5-HT1B基因A161T多态性与抑郁症的关联研究

目的探讨抑郁症患者与5-HT1B受体基因A161T多态性之间的关系。方法应用聚合酶链式反应（PCR）扩增技术及限制性片段长度多态性（arLP）分别检测365例抑郁症患者（病例组）、365名健康人（对照组）的5-HT1B受体基因A161T多态性。结果5-HT1B受体基因A161T多态性在病例组和对照组的基因型和等位基因分布频率无显著性差异；按照发病年龄（30岁为界）、有无家族史及有无自杀观念分层后，各亚组与对照组间基因型和等位基因分布也无显著性差异。经多因素分析控制年龄、性别因素后各组基因型分布仍无显著性差异。结论5-HT1B受体基因A161T多态性可能不是抑郁症及其各临床亚型发病的一个危险因素。     

5-羟色胺2A受体基因多态性与抑郁症的关联

目的：探讨中国汉族人群难治性抑郁症患者与5-羟色胺2A(5-HT2A)受体基因的T102C多态性之间的关系。方法：抽取79例难治性抑郁症患者作研究，以102名正常人作对照。应用聚合酶链式反应(PCR)扩增技术及限制性片段长度多态性(RFLP)分别测定所有研究对象的5-HT2A受体基因的基因型和等位基因。结果：5-HT2A受体基因的3种基因型(A1／A1，A1／A2和A2／A2)在难治性抑郁症组的分布分别为31．6％、54．4％和13．9％，在对照组分别为29．4％、45．1％和25．5％，两组间差异无显著性。结论：5-HB。受体基因的T102C多态性与难治性抑郁症之间无显著关联。     

精神分裂症患者5-HT2A受体基因相关因素的研究

目的　分析汉族人 5 HT2A受体基因与精神分裂症易感性之间的关系以及影响患者 5 HT2A受体基因的相关因素。方法　 2 6 9例精神分裂症病人 ,310例正常对照 ,用聚合酶链式反应 (PCR)扩增及限制性片段长度多态性 (RFLPs)技术测定其 5 HT2A受体基因型和等位基因。结果　发现含 5 HT2A受体基因的等位基因A2的精神分裂症患者平均发病年龄明显大于含等位基因A1的患者 ,但 5 HT2A受体基因与精神分裂症的易感性、患者的性别、家族史、症状严重度均无显著相关。结论　 5 HT2A受体基因的等位基因A2可明显推迟精神分裂症患者的发病年龄 ,但 5 HT2A受体基因不影响汉族人精神分裂症的易感性、患者的症状严重度 ,患者 5 HT2A受体基因的频率分布也不受患者的性别、家族聚集性的影响     

精神分裂症与5—HT2c受体基因的关系

目的探讨上海地区汉族人５－ＨＴ２ｃ受体基因Ｃｙｓ２３Ｓｅｒ多态性的发生率及其与精神分裂症之间的关系。方法随机抽取２７４例精神分裂症患者作研究,以１８７例正常人作对照。用多聚酶链式反应（ＰＣＲ）扩增及单链构橡多态性（ＳＳＣＰ）分析、限制性片段长度多态性（ＲＦＬＰｓ）技术检测所研究对象的５－ＨＴ２ｃ受体基因Ｃｙｓ２３Ｓｅｒ多态性。结果仅在１个正常个体发现Ｃｙｓ－２３－Ｓｅｒ突变,精神分裂症患者中均未见     

5—HT6受体基因多态性与阿尔茨海默病的关联分析

目的探讨中国上海地区汉族人群中5-HT6受体基因多态性与阿尔茨海默病(AD)的相互关系.方法应用聚合酶链式反应(PCR)-限制性片段长度多态性(RFLP)方法,在106例AD患者,87例血管性痴呆(VD)患者和140例正常健康人中观察了5-HT6受体基因多态性的分布,并对5-HT6受体基因多态性与阿尔茨海默病之间的关系进行探讨.结果①阿尔茨海默病与5-HT6受体基因的多态性之间无显著意义的关联(P＞0.05);②在将受试人群进行ApoE基因分型后,ApoEε4型与非ApoEε4型人群中AD与5-HT6受体基因各基因型或等位基因均无关联(P＞0.05);③将AD患者进行ApoE基因分型后,非ApoEε4型AD与5-HT6的267C/T基因型正相关(OR=2.46,95%CI5.43-1.11,P＜0.05).结论中国上海地区汉族人群中5-HT6受体基因多态性与非ApoEε4型阿尔茨海默病相关联,表现为C/T型频率的升高.     

