Anti-Anxiety Effects of Prelimbic 5-HT4 Receptors in the Rat Model of Parkinson’s Disease: Evidence from Behavioral and Electrophysiological Study

Objective:Clinical and laboratory studies have demonstrated that prelimbic(PrL)and serotonin-4(5-HT4)receptors may have the key role in regulating anxiety.However,the pathophysiology of anxiety in Parkinson’s disease(PD)remains obscure.In this research,the effects of PrL 5-HT4 receptors on anti-anxiety behaviors in hemiparkinsonian rats were investigated.Methods:PD model rats were used as the research subjects,starting with behavioral changes,from the point of view of electrophysiology,the regulatory effect of PrL 5-HT4 receptors on PD-related anxiety and the possible mechanism were explored.Results:Anxiety-like behaviors were induced via MFB lesion in rats.Intra-PrL injection of 5-HT4 receptors agonist RS67333 induced anti-anxiety effects in both sham and PD group.In the sham group,PrL administration of 5-HT4 receptors antagonist SB204070 produce anti-anxiety effects,but in the PD group,the expression of anxiety-like behavior was increased.Compared to the sham group,the effective dose of the behavioral effects of the two drugs in the PD group was obviously higher.Electrophysiological data suggested that PrL administration of RS67333(SB204070)increased(decreased)the firing activities ofγ-aminobutyric acid(GABA)neurons in both groups.Compared with rats in sham group,lesioned rats had a shorter duration of the excitation(inhibition)effects on firing activities of GABA neurons.Conclusion:PrL 5-HT4 receptors regulate anxiety behaviors in PD rats,and its mechanism may be related to the down-regulation of expression or function of PrL 5-HT4 receptors in PD.

Domesticated HERV-W env contributes to the activation of the small conductance Ca^(2+)-activated K^(+)type 2 channels via decreased 5-HT4 receptor in recent-onset schizophrenia

The human endogenous retroviruses type W family envelope(HERV-W env)gene is located on chromosome 7q21-22.Our previous studies show that HERV-W env is elevated in schizophrenia and HERV-W env can increase cal-cium influx.Additionally,the 5-HTergie system and particularly 5-hydroxytryptamine(5-HT)receptors play a prominent role in the pathogenesis and treatment of schizophrenia.5-hydroxytryptamine receptor 4(5-HT4R)agonist can block calcium channels.However,the underlying relationship between HERV-W env and 5-HT4R in the etiology of schizophrenia has not been revealed.Here,we used enzyme-linked immunosorbent assay to detect the concentration of HERV-W env and 5-HT4R in the plasma of patients with schizophrenia and we found that there were decreased levels of 5-HT4R and a negative correlation between 5-HT4R and HERV-W env in schizophrenia.Overexpression of HERV-W env decreased the transcription and protein levels of 5-HT4R but increased small conductance Ca^(2+)-activated K^(+)type 2 channels(SK2)expression levels.Further studies revealed that HERV-w env could interact with 5-HT4R.Additionally,luciferase assay showed that an essential region(-364 to-176 from the transcription start site)in the SK2 promoter was required for HERV-W env-induced SK2 expression.Importantly,5-HT4R participated in the regulation of SK2 expression and promoter activity.Electrophysiological recordings suggested that HERV-Wenv could increase SK2 channel currents and the increase of SK2 currents was inhibited by 5-HT4R.In condusion,HERV-W env could activate SK2 channels via decreased 5-HT4R,which might exhibit a novel mechanism for HERV-Wenv to influence neuronal activity in schizophrenia.

