中枢单胺类神经递质在酒精依赖中的分子作用机制

酒精依赖是以失去控制地饮用酒精为特征的慢性、复发性脑疾病, 业已成为严重的社会问题。中枢单胺类神经递质(包括多巴胺、5-羟色胺等)在酒精依赖症的发生、发展和系统功能失调中发挥着重要作用。文章探讨了单胺类神经递质关键调控点多巴胺受体、5-羟色胺受体、转运体、酪氨酸羟化酶、色氨酸羟化酶及单胺氧化酶基因等在酒精依赖中的作用机制, 结合本实验室在基因敲除小鼠模型方面的研究进展提出了酒精依赖分子机制的研究策略。在系统评述中枢单胺类神经递质介导的酒精依赖分子作用机制的基础上, 结合本实验室在酪氨酸羟化酶激活剂钙调蛋白依赖的蛋白激酶Ⅱ方面的研究成果探讨了可用于酒精依赖症治疗的作用靶点, 提出通过调整基因调控区的甲基化程度和改变pre-mRNA的选择性剪切等表观遗传学策略预防和治疗酒精依赖症, 同时根据基因多态性研究结果提出对酒精依赖症患者进行个性化预防和治疗的新策略。     

中枢表达c-fos的细胞与疼痛有关

第六届世界疼痛大会(1990年4月1～6日在澳大利亚召开)的进程表明:疼痛研究正经历一场重大变革,以往寻找躯体感觉标记线式(lablled line)感觉通路的研究已被针对感觉神经元可塑性的研究所取代。也就是说一个神经元的兴奋性和对突触传入的反应性易于发生改变;它们依据环境条件对伤害性和/或无害刺激发生反应。现已证明,脊髓神经细胞在外周组织受损时具有这种可修饰性。人们终于接受传导痛觉的神经     

4-Aminoethylpiperazinyl aryl ketones with 5-HT₁A/5-HT₇ selectivity

The well-known 5-HT(1A)/5-HT(7) selectivity issue was tackled by a new series of 4-aminoethylpiperazinyl aryl ketones (1a-1l) specifically designed to distinguish the two hydrophobic sites centered at the anchoring salt bridge. The 4-aminoethylpiperazinyl aryl ketones showed a wide spectrum of activity and selectivity for the 5-HT receptors depending on the type of the hydrophobic groups attached at the aryl piperazinyl ketone scaffold. Docking study of the most active compounds against 5-HT(7)R and 5-HT(1A)R revealed that both receptors have two hydrophobic pockets around the anchoring salt bridge. These two binding sites are perpendicular to each other in 5-HT(7)R but parallel in 5-HT(1A)R, and this observation is well matched with the previous report which claimed that 5-HT(7)R affinity arises from bent conformation of the bound ligand whereas an extended one is best suited for 5-HT(1A)R selectivity. Also, as these pockets have different size and shape, inhibitory activity as well as selectivity of the 4-aminoethylpiperazinyl aryl ketones against 5-HT(7)R and 5-HT(1A)R seemed to be determined by combination of two hydrophobic substituents attached at both ends of the title compounds.     

中枢5-羟色胺与心血管活动调节

中枢神经系统中不同的5-HT通路,在心血管活动调节中可能具有不同的效应。兴奋脑干-下丘脑5-HT的上行通路可升高血压;兴奋脑干-脊髓的5-HT下行通路则降低血压,抑制交感神经活动。二条5-HT通路通过下丘脑和孤束核相互联系,在心血管反射通路的不同环节中起不同作用。     

中枢5-羟色胺缺损引起的高血压及其中枢机理

目的：建立中枢５羟色胺（５－ＨＴ）缺损所致的实验性高血压大鼠（ＥＨＲ）模型并探讨其中枢机理。方法：侧脑室埋植瘘管及药物注射。大鼠尾动脉血压及心率启示仪记录清醒大鼠动脉压（ＡＰ）及心率（ＨＲ）。高效液相色谱－电化学检测法ＨＰＬＣ－ＥＣＤ）检测大鼠脑内单胺类递质含量。结果：（１）给大鼠侧脑室（ＩＣＶ）注射选择性神经化学切除剂５,６－双羟色胺（５,６－ＤＨＴ）引起中枢５－ＨＴ神经元缺损,使脑同５－ＨＴ含     

