-induced amnesia in rats. Step-through inhibitory avoidance of memory was used to examine the retrieval of memory, 24 h after training. All drugs were injected bilaterally into the dorsal hippocampus (intra-CA1) of rats. Pretraining and posttraining or pretesting administration of the nonselective CB1/CB2 receptor agonist, WIN (0.5 μg/rat), decreased the step-through latency. However, amnesia induced by pretraining or posttraining injections of WIN was reversed by a pretest administration of WIN (0.25 and 0.5 μg/rat). Pretest microinjections of different doses of NMDA (0.1, 0.5, and 1 μg/rat) elicited no response, but NMDA (0.5 and 1 μg/rat) did induce full recovery from amnesia induced by WIN (0.5 μg/rat). The posttraining and pretest injection of a higher dose of the NMDA receptor antagonist, MK801 (MK; 4 μg/rat), caused an impairment in the memory retrieval. However, amnesia induced by posttraining injections of MK (4 μg/rat) was reversed by a pretest administration of MK (4 μg/rat). In addition, pretest administration of different doses of the antagonist (2 and 4 μg/rat) induced full recovery of WIN-induced amnesia, but did not influence memory recovery in the subjects, which had received posttraining (0.5 μg/rat) and pretest WIN (0.25 and 0.5 μg/rat). Pretesting coadministration of ineffective doses of WIN (0.1 μg/rat) with NMDA (0.1 μg/rat), but not with MK (1 μg/rat), restored WIN-induced (0.5 μg/rat) amnesia. It can be concluded that the NMDA receptor mechanism located in the dorsal hippocampus may be involved in WIN-induced amnesia. 相似文献
20.
Ifenprodil is a novel type of N-methyl-D-aspartate receptor antagonist: interaction with polyamines 总被引:13,自引:0,他引:13
We have investigated the interactions of polyamines and the N-methyl-D-aspartate (NMDA) receptor antagonist ifenprodil with the binding of [3H]MK801 to the NMDA receptor. Spermine and spermidine but not putrescine substantially increase [3H]MK801 binding to well washed rat brain membranes in the absence or presence of saturating concentrations of glutamate and glycine. Spermine also increased the association and dissociation of [3H]MK801 from its binding site, suggesting that polyamines activate the NMDA receptor in a similar manner to glycine. Ifenprodil inhibited the binding of [3H]MK801 in a biphasic fashion. The high affinity phase of binding (Ki of approximately 15 nM) accounted for 50-60% of total [3H]MK801 binding in the nominal absence of glutamate, glycine, and polyamines or in the presence of 100 microM glutamate. This fraction was reduced to 20% by the addition of 30 microM glycine and could be abolished by the addition of 50 microM spermine. However, ifenprodil apparently did not act by binding to the polyamine recognition site. The low affinity phase (Ki of 20-40 microM) was insensitive to the presence of positive modulators and may represent binding to the Zn2+ regulatory site. Ifenprodil decreased NMDA and glycine-induced Ca2+ influx into cultured rat brain neurons. The potency of ifenprodil suggests that spermine may activate NMDA receptors in vivo. These data indicate that ifenprodil may bind to the NMDA receptor in a state-dependent fashion and preferentially stabilize an inactivated form of the channel. 相似文献