Predominant mucosal expression of 5-HT_(4(+h)) receptor splice variants in pig stomach and colon

AIM: To investigate cellular 5-HT4(-h/+h) receptor distribution, particularly in the epithelial layer, by laser mi-crodissection and polymerase chain reaction (PCR) in porcine gastrointestinal (GI) tissues. METHODS: A stepwise approach was used to evaluate RNA quality and to study cell-specific 5-HT4 receptor mRNA expression in the porcine gastric fundus and colon descendens. After freezing, staining and laser microdissection and pressure catapulting (LMPC), RNA quality was evaluated by the Experion automated electrophoresis system. 5-HT4 receptor and glyceral-dehyde-3-phosphate dehydrogenase (GAPDH) expressions were examined by endpoint reverse transcription (RT)-PCR in mucosal and muscle-myenteric plexus (MMP) tissue fractions, in mucosal and MMP parts of hematoxylin and eosin (HE) stained tissue sections andin microdissected patches of the epithelial and circular smooth muscle cell layer in these sections. Pig gastric fundus tissue sections were also stained immunohisto-chemically (IHC) for enterochromaffin cells (EC cells; MAB352); these cells were isolated by LMPC and examined by endpoint RT-PCR. RESULTS: After HE staining, the epithelial and circular smooth muscle cell layer of pig colon descendens and the epithelial cell layer of gastric fundus were identified morphologically and isolated by LMPC. EC cells of pig gastric fundus were successfully stained by IHC and isolated by LMPC. Freezing, HE and IHC staining, and LMPC had no influence on RNA quality. 5-HT4 recep-tor and GAPDH mRNA expressions were detected in mucosa and MMP tissue fractions, and in mucosal and MMP parts of HE stained tissue sections of pig colon descendens and gastric fundus. In the mucosa tissue fractions of both GI regions, the expression of h-exon containing receptor [5-HT4(+h) receptor] mRNA was significantly higher (P<0.01) compared to 5-HT4(-h) re-ceptor expression, and a similar trend was obtained in the mucosal part of HE stained tissue sections. Large microdissected patches of the epithelial and circular smooth muscle cell layer of pig colon descendens and of the epithelial cell layer of pig gastric fundus, also showed 5-HT4 receptor and GAPDH mRNA expression. No 5-HT4 receptor mRNA expression was detected in gastric LMPC-isolated EC cells from IHC stained tissues, which cells were positive for GAPDH. CONCLUSION: Porcine GI mucosa predominantly expresses 5-HT4(+h) receptor splice variants, suggesting their contribution to the 5-HT4 receptor-mediated mu-cosal effects of 5-HT.

5-HT₄Receptor Agonists for the Treatment of Alzheimer’s Dsease

Alzheimer’s disease (AD) is a progressive neurological disorder primarily affecting new memory formation as well as retrieval of previously acquired memories. According to World Health Organization, current global population suffering from cognitive impairment is estimated to 37 million. The number is projected to double in next one and half decade. Half of the population afflicted with dementia is represented by AD patients. Current therapies, which provide marginal symptomatic relief to AD patients, are effective only in half of the patient population. In depth understanding of the molecular mechanism of the disease is urgently required to develop more effective therapies. Therapies in clinical development may either offer symptomatic relief to patients or provide pure disease modifications, thus limiting benefit to patients. 5-HT4 receptor agonists offer an attractive option for the treatment of AD patients. Activation of 5- HT4 receptor under preclinical conditions is demonstrated to improve neurotransmission and enhance the release of acetylcholine resulting in the memory formation. In various cell based and animal models, partial 5-HT4 receptor agonists are demonstrated to promote the release of soluble amyloid precursor protein alpha and block the release of amyloid beta peptide offering suitable candidates as disease modification agents. Remarkably, 5-HT4 receptor agonists are also reported to induce neurogenesis in hippocampus as well as enteric system through the activation of cyclic AMP response element binding protein in rodents. Taken together, 5-HT4 agonists address all major facets of Alzheimer’s disease and may provide therapeutic potential for other neurological disorders.