5-HT受体亚型在大鼠颌下腺的免疫组织化学定位及5-HT的功能研究

目的 研究探讨了大鼠颌下腺中5-羟钩胺受体亚型的分布以及5-HT功能。方法 免疫组织化学法和免疫酶联检测法,结果 大鼠颌下腺的浆液性腺泡上皮细胞,闰管,颗粒曲管,纹状管和排泄管的管壁上皮细胞均呈5-HT1AR离体培养的颌下腺分泌神经生长因子（NGF）,但是,当外源5-HT浓度大于10^-7时却抑制NGF的分泌。结论 提示5-HT对颌下腺NGF的分泌可能起双向调节的作用。     

Computational exploration of polymorphisms in 5-hydoxytryptamine 5-HT₁A and 5-HT₂A receptors associated with psychiatric disease

The huge polymorphic data have been prioritized towards a specific disease based on sequence and structure homology tools to a large extent. In this study, we have explored the potential non-synonymous Single Nucleotide Polymorphism (nsSNP) in serotonin (5-HT) receptors involved in psychotic syndromes and their response pathway. The most damaging point mutations were screened from 12 classes of serotonin receptors comprising 7743 variants. In 5HT(1A) receptor, two alleles were found to be highly deleterious located at ligand binding extracellular-2 and one at intracellular loop-3 domains. Similarly, we found two alleles predicted to be highly damaging in 5HT(2A) residing at N and C-Terminal domains. The above alleles were further confirmed based on their flexibility and stability difference using the molecular dynamic simulation analysis. Integrating these results appeared promising for being able to filter out potential non-synonymous Single Nucleotide Polymorphisms for neuropsychiatric disorders.     

《酒精中毒：临床与实验研究》：人体酒精依赖同基因有关

美国弗吉尼亚大学医学部的研究人员发现,血清素的运输蛋白SLC6A4基因在影响酒精依赖者的饮酒强度方面起关键作用。这是科学家首次发现酒精依赖的强度同基因的联系,研究人员希望,在未来能够通过基因靶向疗法缓解嗜酒者依赖酒精的程度,相关论文发表在近期出版的《酒精中毒：临床与实验研究》（Alcoholism—Clinical and Experimental Research）杂志上。     

荷叶中的生物碱及其对5-HT 2A和5-HT 2C受体的激动作用研究CSCD

对荷叶中的生物碱进行了分离、鉴定和调脂减肥活性研究。本研究结合传统酸提碱沉法与现代高效液相色谱制备技术,从荷叶中分离、纯化到11个生物碱,分别被鉴定为N-氧基原荷叶碱(1)、原荷叶碱(2)、莲碱(3)、降氧化北美黄连次碱(4)、荜茇宁(5)、巴婆碱(6)、O-去甲基荷叶碱(7)、N-去甲基荷叶碱(8)、荷叶碱(9)、衡州乌药碱(10)和亚美罂粟碱(11),其中,化合物1、4和5为首次从荷叶中分得。测试所得化合物对5-HT_(2A)和5-HT_(2C)受体的激动作用,结果表明11个生物碱对5-HT_(2A)受体均具有一定的激动作用,进一步揭示了荷叶调脂减肥的可能药效基础和作用机理。     

Do imipramine and dihydroergosine possess two components--one stimulating 5-HT1 and the other inhibiting 5-HT2 receptors?

The mechanisms by which imipramine and dihydroergosine stimulate the 5-HT syndrome in rats and inhibit the head-twitch response in rats and mice were studied. Imipramine- and dihydroergosine-induced stimulation of the 5-HT syndrome was inhibited stereoselectively by propranolol, a high affinity ligand for 5-HT1 receptor sites, but not by ritanserin, a specific 5-HT2 receptor antagonist. (-)-Propranolol potentiated the inhibitory effect of imipramine, but not of dihydroergosine on the head-twitch response, while ritanserin was without effect. Neither imipramine nor dihydroergosine were able to stimulate the 5-HT syndrome in the animals pretreated with p-chlorophenylalanine. As expected, 8-OH-DPAT, a selective 5-HT1A receptor agonist, stimulated, and 5-HT1B agonists CGS 12066B and 1-(trifluoromethylphenyl)piperazine (TFMPP) failed to stimulate the 5-HT syndrome induced in rats by pargyline and 5-HTP administration. A higher dose of ritanserin inhibited the syndrome. While 8-OH-DPAT alone produced all behavioral components of the 5-HT syndrome, dihydroergosine or imipramine alone even at very high doses never produced tremor or a more intensive forepaw padding as seen when these drugs were given in combination with pargyline and 5-HTP. A single administration of (-)-propranolol also inhibited the head-twitch response. This effect lasted in mice longer than after ritanserin administration. In in vitro experiments dihydroergosine expressed approximately twenty-fold higher affinity for 3H-ketanserin binding sites than imipramine. The results suggest that imipramine and dihydroergosine possess two components--one stimulating the 5-HT syndrome in rats by a presynaptic, presumably 5-HT1A-mediated mechanism, and the other inhibiting 5-HT2 binding sites.     