Association of a polymorphism of the serotonin 1B receptor gene and alcohol dependence with inactive aldehyde dehydrogenase-2

Summary. The use of persons who become alcoholic despite having a well-defined negative risk for alcoholism (inactive aldehyde dehydrogenase-2 or ALDH2) is advantageous in genetic research because of this population's reduced heterogeneity and possible genetic factors conferring susceptibility to alcohol dependence. This investigation of central serotonin neurotransmission, specifically the serotonin 1B (5HT1B) receptor gene and its role in both regulating alcohol consumption and developing alcohol dependence revealed overrepresentation of the C allele of the 861G>C polymorphism of 5HT1B in alcoholics with inactive ALDH2, compared with its frequency in nonalcoholic controls. No significant differences in 5HT1B genotype and allele distributions were observed between alcoholics with active ALDH2 and controls, however. Taken together with recent observations, these results suggest that genetic variability of the 5HT1B receptor is involved in the development of some type of alcohol dependence. Received October 10, 2001; accepted November 9, 2001     

单相抑郁症中5-HT2A受体基因及MAOA型 基因的相互影响

目的探讨单相抑郁症病因中５－ＨＴ２Ａ受体基因与ＭＡＯＡ型基因的相互影响。方法在７２例单相抑郁症患者和８１例正常健康人中,采用ＰＣＲ－ＲＦＬＰ和Ａｍｐ－ＦＬＰ技术检测５－ＨＴ２Ａ和ＭＡＯＡ型的等位基因和基因型分布。结果单相抑郁症与５－ＨＴ２Ａ基因间无遗传关联,但是具５－ＨＴ２Ａ的Ａ２／Ａ２基因型患者与ＭＡＯＡ型的１１４ｂｐ等位基因呈强烈关联（ＲＲ＝６．２５,Ｐ＜００５）。结论５－ＨＴ２Ａ受体基因和ＭＡＯＡ型基因在单相抑郁症发生中可能起有一定相互作用。     

孤独症核心家系5—HT和APOE基因的关联研究

目的 探讨孤独症与5-HT基因和APOE基因之间的关系。方法 应用PCR-RFLP技术对符合国际疾病分类第10版(ICD-10)中孤独症诊断标准的21例孤独症患儿和他们的父母进行了5-HT2a,5-HT6和APOE多态性的检测。结果 孤独症患儿与对照组5-HT2a,5-HT6和APOE的基因频率和基因型频率的分布呈基本一致的趋势,两组间未显示具有统计学意义的差别。采用基于单体型的单体型相对风险率分析方法,发现仅5-HT6基因中T等位基因与孤独症显著关联(RR=3.59,P<0.05)。传递不平衡检验(TDT)发现孤独症可能与5-HT6中T等位基因相连锁(McNemarX~2=5.4,P<0.05)。结论 5-HT6基因与孤独症的发病可能存在关联或连锁关系。     

5-HT6受体基因多态性与双相情感障碍的关联研究

目的探讨5-HT6受体基因多态性与双相情感障碍之间的关系。方法应用聚合酶链反应(PCR)和限制性片段长度多态性(RFLP)技术，对93例双相情感障碍病人和102例正常对照者的5-HTs受体基因多态性(267C／T)进行了检测。结果双相情感障碍与5-HT。受体基因的多态性(267C／T)之间无显著意义的关联，发病年龄也与此多态性无关。结论5-HT。受体基因的267C／T多态性可能与双相情感障碍的发生无直接关联。     