5-HT4受体激动剂对肠易激综合征患者消化间期运动及胃肠激素的影响

目的探讨5-羟色胺4(5-HT4)受体激动剂对便秘型肠易激综合征患者(IBS-C)消化间期移行性复合运动(MMC)及血浆胃动素(MOT)、生长抑素(SS)、一氧化氮(NO)等胃肠激素有无影响。方法按照罗马Ⅲ标准招募26例IBS-C患者,同时招募28例健康对照者,对2组人进行MMC的监测,观察IBS-C患者给予5-HT4受体激动剂后MMC的变化。并且在给药前后留取MMC不同时期(Ⅰ、Ⅱ、Ⅲ期)的血液样本,对MOT、SS、NO浓度进行检测。结果①IBS-C患者给予5-HT4受体激动剂后,MMC周期显著缩短,MMCⅢ期收缩波幅均显著升高(P<0.01),MMCⅢ的传播速度加快(P<0.001)。②IBS-C患者给5-HT4受体激动剂后,血浆MOT水平显著升高(P<0.001),SS水平无显著变化(P>0.05),而NO水平显著降低(P<0.01)。③与健康人相比,IBS-C患者不同MMC时期血浆MOT浓度均显著降低(P<0.01),而SS浓度及NO浓度均显著高于健康人(P<0.001,及P<0.01)。结论上述结果为5-HT4受体激动剂治疗IBS-C的机制提供新依据,为研究IBS发病机制提供新的依据。

痛泻要方对内脏高敏性大鼠结肠5-HT、5-HT_4受体表达影响的研究

目的:通过对内脏高敏性大鼠肠道敏感性、5-HT、5-HT4受体蛋白表达的影响,研讨痛泻要方对内脏高敏性大鼠干预作用。方法:采用乳鼠结肠刺激方法复制内脏高敏性大鼠IBS模型,以直肠内球囊扩张时行为学及腹壁收缩情况代表其内脏敏感性,观察各组大鼠肠道内扩张引起的腹部抬起和背部拱起的容量阈值和不同容量下扩张期间腹壁收缩次数,及其对结肠组织中5-HT、5-HT4受体蛋白表达的影响,观察痛泻要方对其干预作用。结果:经乳鼠结肠刺激方法复制内脏高敏性模型后,大鼠肠道敏感性增加强,5-HT蛋白表达增高,5-HT4受体蛋白表达降低;经痛泻要方干预后,大鼠肠道敏感性、5-HT表达降低,5-HT4受体蛋白表达增强。结论:痛泻要方可降低内脏高敏性大鼠肠道敏感性,其作用机理与降低内脏高敏性大鼠结肠5-HT表达,增强5-HT4受体蛋白表达,从而提高内脏痛阈值,降低肠道过敏性有关。

生白术对高原缺氧大鼠小肠运动和5-HT_4受体的影响

背景:急进高原缺氧引起的胃肠道运动功能紊乱发病率较高,目前其发生机制仍不明确,相关干预研究较少。目的:探讨高原缺氧对大鼠小肠运动的影响及其可能机制以及生白术的干预作用。方法:70只Wistar大鼠随机分为7组,分别为对照组、3 500 m和5 000 m海拔模型组以及相应海拔曲美布汀、生白术干预组。6组造模大鼠置于相应海拔低压低氧舱中并予相应药物溶液或0.9%Na Cl溶液灌胃3 d。3 d后所有大鼠于墨汁灌胃后30 min处死,测量墨汁小肠推进率,观察小肠组织病理学变化,免疫组化法检测5-HT4受体表达。结果:与对照组相比,海拔3 500 m模型组小肠推进率减缓,5-HT4受体免疫阳性面积减少,海拔5 000 m模型组小肠推进率加快,5-HT4受体免疫阳性面积增加(P均<0.05),两组小肠黏膜表现为中-重度损伤。生白术干预能有效纠正海拔3 500 m和5 000 m引起的小肠推进率和5-HT4受体数量异常(P均<0.05),使之接近对照组水平,并减轻小肠黏膜损伤,效果优于阳性对照药物曲美布汀。结论:急进高原缺氧引起的小肠运动功能紊乱与海拔高度密切相关,临床表现各异。生白术可能通过调节5-HT4受体有效改善此种运动功能紊乱,对小肠黏膜损伤亦有一定修复作用。