中枢5－羟色胺能系统与下丘脑－垂体应激激素

存在于下丘脑的神经末梢所释放的５－羟色胺（５－ＨＴ）可增加ＣＲＨ和肾素释放因子、垂体前叶ＡＣＴＨ和催乳素（ＰＲＵ、垂体后叶加压素（ＶＰ）和催产素（ＯＴ）的分泌。５－ＨＴ１和／或５－ＨＴ２受体激活介导了这些激素分泌。     

中枢5—羟色胺能系统与下丘脑—垂体应激激素

存在于下丘脑的神经末梢所释放的５－羟色胺（５－ＨＴ）可增加ＣＲＨ和肾素释放因子、垂体前叶ＡＣＴＨ和催乳素（ＰＲＬ）、垂体后叶加压素（ＶＰ）和催产素（ＯＴ）的分泌。５－ＨＴ１和／或５－ＨＴ２受体激活介导了这些激素分泌。     

5-HT2和5-HT3受体在外周初级感觉神经末梢痛反应和痛调制中的相互作用

目的：探讨5-HT2和5-HT3受体亚型在5-HT引起外周痛反应和痛调制中的相互作用及其机制;方法：在大鼠三又神经节神经元标本上应用全细胞膜片钳技术记录5-羟色胺激活电流（15_HT）,并结合痛行为实验进行观察。结果：在大多数受检细胞（54／88,61．4％）特别是中、小型细胞外加5-HT可引起一快去敏感的内向电流,此内向电流能被5-HT,受体特异性激动剂2-甲基-5-羟色胺所模拟,被5-HT3受体拮抗剂ICS250-930可逆性阻断,而5-HT2受体激动剂α-甲基-5-羟色胺则有明显增强15-HT的作用,5-HT1受体激动剂R-（＋）-UH301无明显反应。在进一步的整体清醒动物的行为学试验中我们观察到,大鼠后肢掌底皮下注射5-HT（10-5,10-4和10-3mol／L）引起浓度依赖性的痛行为反应,而用5-HT2和5-HT3受体特异性拮抗剂Cyproheptadine和ICS250-930分别阻断相应受体亚型后,5-HT引起的痛行为反应的强度序列为：5-HT〉5-HT＋ICS〉5-HT＋Cyp。结论：本文结果提示：5-HT所引起的痛反应中,在初级感觉神经元水平5-HT3受体可能仅起着启始作用,而5-HT,受体则在伤害性信息的维持和调制过程中发挥更大的作用。     

ABC法显示5-HT与脑血管双染技术及意义

5-羟色胺(5-HT)是己知最强的颅内血管收缩剂之一,对维持脑血管结构的完整性有十分重的意义.由于研究5-HT 在急性脑缺血病发生、发展过程中的作用,我们对5-HT 与脑血管在同一切片上进行了双标染色,取得了满意结果。1 材料与方法:选用健康 Wistar 大白鼠用过量比妥钠经腹腔麻醉后,结扎一侧颈内动脉30分钟,取脑组织1.5cm×1 cm×0.5cm 用0.5%戊二醛—4%多聚甲醛4℃固定6～9小时,切成40μm 冰冻切片用 DBA液(0.05mol/L pH7.6TBS 100ml、DAB 50mg、30%H_2O?_2 30u])显示血管10～15分钟,然后再用 ABC 法结合改良的 DAB 显色法(0.05mol/LpH 7.6 TBS 10ml,TAB 4mg、8%Nicl 50ul、3%H_2O_2 25ul)     