Autoradiographic analyses of 5-HT1A and 5-HT2A receptors after social isolation in mice

Social isolation of rodents is used to model human psychopathological processes. In the present study, the effects of intermediate and long term isolation housing on postsynaptic 5-HT_1A and 5-HT_2A receptors were analyzed in male mice housed in groups or isolation for 4 and 12 weeks. [³H]8-OH-DPAT and [³H]ketanserin were used to label 5-HT_1A and 5-HT_2A receptors. Four representative sagittal sections (planes 1–4) were scored by in vitro autoradiography. Whereas after 4 weeks of housing both receptor densities were lowered significantly in isolated mice, after 12 weeks of housing only marginal isolation effects were seen. Intermediate isolation reduced 5-HT_1A receptors especially in the lateral frontal, parietal and entorhinal cortex (−63%), in the lateral CA1–3 and dentate gyrus region of the hippocampus (−68%), in the basolateral, basomedial, central and medial amygdaloid nuclei (between −38 and −66%), and in the hypothalamus (−28%). 5-HT_2A receptors were strongly reduced in the frontal cortex (between −47 and −74%), in the hippocampus (between −47 and −95%), in the striatum (between −66 and −76%), and in the accumbens nucleus (between −59 and −73%) in comparison to group housed control mice. After 12 weeks of isolation in the hippocampus continuously decreased 5-HT_1A receptor densities were demonstrated (between −24 and −61%). But increased 5-HT_2A receptor densities were seen in the lateral striatum (+86%) compared to control mice. Age-dependent effects were also found. After 12 weeks of group housing the 5-HT_1A and 5-HT_2A receptor densities were decreased (between −28 and −54%) in all analyzed brain regions in comparison to 4 weeks of group housing. Isolated animals showed diminished 5-HT_1A receptor densities in the cortex (−14%) and hippocampus (−15%), but increased 5-HT_1A receptor densities in the amygdala (+33%) after 12 weeks. The 5-HT_2A receptor densities were increased in all analyzed regions (between +31 and +96%) after 12 weeks of isolation compared to 4 weeks. To explain these dynamic, time-dependent pattern of isolation-induced changes different regulation processes are supposed regarding 5-HT_1A and 5-HT_2A receptors. Besides metabolism-related adaptation processes also neurotransmitter and hormonal (e.g., glucocorticoid) interactions especially in limbic regions have to be considered.     

儿童焦虑症与5-HT2A受体基因多态性的关联分析

目的 探讨儿童焦虚症与５－ＨＴ２Ａ受体基因多态性之间的遗传关联。方法 采用聚合酶链式反应（ＰＣＲ）和限制性片段长度多态性（ＲＦＬＰｓ）方法,对６１个符合ＤＳＭ－Ⅳ与ＣＣＭＤ－２－Ｒ诊断标准的焦虚症儿童及其父母的５－ＨＴ２Ａ受体基因多态性进行分型,分型结果用单体型相对风险方法（ＣＨＲＲ和ＨＨＲＲ）与传递不平衡检验（ＴＤＴ）进行分析。结果 儿童焦虑症与５－ＨＴ２Ａ受体基因无显著性关联。ＣＨＲＲ、ＨＨＲＲ和ＴＤＴ值分别为２．３６０７～０．９２１３,１．０９５５和１．８８,Ｐ值均〉０．０５。结论 儿童焦虑症与５－ＨＴ２Ａ受体基因Ｔ１０２Ｃ多态性无关联。     

精神分裂症与5—HT2A受体基因相关联

目的：探讨中国汉族人群精神分裂症与5－HT2A受体基因T102C多态性之间的关系。方法：选择精神分裂症患者286例,按病期分一般组和慢性组;以291例正常人对照,也按现年龄相应地分为一般对照组和慢性对照组,分生物学技术采用PCR扩增及MSPI内切酶酶切技术,检测各组研究对象的5－HT2A受体基因的基因型和等位基因的频率分布,结果：一般组精神分裂症患者5－HT2A受体基因A2／A2型频率及A2等位基因频率均显著高于对照组（ZA2／A2＝2．97,P＜0．05;ZA2＝2．19,P＜0．05）。经关联分析,其OR值分别为2．35（P＜0．05）和1．45（P＜0．05）。结论：提示中国汉族人群中5－HT2A受体基因多态性可能与精神分裂症呈正关联,而与慢性精神分裂症无关联。     

Gene structure and expression of the mouse 5-HT2 receptor.