5-HT4受体对人消化间期小肠运动调控及其机制研究

目的通过观察5-羟色胺(5-HT4)受体激动剂对人消化间期移行性复合运动(MMC)及血浆胃肠激素的影响,探讨5-HT4受体激动剂对MMC的调控作用及其可能的介导因素。方法选取健康志愿者18人并观察给予选择性5-HT4受体激动剂后MMC的变化。并且在给药前后检测MMC不同时期血浆胃动素(MOT)、生长抑素(SS)、NO的浓度。结果健康人给药后MMC周期显著缩短[(87.5+24.2)min vs(60.5±18.4)min,P<0.001],MMCⅢ期波幅、动力指数、传播速度均比给药前显著升高(P<0.05)。MMC不同时期血浆MOT含量无显著变化(P>0.05),SS水平显著升高(P<0.01),而NO含量显著降低(P<0.05)。结论 5-HT4受体激活对人MMC有兴奋性作用,该兴奋作用可能通过SS、NO等胃肠激素起作用。

3种5-HT_4受体激动剂对胃肠道动力与心功能影响的实验研究

目的检测3种5-羟色胺4(5-HT_4)受体激动剂对胃肠道动力与心功能的影响,以期找到既具胃肠动力又无心脏副作用的药物。方法分别应用炭末法和张力换能器以及Langendorff离体灌流装置,观察西沙必利、RS67506和扎考必利低剂量、中等剂量、高剂量3种剂量对小鼠和大鼠胃肠动力与心功能影响。结果扎考必利和RS67506在剂量稍大的条件下,具有与西沙必利相同的促肠道动力作用;西沙必利在1μmol/L^30μmol/L范围内对大鼠心律影响较大,出现室性期前收缩和二联律,对心功能无显著变化。RS67506和扎考必利在一定的浓度范围内对大鼠心脏无致心律失常作用,对心功能也无影响。结论西沙必利、RS67506和扎考必利均可不同程度地促进小鼠肠推进运动并增加大鼠离体肠管环行肌的收缩张力;西沙必利在具有致心律失常作用,而RS67506和扎考必利则无此副作用。

心房组织中5-HT_4受体亚型mRNA的变化与房颤发生与维持

目的:探讨房颤患者房间隔5-HT4受体4种亚型(5-HT4Ra、5-HT4Rb、5-HT4Rg、5-HT4Ri)mRNA的表达及其临床意义。方法:将行瓣膜置换手术的患者36例,分为窦性心律(SR)组和房颤(AF)组。术中取房间隔组织,采用SYBRGreen实时荧光定量PCR检测各组中5-HT4受体亚型mRNA的表达。结果:5-HT4RamRNA在SR组和AF组中的表达水平分别为(19.89±9.68)×10-4和(336.86±255.56)×10-4,AF组比SR组增加了1593.61%(P<0.01);5-HT4RbmRNA在SR组和AF组中的表达水平分别为(23.32±8.37)×10-4和(240.32±242.49)×10-4,AF组比SR组增加了930.53%(P<0.01);5-HT4RgmRNA在SR组和AF组中的表达水平分别为(2.23±0.77)×10-4和(0.72±0.45)×10-4,AF组比SR组减少了67.71%(P<0.01);5-HT4RimRNA在SR组和AF组中的表达水平分别为(34.95±8.08)×10-4和(392.15±347.75)×10-4,AF组比SR组增加了1022.03%(P<0.01)。结论:5-HT4受体亚型mRNA表达的变化可能在房颤的发生和维持中发挥一定的作用。

