Dopamine D4 receptor gene polymorphism and personality traits in healthy volunteers

An association between long alleles of a variable number tandem repeat (VNTR) polymorphism in the dopamine receptor D4 gene and the extraversion related personality traits Excitement and Novelty Seeking has been reported in healthy subjects. In an attempt to replicate the previous findings, 256 healthy Caucasian volunteers were analysed for a potential relationship between the dopamine receptor D4 exon III VNTR polymorphism and Extraversion as assessed by the Revised Neo Personality Inventory (NEO PI-R). The present study did not yield evidence for an association between Extraversion and the dopamine receptor D4 polymorphism. Received: 8 June 1999 / Accepted: 4 April 2000     

Dopamine D 4 receptor gene polymorphism and extraversion revisited: results from the Munich gene bank project for alcoholism

In 1998 a gene bank project for association studies in alcoholism was initiated at the Psychiatric Hospital of Munich. The research instruments used were partly adopted from the US collaborative study of the genetics of alcoholism and include the family history assessment module (FHAM), the semi-structured interview for assessment of genetics in alcoholism (SSAGA) and a number of personality inventories such as the Zuckerman's sensation-seeking scale, the NEO Five factor inventory and the temperament and character inventory. Based on the examination of 181 alcoholic subjects, no association was found between Dopamine D4 receptor gene polymorphism and novelty-seeking or extraversion as assessed by the three personality inventories. These findings are in line with a number of more recent studies questioning the association between novelty-seeking and DRD4 dopamine receptor gene polymorphism. Possible implications of these findings are discussed.     

Association of dopamine D4 receptor (<Emphasis Type="Italic">DRD4</Emphasis>) exon III repeat polymorphism with temperament in 3-year-old infants

The long forms of the dopamine D4 receptor (DRD4) exon III repeat polymorphism (L-DRD4) have been linked in some studies to the adult personality trait of novelty seeking (NS), as well as to infant personality traits related to interest and activity. The current investigation extends the results of our previous longitudinal study on 1- to 5-month-old neonates assessed by the Early and Revised Infancy Temperament Questionnaire (EITQ/RITQ), in which we found a significant correlation between the DRD4 polymorphism and the adaptability trait at 1 month of age. In this study, we examined the relationship between children′s behavior at 3 years of age, measured with the Toddler Temperament Scale (TTS), and DRD4 exon III repeat polymorphism. We found a significant association between the behavioral dimension of intensity of reaction and DRD4 genotypes. Current data failed to confirm the association with the adaptability trait. None of the extraversion and/or exploratory behavior measures was related to the L-DRD4 allele, as expected. In contrast, children with 4/7 genotypes showed worse response to new stimuli compared with 4/4 genotypes. This study corroborates only in part previous results on the link between the DRD4 gene and human temperament.     

Genetic structure of the dopamine receptor D4 gene (DRD4) and lack of association with schizophrenia in Japanese patients

In order to investigate the contribution of genetic variation in the human dopamine receptor D4 gene (DRD4) to the risk of developing schizophrenia, we carried out a genetic analysis of 27 polymorphisms in 216 schizophrenic patients and 243 healthy controls from the Kyushu region of Japan. Twenty-two single nucleotide polymorphisms (SNPs) and five insertion/deletion polymorphisms were analyzed in this study, including four novel SNPs and a novel mononucleotide repeat. Linkage disequilibrium (LD) and haplotype analyses reveal weak LD across the DRD4 gene. In univariate analysis female individuals with allele -521C had a higher risk for schizophrenia. However, this finding was not significant after correction for multiple hypothesis testing. No other polymorphisms or haplotypes differed between schizophrenic patients and controls. Likewise, multivariate analyses did not reveal any statistically significant associations.     

多巴胺D4受体基因多态性与海洛因依赖及渴求程度的关系

目的 探讨DRD4 exon Ⅲ 48bp可变串连重复序列（VNTR）与海洛因成瘾及线索诱发海洛因渴求程度的关系。方法 采用美国ABI公司3100基因分析仪对380名海洛因依赖者（依赖组）和275名健康对照者（对照组）的DRD4 exon Ⅲ 48bpVNTR基因多态进行检测,并给予依赖组实施线索诱发海洛因渴求实验。比较依赖组和对照组的DRD4 exon Ⅲ 48bpVNTR多态的基因型及等位基因频率是否有差异,分析不同基因型与线索诱发海洛因渴求程度的关系。结果 （1）依赖组与对照组相比．DRD4exon Ⅲ 48bpVNTR多态的基因型和等位基因频率差异均无显著性（P〉0．05）。（2）依赖组中,DRD4 exon Ⅲ 48bpVNTR长重复基因型诱发的渴求高于短重复基因型（P〈0．05）。结论 未发现DRD4 exon Ⅲ 48bpVNTR基因多态与海洛因成瘾有关,但该基因多态与线索诱发海洛因的渴求程度有关,长重复基因型线索诱发的海洛因渴求程度明显高于短重复基因型。     