重庆居民5-HT2A基因多态性与原发性高血压关系

以聚合酶链PCR法分析重庆市一般人群的5-HT2A基因C102T多态性(样本总数348人,其中高血压组:HT=137例,非高血压组:NT=211例)的临床指标间的相关性与频率分布。了解重庆地区汉族人群5-羟色胺受体2基因(5-hydroxytryptamine receptor gene,5-HT2A)C102T多态性与原发性高血压病(essential hypertension,EH)的关系。卡方检验结果显示5-HT2A的C102T基因多态性(P=0.549)与等位基因频率(P=0.263)在HT与NT之间没有显著性统计学差异;5-HT2A的C102T基因多态性与高血压logistic回归模型分析结果显示也未见显著性差异,卡方值(Wald)为0.399;比值比为0.884;95%的可信区间为0.603~1.296,P值为0.528。一般线性模型分析结果:5-HT2A基因C102T多态性与收缩压,舒张压之间没有显著性统计学差异,PSBP=0.868,PDBP=709。5-HT2A的C102T多态性可能与重庆汉族人群EH无关。     

Novel brain penetrant benzofuropiperidine 5-HT₆ receptor antagonists

7-Arylsulfonyl substituted benzofuropiperidine was discovered as a novel scaffold for 5HT(6) receptor antagonists. Optimization by substitution at C-1 position led to identification of selective, orally bioavailable, brain penetrant antagonists with reduced hERG liability. An advanced analog tested in rat social recognition model showed significant activity suggesting potential utility in the enhancement of short-term memory.     

Synthesis and structure–affinity relationships of novel small molecule natural product derivatives capable of discriminating between serotonin 5-HT1A, 5-HT2A, 5-HT2C receptor subtypes

Efforts to develop ligands that distinguish between clinically relevant 5-HT2A and 5-HT2C serotonin receptor subtypes have been challenging, because their sequences have high homology. Previous studies reported that a novel aplysinopsin belonging to a chemical class of natural products isolated from a marine sponge was selective for the 5-HT2C over the 5-HT2A receptor subtype. Our goal was to explore the 5-HT2A/2C receptor structure–affinity relationships of derivatives based on the aplysinopsin natural product pharmacophore. Twenty aplysinopsin derivatives were synthesized, purified and tested for their affinities for cloned human serotonin 5-HT1A, 5-HT2A, and 5-HT2C receptor subtypes. Four compounds in this series had >30-fold selectivity for 5-HT2A or 5-HT2C receptors. The compound (E)-5-((5,6-dichloro-1H-indol-3-yl)methylene)-2-imino-1,3-dimethylimidazolidin-4-one (UNT-TWU-22, 16) had approximately 2100-fold selectivity for the serotonin 5-HT2C receptor subtype: an affinity for 5-HT2C equal to 46 nM and no detectable affinity for the 5-HT1A or 5-HT2A receptor subtypes. The two most important factors controlling 5-HT2A or 5-HT2C receptor subtype selectivity were the combined R1,R3-alkylation of the imidazolidinone ring and the type and number of halogens on the indole ring of the aplysinopsin pharmacophore.     

5-HT metabolism in the intestinal wall of the rat—II. The nerves plexuses—interactions between 5-HT containing cells

The presence of serotonin (5-HT) in dissected intestinal muscular wall of the caecum was demonstrated by the determination of endogenous level of the amine by both spectrofluorimetric and radioenzymatic assays. Biosynthesis of [³H]5-HT from [³H]tryptophan in in vitro conditions revealed the presence of tryptophan hydroxylase in these muscular layers and therefore strongly suggest the presence of serotoninergic neurons. Following dissection of the mucosa from the muscular layers containing the nerve plexuses, endogenous 5-HT and 5-hydroxyindol acetic acid levels as well as amounts of [³H]5-HT synthesized from [³H]tryptophan were always higher than those found in intact fragments of the caecum. These results are discussed in terms of metabolic processes involved in the regulation between the two 5-HT containing compartments.     

云南汉族人群5-羟色胺转运体基因启动子区多态性与酒精依赖的相关性

为了探讨云南汉族人群中5-羟色胺转运体基因启动子区多态性(5-HTTLPR)与酒精依赖的关联性, 文章采用PCR扩增和DNA测序技术, 对云南地区118例酒精依赖患者和214例健康对照个体进行了5-HTTLPR的基因多态性分析。结果表明: 酒精依赖患者组和正常对照组的5-HTTLPR的基因型分布存在显著性差异, L/L和L/S基因的携带者人群嗜酒发生率显著低于S/S基因型人群(OR: 0.581, P=0.026)。S和L等位基因频率在两组间无统计学差异(χ²=2.594, P=0.107), 但其分布存在种族差异性。因此, 云南地区人群中5-HTTLPR多态与酒精依赖存在相关性, L/L和L/S基因型可能是降低酒精依赖发病的影响因子之一。