电针对便秘型肠易激综合征大鼠结肠组织5-HT、5-HT_4受体的调节作用

目的通过观察电针对便秘型肠易激综合征大鼠结肠组织5HT、5-HL受体的调节作用，探讨电针治疗便秘型肠易激综合征的效应机制。方法将40只SD大鼠随机分为正常组、模型组、电针组和西药组，采用0～4℃生理盐水灌胃方法建立便秘型肠易激综合征大鼠模型：模型制备成功后电针组和西药组均连续治疗7d。治疗结束后，对大鼠直肠扩张刺激诱导的腹部撤回反射（AWR）进行半定量评分，采用酶联免疫技术检测结肠黏膜5-HT含量，采用免疫组化法观察结肠黏膜5-HT。受体的表达。结果与正常组相比较，模型组大鼠在肠道压力为20mmHg时腹部撤回反射评分降低（P〈0．01）：与模型组相比较，电针组和西药组在肠道压力为20mmHg时腹部撤回反射评分增高（P〈0．05）。与正常组相比较，模型组大鼠结肠5-HT含量增高（P〈0．05），5HTa受体平均光密度降低（P〈0．05）：与模型组比较，电针组和西药组结肠5-HT含量降低（P〈0．01，P〈0．05），电针组5-HT。受体平均光密度增加（P〈0．05）：电针组与西药组5-HT浓度降低之间的差异无统计学意义（P〉0．05）。结论电针能够抑制5-HT在便秘型肠易激综合征大鼠肠道的异常表达，增加5-HT4R表达。

健脾化湿颗粒对D-IBS模型大鼠脑中5-HT及5-HTR3,5-HTR4表达的影响

目的:从前额叶皮质、海马及下丘脑中5-羟色胺(5-hydroxytryptamine,5-HT)和5-羟色胺受体3(5-hydroxytryptamine receptor3,5-HTR3),5-羟色胺受体4(5-HTR4)角度探讨健脾化湿颗粒改善腹泻型肠易激综合征(diarrhea-predominant irritable bowel syndrome,D-IBS)模型大鼠结肠运动和内脏敏感性的作用机制.方法:采用番泻叶灌胃结合束缚应激法建立D-IBS大鼠模型,应用健脾化湿颗粒进行干预,采用酶联免疫法(ELISA)检测大鼠海马中5-HT含量,采用免疫组织化学法检测前额叶皮质、海马及下丘脑中5-HT、5-HTR3、5-HTR4阳性表达,采用逆转录-聚合酶链反应法检测海马中5-H T R3 m R N A和5-H T R4m RNA的表达水平.结果:与正常组相比,模型组海马中5-HT含量(327.30±22.35 vs 265.33±13.60),前额叶皮质、海马、下丘脑中5-HT阳性表达(0.16±0.02 vs 0.08±0.01,0.19±0.02 vs 0.09±0.01,0.17±0.02 vs 0.08±0.01)明显升高(P<0.01);前额叶皮质、海马、下丘脑中5-HTR3阳性表达(0.29±0.02 vs 0.10±0.01,0.23±0.02 vs 0.09±0.01,0.22±0.02 vs 0.09±0.02)及5-HTR4阳性表达(0.25±0.02 vs0.11±0.01,0.28±0.02 vs 0.10±0.02,0.27±0.02 vs 0.11±0.02)明显升高(P<0.01);海马中5-H T R3 m R N A和5-H T R4 m R N A的表达(0.54±0.01 vs 0.17±0.05,0.73±0.08 vs 0.10±0.02)显著升高(P<0.01).与模型组相比,阳性对照组、中、高剂量组海马中5-H T含量(298.92±12.16、286.29±24.43、279.86±20.05 vs 327.30±22.35)显著下降(P<0.05,P<0.01),中、高剂量组前额叶皮质中5-HT表达(0.12±0.01、0.11±0.01 vs 0.16±0.02)显著下降(P<0.01),阳性对照组、中、高剂量组海马、下丘脑中5-H T表达显著下降(P<0.05,P<0.01);各治疗组前额叶皮质、海马、下丘脑中5-H T R3表达及5-H T R4表达下降显著(P<0.05,P<0.01);各治疗组海马中5-H T R3 m R N A表达及5-H T R4 m R N A表达显著降低(P<0.05,P<0.01).结论:健脾化湿颗粒可能通过下调脑中5-HT、5-HTR3、5-HTR4表达来改善D-IBS模型大鼠结肠运动和内脏敏感性.

