多巴胺D2受体基因多态性与脑出血的相关性研究

目的 探讨多巴胺D2受体（DRD2）基因TaqI位点多态性与中国湖南地区汉族人群脑出血发病的相关性.方法 本研究筛选121例脑出血患者,匹配103例正常体检人群为对照,PCR-RFLP检测DRD2 TaqI基因多态性.结果 DRD2 TaqI三种基因型（A1A1,A1 A2,A2A2）频率及两种等位基因（A1,A2）频率在脑出血组和正常对照组分布的差异无统计学意义（P＞0.05）.脑出血组中高血压亚组、非高血压亚组及对照组三者两两比较DRD2 TaqI基因型频率分布的差异无统计学意义（P＞0.05）.Logistic回归调整了脑出血环境因素的影响后,DRD2 TaqI基因多态性仍与脑出血的无相关性（P＞0.05）.结论 DRD2 TaqI基因多态性可能与中国湖南地区汉族人群脑出血无关.     

精神分裂症患者多巴胺D2受体基因多态性与利培酮治疗效应的关联分析

目的:探讨多巴胺D_2受体基因(DRD2)多态性与利培酮治疗精神分裂症临床疗效的关系。方法:纳入汉族精神分裂症患者304例(研究组)和汉族健康对照120名(对照组),研究组服用利培酮8周后以阳性与阴性症状量表(PANSS)评估疗效,同时检测两组DRD2基因rs6275、rs1801028和rs6277位点多态性。结果:rs6277位点在研究组和对照组中的等位基因频率与基因型频率的分布差异有统计学意义(χ~2=8.37,P=0.02)。研究组rs6275(F=15.52,P0.001)、rs1801028(F=19.74,P0.001)和rs6277(F=10.67,P0.001)位点不同基因型在PANSS总分减分率上差异均有统计学意义;同时rs1801028位点不同基因型在阴性症状减分率上差异有统计学意义(F=15.29,P0.001),rs6277位点在阳性症状减分率上差异有统计学意义(F=14.74,P0.001)。结论:DRD2基因rs6277位点多态性与精神分裂症易感性存在关联;不同DRD2基因型患者利培酮疗效可能存在差异。     

多巴胺D3受体基因多态性与精神分裂症亚型及利培酮疗效相关性分析

目的探讨多巴胺D3受体(dopamine D3 receptor,DRD3)基因第一外显子丝氨酸9甘氨酸(Ser9Gly)多态性与精神分裂症临床亚型、药物疗效的关联.方法 241 例汉族首发精神分裂症患者,采用限制性片段长度多态性(restriction fragment length polymorphism,RFLP)技术测定基因型.分析判断基因多态性与精神分裂症的临床亚型、药物疗效的关联. 结果精神分裂症各亚型Ser9Gly等位基因分布存在显著性差异(p <0.05).利培酮疗效不同的患者间Ser9Gly等位基因多态性均无显著性差异. 结论 DRD3受体基因第一外显子Ser9Gly多态性可能与精神分裂症亚型相关,而与患者对药物的反应不相关.     

帕利哌酮缓释片与利培酮治疗精神分裂症的对照研究

目的讨论帕利哌酮缓释片对精神分裂症的治疗效果及对患者社会功能的影响。方法采用随机数字表将84例精神分裂症患者分为帕利哌酮缓释剂组和利培酮组,各42例,分别使用帕利哌酮缓释剂和利培酮片治疗,疗程均为8周。两组均在治疗前及治疗第2、4、8周末采用阳性与阴性症状量表(PANSS)评定疗效,副反应量表(TESS)评定不良反应,在治疗前和8周末采用个人和社会功能量表(PSP)评定社会功能恢复状况。结果PANSS评定:两组在治疗前后差异均有统计学意义(P均0.05),同时两组在8周末差异有统计学意义(P0.05)。TESS评定:两组药物的副反应差异无统计学意义(P0.05)。PSP量表评定:两组治疗前后及两组之间相比差异有统计学意义(P0.05),并且帕利哌酮缓释片优于利培酮。结论帕利哌酮缓释片和利培酮治疗精神分裂症阳性及阴性症状均有效。但帕利哌酮缓释片起效相对迅速,不良反应少且轻微,对于精神分裂症患者的整体社会功能改善具有明显的效果。     

帕利哌酮成功治疗使用利培酮疗效不佳的精神分裂症患者1例

1 病例 患者,女,15岁,因"凭空闻语,感被议论1年"于2018年8月1日就诊.1年前患者无明显诱因出现凭空闻语,听到两个女生在说她,变得敏感多疑,别人在一边聊天,也认为是在议论她.感有人在跟踪监视她,要害她.情绪不稳,暴躁易怒,院子里小朋友在玩耍,也会无缘无故冲下去骂人家,甚至从楼上丢东西下去.家人认为其不正常,故...     

