Neurophysiological investigation of effects of the D-1 agonist SKF 38393 on tonic activity of substantia nigra dopamine neurons

The effects of the D-1 agonist SKF 38393 on tonic activity of rat substantia nigra pars compacta dopamine neurons were studied using extracellular, single-unit recording techniques. Unlike nonselective D-1/D-2 dopamine agonists or the D-2 agonist quinpirole, SKF 38393 did not inhibit dopamine neuronal activity when applied iontophoretically or when administered intravenously in doses up to 20 mg/kg to chloral hydrate-anesthetized rats. Moreover, pretreatment with SKF 38393 did not alter the inhibitory response of these neurons to apomorphine or the D-2 agonist quinpirole. However, in locally anesthetized, gallamine-treated, artificially respired rats, dopamine cell activity was significantly altered by i.v. administration of SKF 38393; firing rate increases and decreases were observed. Administration of the inactive enantiomer of SKF 38393, S-SKF 38393, did not induce similar changes in parallel experiments. These results support the idea that unlike D-2 autoreceptor stimulation, D-1 receptor stimulation does not exert a direct local effect on dopamine neurons in the substantia nigra pars compacta and suggest that D-1 receptor stimulation at sites postsynaptic to the dopamine cells may indirectly affect the activity of some dopamine neurons through long-loop feedback mechanisms.     

AMPA受体的代谢

近年来研究表明AMPA受体和突触可塑性密切相关，了解AMPA受体的整个生命过程有助于进一步认识突触可塑性，进而认识学习记忆的分子机制。AMPA受体在粗面内质网合成，经高尔基体修饰后，更多地分布在树突柄等非突触部位，LTP和CaMKⅡ可以启动AMPA受体的突触插入，之后通过其胞质内C端，由ABP，GRIP和NSF等蛋白介导，锚定于突触后致密斑。PICK1和PKC可以介导突触膜上AMPA受体的胞吞过程，离开突触后，AMPA受体或被重新循环利用，或被溶酶体最终降解。     

Growth factor pre-treatment differentially regulates phosphoinositide turnover downstream of lysophospholipid receptor and metabotropic glutamate receptors in cultured rat cerebrocortical astrocytes

Reactive gliosis is an aspect of neural plasticity and growth factor (GF) stimulation of astrocytes in vitro is widely regarded as a model system to study astrocyte plasticity. Astrocytes express receptors for several ligands including lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P), agonists for the G-protein-coupled lysophospholipid receptors (lpRs). Activation of lpRs by LPA or S1P leads to multiple pharmacological effects including the influx of calcium, phosphoinositide (PI) hydrolysis, phosphorylation of extracellular receptor regulated kinase (ERK), release of arachidonic acid, and induces mitogenesis. Treatment of astrocytes in vitro with a growth factor cocktail (containing epidermal growth factor [EGF], basic fibroblast growth factor [bFGF] and insulin) led to a marked attenuation of lpR-induced PI hydrolysis. In contrast, under identical conditions, GF treatment led to marked potentiation of PI hydrolysis downstream of activation of another abundantly expressed G-protein coupled receptor, mGluR5. Quantitative gene expression analysis of GF-treated or control astrocytes by TaqMan RT-PCR indicated that GF treatment did not change gene expression of lpa1 and s1p1, but increased gene expression of s1p5 which is expressed at very low levels in basal conditions. These results suggest that GF differentially affected PLC activation downstream of mGluR5 versus lpR activation and that the changes in mRNA levels of lpRs do not account for marked attenuation of agonist-induced phosphoinositide turnover.     