IL-4、5-HT在过敏性休克死亡豚鼠脏器中的表达及其意义

目的寻找法医学鉴定过敏性休克死亡的病理形态学诊断指标。方法利用组织芯片技术采用免疫组化方法(SP法)检测42只过敏性休克豚鼠(实验组28只,空气栓塞组7只,对照组7只)死后0,6,12,24h4个时间点的心、肝、肺、肾、脾、胃、肠、气管及扁桃体组织中的IL-4和5-HT的表达情况。结果(1)IL-4的表达:实验组肺、气管及胃组织呈阳性表达,并以0、6h表达最强,各时间点的表达强度有统计学意义,P<0.01;肠组织呈弱阳性表达,各时间点的表达强度无统计学意义,P>0.05;实验组其它脏器、空气栓塞组及对照组所有脏器均无表达。(2)5-HT的表达:实验组肠组织呈弱阳性表达,各时间点的表达强度无统计学意义,P>0.05;实验组其它脏器、空气栓塞组及对照组所有脏器均无表达。结论免疫组化方法检测IL-4的表达,可望作为鉴定过敏性休克死亡的病理形态学诊断参考指标;肺、气管及胃组织IL-4表达以0、6h表达最强,提示法医学鉴定过敏性休克死亡应尽早尸检。

5-HTR4和GABRG2基因多态性与精神分裂症关系

目的探讨5-羟色胺4受体基因(5-HTR4)和γ-氨基丁酸-γ2受体基因(GABRG2)基因多态性与精神分裂症的关系。方法在95个中国北方汉族精神分裂症患者和他们的健康父母组成的核心家系中,以聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)方法对5-HTR4基因rs888957(C/T碱基改变)和GABRG2基因rs211014(T/G碱基改变)单核苷酸多态性(SNP)进行检测。应用基于家系的连锁不平衡方法分析基因型数据。结果(1)5-HTR4基因rs888957及GABRG2基因rs211014基因型频率的分布均符合Hardy-Weinberg平衡;(2)传递不平衡检验(TDT)结果提示,5-HTR4基因rs888957及GABRG2基因rs211014与精神分裂症无连锁及关联;(3)UNPHASED双位点单体型分析结果显示,rs888957-rs211014单体型系统与精神分裂症无关联(P>0.05);(4)5-HTR4基因的rs888957位点等位基因分布与精神分裂症的阳性症状钟情妄想相关联(P<0.01)。GABRG2基因的rs211014位点等位基因分布与精神分裂的阳性症状冲动伤人行为相关联(P<0.05)。结论5-HTR4基因rs888957位点及GABRG2基因rs211014位多点态性可能与精神分裂症无关,但不能排除5-HTR4基因及GABRG2基因其他SNPs与精神分裂症相关联。

戊己丸不同配伍方对结肠平滑肌细胞5-HT3,4受体及下游信号传导通路主要元件的影响

目的:观察戊己丸不同配伍方对平滑肌细胞5-羟色胺3,4受体及其下游信号通路的影响。方法:采用Bitar的方法分离培养大鼠结肠平滑肌细胞,α-actin免疫组化鉴定。应用免疫荧光法和钙离子探针检测5-羟色胺3,4受体表达及Ca2+浓度;应用ELISA试剂盒检测cAMP,PKA的浓度。结果:1号方和2号方对大鼠结肠平滑肌细胞5-羟色胺3,4受体的表达及Ca2+浓度均具有抑制作用(P<0.05);可显著下调平滑肌细胞的cAMP和PKA水平(P<0.05);2号方作用效果优于1号方。结论:戊己丸可抑制5-羟色胺3,4受体表达及下调Ca2+,cAMP,PKA水平。