Serotonin (5-hydroxytryptamine, 5-HT) is an important neurotransmitter which mediates numerous physiological functions. Using the SacI-EcoRI restriction fragment of the rat brain 5-HT2 receptor cDNA as a probe, we have screened a mouse brain cDNA library, created by random priming and constructed in SWAJ vectors, and have isolated a cDNA encoding a 1.4 kb open reading frame which codes for a functional mouse 5-HT2 receptor identified from pharmacological binding profiles and coupling of phosphoinositide formation in a stably transfected fibroblast cell line. The deduced amino acid sequence is 97.4% identical to the rat 5-HT2 receptor. Using the same 5-HT2 receptor cDNA probe, ten positive genomic clones were isolated from two mouse genomic libraries constructed in the pWE15 cosmid vector and the EMBL-3 phage vector. Extensive mapping and sequencing of these genomic clones indicate the mouse 5-HT2 receptor coding region spans over 20 kb and is composed of three exons split by two introns. Northern blot analysis shows one band of 5-6 kb in the mouse brain, but not in the heart, lung, liver, or kidney total RNA. Southern analysis of mouse liver genomic DNA shows a simple pattern of digestion by several restriction enzymes, which suggests that one copy of the 5-HT2 receptor gene may exist in the mouse genome.     

No association of C-1019G promoter polymorphism of 5-HT1A receptor gene with migraine

It is well known that migraine has a strong genetic component, although the type and number of genes involved remains unclear. There is evidence to suggest that serotonin-related genes may be involved in the pathogenesis of migraine. To investigate whether the 5-HT1A receptor gene contributes to the risk of migraine we performed an association study of C-1019G promoter polymorphism of the gene in 102 migraineurs and 93 controls. Subjects were of Han Chinese origin. No significant differences in allele (P=0.82) or genotype frequencies (P=0.71) were seen in migraineurs compared with the controls. When migraine with aura, without aura, with family history, without family history were analyzed separately, the frequencies did not vary significantly. Our results suggest that C-1019G in 5-HT1A is not a major genetic risk factor for migraine.     

5-HT6受体基因多态与精神分裂症患病风险的关联分析

目的探讨5-HT6受体基因多态与中国汉族精神分裂症患病风险的关系。方法入组居住在上海及周边地区的汉族精神分裂症患者333例和健康对照365例,通过TaqMan探针SNP基因分型技术对5-HT6受体基因及基因上游7kb区域的标签SNPs rs3790756和rs4912138进行基因分型,并进行统计分析。结果发现SNPs rs3790756和rs4912138的基因型和等位基因频率分布在精神分裂症病例组和健康对照之间差异未达到统计学意义。进一步进行基因型联合分析,rs3790756和rs4912138共组成7种联合基因型,7种联合基因型在病例组和健康对照组间的分布有显著性差异（χ2=13.5,P〈0.05）,其中rs3790756CC和rs4912138AG组成的联合基因型在病例组和对照组中的频率分别为18.3%和27.1%,相对危险度为0.603（P〈0.05）。结论研究提示5-HT6受体基因多态rs3790756和rs4912138组成的CCAG联合基因型可能与精神分裂症的风险降低有关。     

5-HT1A and 5-HT1B receptors control the firing of serotoninergic neurons in the dorsal raphe nucleus of the mouse: studies in 5-HT1B knock-out mice