精神分裂症与多巴胺D4受体基因多态性不存在连锁

采系、双生子和寄养子研究表明精神分裂症的发病与遗传因索有关,其遗传方式至今不清,并不是简单的孟德尔式遗传,当然在精神分裂症的某个亚群由单基因遗传的可能性还足存在的。从精神分裂症的多巴胺假说看来,加上D4受体与抗精神药物(尤其是非经典精神药物)的高度亲合力,提示D4受体基因多态性可能与精神分裂症发病有关,本研究     

多巴胺D2受体基因多态性与利培酮疗效、锥体外系副反应及治疗前后泌乳素水平变化的关联分析

目的 探讨多巴胺D2受体基因Tqq1A多态性与利培酮的疗效、锥体外系副反应及治疗前后泌乳索水平变化的相关性.方法 纳入198例首发精神分裂症患者和198名健康对照,给予患者利培酮治疗8周;采用阳性和阴性症状量表和修改的Sampson氏锥体外系反应量表分别评定患者的疗效和锥体外系副反应(EPS);测定患者治疗前后泌乳素水平;检测所有受试者的D2受体基因Taq1 A多态性.结果 不同疗效组、有无EPS组的Taq1 A多态性基因型和等位基因频率差异均无统计学意义(P>0.05),不同基因型组和不同等位基因组患者之间治疗前后泌乳素升高的差异无统计学意义(P>0.05).结论 未发现D2受体基因Taq1 A多态性与利培酮的疗效、锥体外系副反应及治疗前后泌乳素变化存在关联.     

多巴胺D3受体基因多态性与精神分裂症初发期患者抗精神病药疗效关系的研究

目的　探讨多巴胺D3 受体 (DRD3)基因多态性与精神分裂症初发期患者精神症状严重度和抗精神病药疗效是否相关。方法　对 10 9例精神分裂症初发期患者分别进行利培酮治疗 [4 3例 ,3～ 5mg/d ,平均 ( 4 0± 0 5 )mg/d]和氯丙嗪治疗 [6 6例 ,15 0～ 6 0 0mg/d ,平均 ( 339± 87)mg/d],疗程 10周。采用聚合酶链反应 限制性片段长度多态性技术检测其中 10 8例患者 (男 5 2例 ,女 5 6例 )DRD3基因ser9gly多态性。采用阳性和阴性症状量表 (PANSS)评定患者治疗前和治疗第 10周末的精神症状 ,并分析基因型及其他临床指标与PANSS分值和减分率的关系。结果　DRD3ser9gly基因型在各患者组分布频率均符合Hardy Weinberg定律 (P >0 0 5 ) ;基因型在治疗显效和未显著进步组分布频率的差异有显著性 ( χ2 =6 4 4 ,ν=2 ,P <0 0 5 ) ;各基因型亚组临床指标的差异均无显著性 (均P >0 0 5 ) ;基因型与患者治疗前PANSS总分及治疗第 10周末PANSS总减分率、阳性症状减分率的差异均有显著性(均P <0 0 5 )。结论　DRD3基因ser9gly功能多态性可能是精神分裂症初发期患者精神症状严重程度和抗精神病药疗效 (尤其对阳性症状疗效 )的遗传影响因子。     

Dopamine D2 (DAD2) and dopamine D3 (DAD3) receptor gene polymorphisms and treatment outcome in alcohol dependence

Summary. The dopaminergic system is critically involved in reward mechanisms mediating the reinforcing effects of alcohol. The intention of this study was to investigate the genotypic frequencies of the −141C Ins/Del polymorphism of the DAD2 receptor gene as well as the Bal I polymorphism of the DAD3 receptor and their potential association with treatment outcome in alcoholism. Therefore, individuals suffering from primary alcohol dependence were clinically and genetically characterized and followed prospectively over a period of one year after inpatient treatment. No association was found between DAD2 or DAD3 receptor gene variants and treatment outcome as reflected by abstinence/relapse after one year. Taking into account potential stratification effects, such as family history, gender, age of onset, or severity of the disease an association with DAD2 or DAD3 gene variants could neither be found. In conclusion, we found no evidence that the DAD2 or DAD3 gene variants investigated have a major influence on treatment outcome in primary alcohol dependence. Received June 2002; accepted February 3, 2003 Published online April 22, 2003 RID="*" ID="*"  This paper is dedicated to Prof. Peter Riederer who celebrated his 60^th birthday in March 2002 Authors' address: PD Dr. G. A. Wiesbeck, Addiction Research Group, Psychiatric Clinic, University of Würzburg, Füchsleinstrasse 15, D-97080 Würzburg, Germany, e-mail: wiesbeck_g@klinik.uni-wuerzburg.de     