重症肌无力抗乙酰胆碱受体单链抗体基因的构建

[目的 ]构建重症肌无力抗乙酰胆碱受体主要免疫原区单链抗体A 7基因 .[方法 ]应用PCR技术及基因克隆技术分两步完成重链和轻链可变区基因的克隆 ,再对构建的单链抗体A 7基因进行序列测定检测其核苷酸序列 .[结果 ]构建的重组质粒经序列分析 ,重链可变区基因长度为 36 9bp ,轻链可变区基因长度为 32 1bp ,单链抗体基因长度为 735bp ;单链抗体A 7基因正确地插入在载体质粒pHEN 2开放读码框架内 .[结论 ]成功地构建重症肌无力抗乙酰胆碱受体主要免疫原区单链抗体A 7基因 ,为进一步制备基因工程抗体奠定了基础 .     

Radioiodinated tracers for the evaluation of dopamine receptors in the neonatal rat brain after hypoxic-ischemic injury

In order to evaluate in vivo single-photon emission tomography (SPET) method of assessing cerebral function after hypoxic-ischemic injury in human neonates, we studied D₁ and D₂ dopamine receptors in a rat model. Seven-day-old rats underwent permanent unilateral common carotid ligation followed by exposure to 8% O₂. Two weeks later, in brains with no visible loss of hemispheric volume, striatal dopaminergic receptors were studied, with [¹²⁵I]TISCH and [1251]IBZM for the D₁ and D₂ dopamine receptors, respectively. Using [¹²⁵I]TISCH, we observed no modifications of D₁ receptors, but in contrast, ex vivo and in vitro autoradiographic experiments showed a 40% decrease in the striatal binding of [¹²⁵I]IBZM on both the ipsilateral and the contralateral side to the carotid ligation. These alterations were detected with IBZM, a D₂ dopamine receptor ligand usable for SPET imaging. Therefore, exploration of D₂ receptors by SPET in human neonates suffering from perinatal hypoxia-ischemia may be valuable for the diagnosis and follow-up of cerebral function damages. Correspondence to: D. Guilloteau     

In vivo receptor binding,neurochemical and functional studies with the dopamine D-1 receptor antagonist SCH 23390

Summary A series of in vivo experiments were undertaken, relating functional (motor activity, body temperature), dopamine (DA) receptor binding and neurochemical (catecholamine synthesis and utilization, DA release) aspects of the pharmacology of SCH 23390 in the rat.The compound inhibited the locomotor hyperactivity, but not the hypothermia, induced by the potent DA stimulant DP-5,6-ADTN. Interstingly, SCH 23390 simultaneously failed to displace DP-5,6-ADTN from its binding sites in the rat striatum—used as a direct in vivo biochemical index of DA (D-2) receptor interaction. The spontaneous locomotion in non-pretreated rats was likewise inhibited by SCH 23390. The locomotor-suppressive action, but not the DP-5,6-ADTN-displacing capcity of the D-2 blocker haloperidol was significantly enhanced by SCH 23390, suggesting that motility can be suppressed by either enhanced D-1 or D-2 (postsynaptic) receptor blockade, but also that the D-1 and D-2 sites involved may be physically distinct.SCH 23390 only slightly altered in vivo neurochemical of DA synthesis, release and nerve-impulse flow, indicating that, while similar in suppressing dopaminergic behaviour, the D-1 antagonist is less effective than traditional neuroleptics as an activator of DA neuronal feedback mechanisms. The weak increases of DA synthesis and release nonetheless obtained were equal in magnitude (30–40%) in the limbic vs. striatal brain areas; also in this respect, SCH 23390 thus differs from classical neuroleptics, which generally display more marked effects in the striatum than in limbic tissue.No major changes in the in vivo indices of NA synthesis and utilization (or in 5-HT synthesis) were found after SCH 23390 administration, by and large supporting the DA receptor specificity of the compound.In summary, the studies demonstrated that SCH 23390 can offset and accentuate, respectively, behavioural consequences of D-2 receptor stimulation and blockade. Importantly, at the same time no direct interaction at the level of D-2 DA receptor sites in the striatum was detected. Only slight, D-2 antagonist-like, changes in neurochemical indices of dopaminergic activity were observed after D-1 receptor blockade by means of SCH 23390. With regard to DA agonist hypothermia, SCH 23390 was without effect per se, but (at a high dose) attenuated the action of the D-2 antagonist haloperidol. The observations may indicate that the complex interactions between central D-1 and D-2 receptor-controlled mechanisms that influence behaviour, neurochemistry, and possibly autonomic nervous expression, are not identical.     