The characteristics of the spontaneous firing of serotoninergic neurons in the dorsal raphe nucleus and its control by serotonin (5-hydroxytryptamine, 5-HT) receptors were investigated in wild-type and 5-HT1B knock-out (5-HT1B-/-) mice of the 129/Sv strain, anaesthetized with chloral hydrate. In both groups of mice, 5-HT neurons exhibited a regular activity with an identical firing rate of 0.5-4.5 spikes/s. Intravenous administration of the 5-HT reuptake inhibitor citalopram or the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) induced a dose-dependent inhibition of 5-HT neuronal firing which could be reversed by the selective 5-HT1A antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohe xane carboxamide (WAY 100635). Both strains were equally sensitive to 8-OH-DPAT (ED50 approximately 6.3 microgram/kg i.v.), but the mutants were less sensitive than wild-type animals to citalopram (ED50 = 0.49 +/- 0.02 and 0.28 +/- 0.01 mg/kg i.v., respectively, P < 0.05). This difference could be reduced by pre-treatment of wild-type mice with the 5-HT1B/1D antagonist 2'-methyl-4'-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-carbox yli c acid [4-methoxy-3-(4-methyl-piperazine-1-yl)-phenyl]amide (GR 127935), and might be accounted for by the lack of 5-HT1B receptors and a higher density of 5-HT reuptake sites (specifically labelled by [3H]citalopram) in 5-HT1B-/- mice. In wild-type but not 5-HT1B-/- mice, the 5-HT1B agonists 3-(1,2,5, 6-tetrahydro-4-pyridyl)-5-propoxypyrrolo[3,2-b]pyridine (CP 94253, 3 mg/kg i.v.) and 5-methoxy-3-(1,2,3, 6-tetrahydropyridin-4-yl)-1H-indole (RU 24969, 0.6 mg/kg i.v.) increased the firing rate of 5-HT neurons (+22.4 +/- 2.8% and +13.7 +/- 6.0%, respectively, P < 0.05), and this effect could be prevented by the 5-HT1B antagonist GR 127935 (1 mg/kg i.v.). Altogether, these data indicate that in the mouse, the firing of 5-HT neurons in the dorsal raphe nucleus is under both an inhibitory control through 5-HT1A receptors and an excitatory influence through 5-HT1B receptors.     

Different allele distribution of a regulatory MAOA gene promoter polymorphism in antisocial and anxious-depressive alcoholics

Summary. Heritable factors account for approximately 40–60% of the total variance of liability to alcohol dependence. The present study tested whether a novel functional polymorphism in the promotor region of the X-chromosomal monoamine oxidase A gene (MAOA) was related to antisocial and anxious-depressive traits in alcoholics. Due to the X-chromosomal localization of the MAOA gene, psychobiological traits were compared separately for both genders of 298 male and 66 female alcoholics. In males, 30 of 59 alcoholics with antisocial personality disorder carried the low-activity 3-repeat allele in contrast to only 7 of 31 anxious-depressive alcoholics (51% vs. 23%; p = 0.02). Likewise, female anxious-depressive alcoholics showed a trend towards a low frequency of genotypes with the 3 repeat allele compared to female alcoholics without these symptoms (29% vs. 53%; p = 0.09). Taken together, these findings suggest that the 3-repeat allele of the MAOA polymorphism contributes modestly to the dimension of over- and underreactive behaviors as possible antecedents of alcoholism. Received June 16, 1999; accepted January 25, 2000     

Involvement of 5-HT1B receptors in the anticonflict effect of m-CPP in rats

Summary The anticonflict activity of m-CPP, a non-selective agonist of 5-HT receptors, was studied in the drinking conflict test in rats. m-CPP administered in doses of 0.125–0. 5 mg/kg increased the number of punished licks, the maximum effect having been observed after a dose of 0.25 mg/kg. The anticonflict effect of m-CPP (0.25 mg/kg) was antagonized by the non-selective 5-HT antagonist metergoline (1–4 mg/kg) and by the -adrenoceptor blocker SDZ 21009 (2 and 4 mg/kg) with affinity for 5-HT_1A and 5-HT_1B receptors. On the other hand, the 5-HT_1A receptor antagonist NAN-190 (0.5 and 1 mg/kg), the 5-HT₂ receptor antagonist ritanserin (0.25 and 0.5 mg/kg), and the -blockers betaxolol (8 mg/kg) and ICI 118,551 (8 mg/kg) with no affinity for 5-HT receptors did not affect the effect of m-CPP. The effect of m-CPP was not modified, either, in animals with the 5-HT lesion produced by p-chloroamphetamine.These results suggest that the anticonflict effect of m-CPP described above results from stimulation of 5-HT_1B receptors — most probably these which are located postsynaptically.     