Memantine agonist action at dopamine D2High receptors

Memantine is reported to improve symptoms in moderate cases of Alzheimer's disease and Parkinson's disease, but is also known to trigger psychosis in some Parkinson patients. Because these clinical features suggested a possible dopamine component of memantine action, we measured the potency of memantine on the functional high-affinity state of dopamine D2 receptors, or D2(High). Using [(3)H]domperidone to label D2 receptors, the memantine dissociation constant at D2(High) was 917 +/- 23 nM for rat striatal D2 receptors and 137 +/- 19 nM for human cloned D2Long receptors. The memantine dissociation constant for striatal N-methyl-D-aspartate (NMDA) receptors labeled by [(3)H]MK 801 was 2200 +/- 400 nM. Memantine stimulated the incorporation of [(35)S]GTP-gamma-S into D2-expressing Chinese Hamster Ovary cells with a dissociation constant of 1200 +/- 400 nM. Memantine, between 200 and 2000 nM, directly acted on D2(High) to inhibit the release of prolactin from isolated anterior pituitary cells in culture. Because the memantine potencies at NMDA receptors and dopamine D2(High) receptors are of a similar order of magnitude, it is likely that the clinical features of memantine can be attributed to its action at both types of receptors.     

多巴胺D2受体基因与迟发性运动障碍关联研究

目的探讨DRD2基因TaqI多态性的分布与迟发性运动障碍(TD)的关联性.方法应用聚合酶链反应-限制性片段长度多态的方法,检测100例精神分裂症伴TD患者、60例无TD患者和102名正常人DRD2基因TaqI多态性,比较各组等位基因和基因型频率分布的差异.结果经吻合度检验,精神分裂症伴有TD组、无TD组和正常对照组DRD2基因各基因型的分布均符合Hardy-Weinberg平衡法则(x2=0.242,0.208,0.002,υ均=1,P均＞0.05);经比较,显示各基因型及等位基因在各组间分布无显著性差异(经Z检验,υ均=1,P均＞0.05);TD患者DRD2基因多态分布在不同性别之间无显著性差异(P＞0.05);在TD组中,基因型频数及等位基因频数与病程、服药时间、药物、剂量和AIM评分无显著性意义(P＞0.05).结论DRD2基因TaqI多态性可能与TD的发生无关联性.     

Prediction and assessment of extrapyramidal side effects induced by risperidone based on dopamine D(2) receptor occupancy

In the present study, we attempted to predict the risk of extrapyramidal side effects of a selective monoaminergic antagonist, risperidone, by analyzing the correlation between the dopamine D(2) receptor occupancy and the degree of extrapyramidal side effects of the drug. The occupancies of D(2) and 5-HT(2) receptors at various doses of risperidone were calculated by means of a receptor occupancy theory. The extrapyramidal side effects after administration of risperidone were attempted to predict by theoretical analysis of the correlation between the calculated occupancies and the evidence of extrapyramidal symptoms using a ternary complex model. The pharmacokinetic/pharmacodynamic analysis utilized the data concerning the pharmacokinetics of risperidone and 9-hydroxyrisperidone (active metabolite), their binding affinities with D(2) and 5-HT(2) receptors, and the clinical evidence of extrapyramidal symptoms (Extrapyramidal Symptom Rating Scale: ESRS), gathered from the literature. The mean occupancy of 5-HT(2) receptors after the administration of regular doses of risperidone was suggested to be more than 90%, whereas the mean occupancy of D(2) receptors varied between 50-80%, depending on the dose. The correlation between the occupancy of D(2) receptors and the extrapyramidal symptoms could be successfully analyzed with a ternary complex model, showing the predictability of the model for the extrapyramidal side effects of risperidone. Since the estimated risk of the extrapyramidal side effects varied with the dose, the present method of predicting the extrapyramidal side effects of risperidone may provide a basis for developing a rational dosing regimen for the drug.     