Clozapine acts as a 5-HT2 antagonist by attenuating DOI-induced inhibition of male rat sexual behaviour

Evidence has been reported that clozapine may derive part of its therapeutic effects in treatment-resistant schizophrenic patients by interacting with the serotonin system. Among the few behavioural models available to test the hypothesis of an interaction of clozapine with 5-HT₂ receptors, male rat sexual behaviour is particularly useful, since in this behaviour 5-HT_1A and 5-HT₂ receptors have opposite functions. Stimulation of 5-HT_1A receptors facilitates ejaculatory behaviour and stimulation of 5-HT₂ receptors inhibit ejaculation. In the present study, male rat sexual behaviour was depressed by treatment with DOI (1.0 mg/kg), a selective 5-HT₂ receptor agonist. The depressive effect of DOI was attenuated by the administration of clozapine (0.1–1.0 mg/kg) in doses that by themselves did not significantly affect sexual behaviour. It was concluded that clozapine in the male rat sexual behaviour model may be interpreted as serving as a 5-HT₂ antagonist.     

吗啡及纳洛酮对淋巴细胞体外增殖的作用(英文)

目的:研究吗啡对不同淋巴细胞增殖的作用及纳洛酮的影响.方法:观察吗啡对未成熟的、静止的及活化的脾脏淋巴细胞体外增殖影响及纳洛酮的阻断作用.结果:吗啡(1×10~(-10)—1×10~(-6)mol L~(-1))能增加Con A诱导的T-细胞的增殖,1 μmol L~(-1)还能促进LPS诱导的B-细胞的增殖,同时这些增强作用都能被纳洛酮50μmol L~(-1)阻断,纳洛酮单独亦能促进活化T-细胞的增殖.而吗啡1×10~(-10)—1×10~(-5)mol L~(-1)对静止的脾脏淋巴细胞及Con A活化的胸腺淋巴细胞的增殖都无影响.但是吗啡1mmol L~(-1)能广泛抑制静止的、LPS活化的脾脏细胞及Con A活化的胸腺,脾脏淋巴细胞增殖,且都不能被纳洛酮阻断.结论:吗啡对活化T-和B-细胞的促进作用是由细胞表面的阿片受体介导的,此阿片受体随着淋巴细胞的成熟和活化而变化,而吗啡1 mmol L~(-1)对淋巴细胞增殖的抑制作用却不是由经典的阿片受体介导的.     

5名电离辐射事故患者外周血T细胞T细胞抗原受体、T细胞分化抗原决定簇－3效应的研究

文中报道了５名事故性急性骨髓型放射病患者照后２．５和３．５年外周血Ｔ淋巴细胞Ｔ细胞受体（ＴＣＲ）基因，ＴＣＲ、Ｔ细胞分化抗原决定簇－３（ＣＤ_３）表达与ＴＣＲ／ＣＤ_３复合物功能的辐射效应．发现５名患者于照后２．５年，２名（５．２Ｇｙ和２．４Ｇｙ，５５岁）于照后３．５年外周血Ｔ细胞应答抗ＣＤ３单抗刺激而增殖的能力尚未完全恢复；经同时用ＩＬ－２和抗ＣＤ_３单抗刺激，增殖能力比单用抗ＣＤ_３单抗刺激有所增强；后２名的外周血ＴＣＲ、ＣＤ_３阳性细胞百分率一直低于正常对照和其他患者；并见一患者出现ＤＮＡ重排杂交带型．本文并从ＴＣＲ／ＣＤ_３在介导Ｔ细胞抗原刺激反应中的作用，电离辐射对ＴＣＲ／ＣＤ_３复合物的影响，后果和意义等方面进行了讨论．