5-HT1B receptor-mediated presynaptic inhibition at the calyx of Held of immature rats

5-hydroxytryptamine (5-HT) inhibits transmitter release via activating GTP-binding proteins, but the target of 5-HT receptors in the nerve terminal is not determined. We addressed this question at the calyx of Held synapse in the brainstem slice of immature rats. Bath-application of 5-HT attenuated the amplitude of nerve-evoked excitatory postsynaptic currents (EPSCs) associated with an increase in the paired-pulse ratio, whereas it had no effect on the amplitude of spontaneous miniature EPSCs. The 5-HT1B receptor agonist CP93129 mimicked the inhibitory effect of 5-HT, but the 5-HT1A agonist (R)-(+)-8-hydroxy-DPAT (8-OHDPAT) had no effect. The 5-HT1B receptor antagonist NAS-181 blocked the inhibitory effect of 5-HT. These results suggest that 5-HT activated 5-HT1B receptors in calyceal nerve terminals, thereby inhibiting transmitter release. In direct whole-cell recordings from calyceal nerve terminals, 5-HT attenuated voltage-dependent Ca2+ currents, but had no effect on voltage-dependent K+ currents. When EPSCs were evoked by presynaptic Ca2+ currents during simultaneous pre- and postsynaptic recordings, the magnitude of the 5-HT-induced inhibition of Ca2+ currents fully explained that of EPSCs. Upon repetitive applications, 5-HT showed tachyphylaxis, with its effect on both EPSCs and presynaptic Ca2+ currents becoming weaker in the second application. 1,2-bis(o-aminophenoxy)ethane-N-N'-N'-N'-tetraacetic acid (BAPTA; 10 mm) loaded into the nerve terminal abolished this tachyphylaxis. The presynaptic inhibitory effect of 5-HT was prominent at postnatal day 5, but became weaker as animals matured. We conclude that activation of 5-HT1B receptors inhibits voltage-gated Ca2+ channels, thereby inhibiting transmitter release at immature calyceal nerve terminals, and that 5-HT1B receptors undergo Ca2+-dependent tachyphylaxis on repetitive activations.     

西酞普兰对脑卒中后抑郁大鼠海马齿状回5-羟色胺1A受体表达的影响

目的 观察西酞普兰对拟脑卒中后抑郁(post-stroke depression,PSD)大鼠海马齿状回5-羟色胺1A(5-HT1A)受体表达的影响,探讨其治疗PSD可能的药理机制.方法 将雄性SD大鼠分为3组正常对照组、拟PSD组和西酞普兰干预组.左侧大脑中动脉阻塞(MCAO)联合慢性不可预见温和应激刺激(CMS)及孤养法建立拟PSD动物模型,同时予西酞普兰(10 mg·kg-1·day-1)干预4周,荧光实时定量PCR和Western印迹方法检测并比较CMS开始后第19、28天各组大鼠海马齿状回5-HT1A受体的基因(mRNA表达水平)和蛋白表达水平.结果 CMS开始后第19天,西酞普兰组5-HT1A受体的基因和蛋白表达均高于拟PSD组[(0.131±0.008)vs(0.012±0.001)和(0.95±0.06)vs(0.40±0.03),P均小于0.001].第28天,西酞普兰组5-HT1A受体的基因和蛋白表达均高于拟PSD组[(0.224±0.012)vs(0.013±0.001)和(0.52±0.06)vs(0.08±0.02),P均小于0.001].结论 西酞普兰促进拟PSD大鼠海马齿状回5-HT1A受体的基因和蛋白表达,从而可促进海马神经重塑,这可能为西酞普兰治疗PSD的分子机制之一.