5-羟色胺2A受体基因多态性与利培酮治疗中国首发精神分裂症患者疗效关联

背景5-羟色胺2A受体基因已经证实为精神分裂症的候选易感基因,因为阐明其作为非典型抗精神病药物重要作用靶点减轻阴性症状已引起业界倍加关注.本研究试图探讨(1)5-HT2A受体基因T102C多态性在不同临床亚型之间等位基因和基因型频率的关系,(2)5-HT2A受体基因T102C在利培酮高剂量组和低剂量组之间基因型和等位基因分布频率的关系,(3)5-HT2A受体基因T102C多态性在治疗有效组与无效组之间的基因型和等位基因分布频率的关系,(4)5-羟色胺2A受体T102C基因多态性是否与中国首发精神分裂症患者利培酮疗效有关.方法对201例精神分裂症初发期患者分别进行利培酮治疗[3～5 mg/d,平均(3.2±1.3)mg/d],疗程8周.采用聚合酶链式反应扩增与限制性片段长度多态性(PCR-RFLP)技术检测5-HT2A受体基因T102C多态性.以临床亚型将精神分裂症患者划分为偏执型、瓦解型、未定型和其他型,分析不同临床亚型等位基因和基因型频率的差异;按服用利培酮剂量划分低剂量组(＜4 mg/d)和高剂量组(≥4 mg/d),经比较利培酮高剂量组和低剂量组的5-HT2A受体基因T102C基因型和等位基因分布频率差异性;同时以阴性和阳性症状量表(PANSS)总减分率＞50%有效,≤50%为无效以分析治疗有效组与无效组之间的基因型和等位基因分布频率差异有无显著性;以PANSS评定患者治疗前及治疗后2周、4周、6周和第8周末的精神症状,比较5-HT2A受体T102C各基因亚型与年龄、发病年龄、PANSS总分值、阳性症状基线分、阴性症状基线分、一般病理症状基线分、PANSS总减分率、阳性症状减分率、阴性症状减分率和一般病理症状减分率的差异.结果5-HT2A受体T102C基因型在患者组分布频率均符合H-W平衡定律(P＞0.05);不同临床诊断亚型精神分裂症患者等位基因和基因型频率无显著性差异(χ2=0.415,P=0.937;χ2=1.705,P=0.941);高剂量组与低剂量组之间的基因型和等位基因分布频率差异均无显著性(χ2=2.402,P=0.301;χ2=2.465,P=0.116);治疗有效和无效组的基因型和等位基因分布频率的差异无显著性(χ2=1.995,P=0.369;χ2=1.939,P=0.164);各基因型亚组的年龄、发病年龄及其病程差异均无显著性(P均大于0.05);但基因亚组A1/A1的治疗前PANSS总分(χ2=4.076,P=0.018)和阴性症状分(χ2=3.946,P=0.021)以及治疗结束PANSS总分减分率(χ2=4.036,P=0.019)和阴性症状减分率(χ2=3.876,P=0.022)均显著高于A1/A2及A2/A2基因型.结论(1)首发精神分裂症患者不同临床亚型5-HT2A受体基因T102C基因型和等位基因频率无显著差异.(2)利培酮高剂量组和低剂量组5-HT2A受体基因T102C基因型和等位基因分布频率没有显著性差异.(3)治疗有效组与无效组之间5-HT2A受体基因T102C基因型和等位基因分布频率也无显著性差异.(4)5-HT2A受体T102C Ai/A1基因亚型可能影响中国首发精神分裂症患者对利培酮的治疗效应.     

-94 G/A polymorphism in the dopamine D1 receptor gene is associated with schizophrenia in a Chinese Han population from Shandong province

The correlation between -94 G/A polymorphism in the dopamine D1 receptor gene and schizophrenia remains poorly understood despite extensive research. This study sought to evaluate the genotypes and allele frequencies of the -94 G/A polymorphism in the dopamine D1 receptor gene by real-time PCR using TaqMan fluorescent probes. One hundred and sixty-two patients with schizophrenia and 101 healthy controls living in Shandong province of China were evaluated. Experimental results showed that the G/A genotype distribution was significantly higher in the schizophrenia patients than in healthy controls. The frequencies of G allele and A allele were not significantly different between the schizophrenia patients and the controls. Thus, the -94 G/A polymorphism in the dopamine D1 receptor gene was found to be associated with schizophrenia in a Chinese Han population from Shandong province.     