4种5-HT_4受体激动剂对大鼠心肌I_(K1)通道的影响及促心律失常风险比较

目的比较4种5-羟色胺4型(5-HT4)受体激动剂西沙必利(cisapride),扎考必利(zacopride),莫沙必利(mosapride)和2[1-(4-胡椒基)哌嗪]基苯并噻唑{2-[1-(4-Piperonyl)piperazinyl]benzothiazole,BZTZ}对大鼠心室肌细胞膜内向整流钾通道(IK1)功能和蛋白表达的影响,并观察其对大鼠离体心脏心律的影响,从而评估其致心律失常的风险。方法应用全细胞膜片钳技术分别观察4种激动剂对胶原酶分解的成年SD大鼠心室肌细胞膜IK1和HEK293细胞异源表达的Kir2.1通道电流的影响。应用免疫印迹法检测4种激动剂孵育大鼠心室肌细胞24 h后IK1主要亚单位Kir2.1通道蛋白表达的变化。将麻醉大鼠的心脏取出进行Langendorff主动脉逆行灌流,分别观察4种激动剂给药30 min内离体心脏节律的变化,全程记录心电图。结果在大鼠心室肌细胞,BZTZ,西沙必利和莫沙必利0.1~10μmol·L-1可浓度依赖性地抑制IK1。在相同浓度(1μmol·L-1)时,BZTZ对IK1的抑制效应最强(P<0.01),其次为西沙必利,莫沙必利最弱。扎考必利可激动IK1(P<0.01)。在Kir2.1重组质粒转染HEK293细胞,扎考必利激动Kir2.1通道电流(P<0.01),而莫沙必利无明显影响。在大鼠离体心脏,BZTZ和西沙必利1μmol·L-1可引起严重的心律失常,期前收缩数分别达到159±28和(61±13)次(P<0.01),室速发生率分别为50%(P<0.05)和25%,室颤发生率分别为37.5%和12.5%。莫沙必利和扎考必利对心律均无明显影响,不引起心律失常的发生。扎考必利还可抑制西沙必利和BZTZ诱发的心律失常。4种激动剂的促心律失常风险等级依次为BZTZ>西沙必利>莫沙必利和扎考必利。结论 IK1可能作为5-HT4受体激动剂致心律失常副作用的独立风险因子和筛选安全5-HT4受体激动剂和促胃肠动力药的新靶点。

电针不同腧穴对功能性腹泻大鼠多组织5-HT3R、5-HT4R的影响

目的观察功能性腹泻(FDr)模型大鼠的下丘脑、脊髓、胃、肠中5-羟色胺3受体(HT3R)、5-羟色胺4受体(HT4R)mRNA的表达,探讨电针治疗FDr的作用机制,并分析经穴脏腑相关性。方法将48只雄性SD大鼠随机分为正常组,模型组,足三里组,阴陵泉组,阴谷组、非经非穴组;每组8只。连续14 d用束缚、冷刺激、饮食失节等综合方法制备FDr模型。模型复制成功后,足三里组、阴陵泉组、阴谷组、非经非穴组给予电针干预20 min,1次/d,共7 d。测定大鼠胃内残留率与小肠推进率,并采取实时荧光定量PCR法检测下丘脑、脊髓、胃肠中5-HT3R、5-HT4R mRNA的表达。结果与正常组相比,造模后胃内残留率与小肠推进率均明显升高(P<0.05);模型组下丘脑、脊髓、胃肠中5-HT3R mRNA表达明显增加,5-HT4R mRNA表达明显减少(P<0.05)。电针后,足三里组和阴陵泉组与模型组相比,胃内残留率明显降低(P<0.05);下丘脑、脊髓、胃肠中5-HT3R mRNA表达明显减少,下丘脑、脊髓、胃窦中5-HT4R mRNA表达明显增加(P<0.05);与模型组相比,足三里组小肠推进率及结肠中5-HT4R mRNA表达明显升高(P<0.05)。与阴谷组、非经非穴组相比,足三里组胃内残留率、小肠推进率均明显降低(P<0.05);足三里组下丘脑、脊髓、胃、肠中5-HT3R mRNA表达明显减少,5-HT4R mRNA表达明显增加(P<0.05)。结论电针足三里穴和阴陵泉穴通过影响5-HT3R、5-HT4R mRNA表达对FDr起整体调节作用,提示经穴与脏腑之间存在特异性联系。