Lack of association between schizophrenia and alleles in the dopamine D3 receptor gene

Dopamine receptor dysfunction has been implicated in the pathophysiology of schizophrenia. Schizophrenic patients (n= 76) and control subjects (n= 53) were examined for allele frequencies in a 2-allele BalI polymorphism, causing a serine → glycine amino acid substitution in the coding sequence of the dopamine D₃ receptor gene. No statistical significant differences of allele frequencies or genotype frequencies could be found between the two groups. Neither were there any significant relationships between allele frequencies and a number of clinical variables within the schizophrenic subsample. However, if not corrected for multiple testing, an association was found between homozygosity and positive response to neuroleptic drugs. The present study does not provide evidence that the BalI polymorphism in the dopamine D₃ receptor gene is involved in the pathophysiology of schizophrenia. Further investigations with an increased number and variety of patients concerning response to neuroleptic drugs and expression of the receptor in human brain should be performed to definitively exclude this hypothesis.     

多巴胺D_3受体基因多态性与精神分裂症临床表型

目的：探讨多巴胺D3受体（DRD3）基因多态性与精神分裂症临床表型的关系。方法：对73个精神分裂症核心家系83例精神分裂症患者（患者组）及其146名父母（父母组）应用聚合酶链反应、限制性内切酶消化方法、琼脂糖凝胶电泳结合紫外凝胶成像系统检测DRD3基因中的3个位点（Ser9Gly、Ala38Thr和-205A/G）的多态性;采用阳性与阴性症状量表（PANSS）评定精神分裂症临床表型。结果：两组DRD3基因中3个位点的基因型分布及等位基因的频率分布差异无显著性;但在患者组中,对Ser9Gly位点3种基因型（Ser9Ser、Ser9Gly和Gly9Gly）进行分组比较时,Gly9Gly组的PANSS抑郁因子评分明显高于Ser9Ser组和Ser9Gly组,3组间比较,差异有显著性（P=0.042）。对Ala38Thr位点3种基因型（Ala38Ala、Ala38Thr和Thr38Thr）进行分组比较,PANSS总分及各因子分在Ala38Ala、Ala38Thr和Thr38Thr组间差异均无显著性。对-205A/G位点3种基因型（A/A、A/G和G/G）进行分组比较,G/G组的PANSS反应缺乏因子评分明显高于A/A组和A/G组,3组间比较,差异有显著性（P=0.048）。结论：DRD3基因变异可能与精神分裂症的病理症状有关。     

Dopamine D2 receptor gene polymorphisms predict well the response to dopamine antagonists at therapeutic dosages in patients with schizophrenia

Abstract Previous reports have shown that both A1 allele carriers of TaqI A and Del allele non‐carriers of −141C Ins/Del for dopamine D₂ receptor (DRD₂) gene polymorphisms have a better antipsychotic drug response. The present study aimed to examine the validity of a combination of these two DRD₂ polymorphisms as predictors for response to DRD₂ antagonists. The subjects consisted of 49 acutely exacerbated inpatients with schizophrenia treated with bromperidol (30 cases, 6–18 mg/day) or nemonapride (19 cases, 18 mg/day) for 3 weeks. Brief Psychiatric Rating Scale and Udvalg for Kliniske Undersøgelser side‐effects rating scale were used for clinical assessments. DRD₂ genotypes were determined using a polymerase chain reaction method. In the overall 49 subjects, combined DRD₂ polymorphisms weakly predicted the response to DRD₂ antagonists (Fisher exact test, P = 0.049), that is, good response in A1(+) or Del(–) subjects and poor response in A1(–) plus Del(+) subjects. In the former subjects, non‐responders with A1(+) or Del(–) showed higher scores of psychic, extrapyramidal and total side‐effects. At therapeutic doses (6–8 mg/day haloperidol equivalent dose) in 30 subjects, the predictability of response was greatly increased (Fisher exact test, P < 0.0045) with higher positive and negative predictive values (78.3% and 85.7%, respectively). These findings suggest that combined DRD₂ polymorphisms can be used as a pretreatment marker for response to DRD₂ antagonists at therapeutic doses, and that A1(+) or Del(–) subjects are highly sensitive to DRD₂ antagonists, expressed as either treatment responders or non‐responders vulnerable to extrapyramidal symptoms.     

Dopamine D2(High) receptors on intact cells

In humans, behavioral dopamine supersensitivity occurs in schizophrenia and in Parkinson's disease. In animals, behavioral dopamine supersensitivity is consistently associated with increased dopamine D2(High) receptors in homogenized striata in vitro. Because D2(High) receptors have not yet been detected in intact cells, we used [(3)H]domperidone to detect D2(High) sites in intact rat anterior pituitary adenoma culture cells. Although [(3)H]raclopride and [(3)H]spiperone did not detect D2(High) receptors in intact cells or in rat fresh striatal slices, [(3)H]domperidone readily detected D2(High) receptors, warranting an in vivo search for D2(High) variations in human diseases.