多巴胺D4受体基因和5-HT2C受体基因与海洛因依赖

目的 探讨多巴胺D4受体基因外显子IIIVNTR多态性和 5 HT2C受体基因cys2 3/ser2 3多态性与海洛因依赖的关联。方法 采用聚合酶链式反应 (PCR)技术 ,对 10 2例海洛因依赖者和 6 4例正常对照者的多巴胺D4受体基因外显子IIIVNTR多态性进行检测 ,同时采用PCR结合限制性片段长度多态性 (RFLP)分析技术 ,检测 5 HT2C受体基因cys2 3/ser2 3多态性分布。结果 海洛因依赖组多巴胺D4受体基因外显子IIIVNTR多态性的基因型和等位基因型的频率与对照组无显著差异 ,5 HT2C受体基因的ser2 3等位基因频率仅为 0 .9%。结论 未发现海洛因依赖与多巴胺D4受体基因外显子IIIVNTR多态性相关联 ,在中国汉族人未发现 5 HT2C受体基因cys2 3/ser2

高选择性5-HT4受体激动剂在慢性便秘治疗中的应用

慢性便秘（chronic constipation，CC）患病率高，美国的患病率高达28％，国内资料成人慢性便秘的患病率为6．07％，随着年龄的增长，便秘的的发病率逐渐增高，60岁及以上老年人中便秘的患病率为11．5％11,210慢性便秘女性发病率明显高于男性，尤其到65岁之后，约为男性的两倍。虽然目前用于治疗便秘的药物以泻剂为主，

5-HT_(3/4)受体在内源性多巴胺调节胃动力中的作用

目的研究5-HT3/4受体在内源性多巴胺调节胃动力中的作用,探讨帕金森病(Parkinson's disease,PD)胃轻瘫发病的可能机制。方法用6-羟多巴(6-hydroxydopamine,6-OHDA)损毁大鼠中枢黑质多巴胺能神经元,建立此模型。采用实时荧光聚合酶链反应法(Real-time PCR)和蛋白免疫印记法(Western blotting),检测5-HT3/4受体在6-OHDA处理模型大鼠胃体的表达。采用Power lab生物信号采集系统记录离体大鼠胃体纵行肌的收缩活动。结果在基础状态下,6-OHDA处理模型组大鼠离体胃体纵行肌的收缩强度明显弱于对照组。加入5-羟色胺(5-hydroxytryptamine,5-HT)后,6-OHDA处理模型大鼠肌条的收缩强度上升幅度明显小于正常对照组。Real-time PCR结果显示6-OHDA处理模型大鼠胃体5-HT3/4受体的基因表达水平显著高于正常组大鼠。Western blotting结果显示6-OHDA处理模型大鼠胃体5-HT4受体蛋白水平下调,5-HT3受体蛋白水平变化不明显。结论损毁中枢黑质多巴胺能神经元可引起外周胃肠道内源性多巴胺(dopamine,DA)含量升高,胃动力减弱,5-HT4受体蛋白水平下调。6-OHDA处理模型大鼠胃动力减弱可能与5-HT受体蛋白水平下调有关。