Association of dopamine D4 receptor (DRD4) gene with attention-deficit/hyperactivity disorder (ADHD) in a high-risk community sample: a longitudinal study from birth to 11 years of age

Summary. Background: In recent years, a growing number of studies has focused on the dopamine D4 receptor gene (DRD4) as mediating the susceptibility to attention-deficit/hyperactivity disorder (ADHD). While their results are contradictory, the reason for this inconsistency remains as yet unclear. Method: The present study sought to examine the association between ADHD and the DRD4 exon III polymorphism during child development using longitudinal data from a high-risk community sample (n=265, 129 females, 126 males) who have been followed from birth to 11 years of age. Results: Higher rates of ADHD were observed in boys with the 7 repeat allele of exon III than in boys with other alleles at the ages of 4 1/2 (Fishers exact test, p=.061), 8 (p=.026), and 11 years (p=.005). Boys with this allele also exhibited higher rates of persistent disorder (p=.024). In girls, a trend towards an association (p=.055) with the 7 repeat allele emerged only at preschool age. Conclusions: These findings provide additional evidence for the role of the dopamine D4 receptor in ADHD during the course of child development.     

多巴胺D5受体基因多态性与慢性抽动障碍的关联分析

目的研究慢性抽动障碍与多巴胺D5受体基因多态性是否相关联。方法采用聚合酶链式反应(PCR)、限制性片段长度多态性(RFLPs)与琼脂糖电泳技术的方法,对176个符合CCMD-3诊断标准的慢性抽动障碍儿童与其亲生父母的多巴胺D5受体基因多态性分型,采用病例对照研究,数据统计采用单体型相对风险(GHRR和HHRR)与传递不平衡检验(TDT)方法进行分析。结果慢性抽动障碍与多巴胺D5受体基因多态性无显著关联。GHRR值为0．32～1．61;HHRR值为1.82;TDT值为2．25,其P值均大于0．05。结论慢性抽动障碍与多巴胺D5受体基因多态性无关联。     

多巴胺D4受体基因与强迫症的关联

目的：探讨多巴胺D4受体DRD4基因多态性同强迫症（OCD）的关系。方法：采用PCR-AmFLP技术测定105例OCD患者和100例健康对照者的DRD4基因48bp可变数目重复序列的多态性。结果：OCD组与对照组间等位基因频数分布差异显著（P〈0.05）;其中患者组在4倍48bp重复序列纯合子的分布上明显低于对照组（P〈0.05）。结论：DRD4基因48bp可变数目重复序列的多态性可能与强迫症的发病有关。     

DRD2/ANKK1 TaqI A polymorphism affects corticostriatal activity in response to negative affective facial stimuli

DRD2/ANKK1 TaqI A polymorphism has been suggested to be involved in a reward-related psychiatric disorders. However, the effect of Dopamine receptor D2 (DRD2) on emotional processing has not been investigated yet. We investigated the possible relationship between DRD2/ANKK1 TaqI A polymorphism and corticostriatal response to negative facial stimuli using functional magnetic resonance imaging. All participants were genotyped with regard to the DRD2/ANKK1 TaqI A polymorphism. Our results suggest an association between the DRD2/ANKK1 TaqI A polymorphism and activations in the putamen, the anterior cingulate cortex, and amygdala in response to negative facial stimuli. Furthermore, molecular heterosis at the TaqI polymorphism of DRD2/ANKK1 may play an important role in affective regulation by corticostriatal pathway.     

多巴胺D4受体基因与氯氮平临床疗效个体差异的关系

目的　探讨多巴胺D4受体基因第 3外显子 4 8bp可变重复序列多态性与氯氮平临床疗效个体差异的关系。方法　 81例精神分裂症患者单一服氯氮平治疗 6～ 8周 ,利用阳性与阴性症状量表 (PANSS)评定氯氮平的疗效。采用聚合酶链式反应 (PCR)、变性聚丙烯酰胺凝胶电泳结合银染技术 ,检测精神分裂症患者的基因型和等位基因频率。同时为排除氯氮平个体代谢能力的遗传差异带来的混淆 ,检测了每个患者的血清氯氮平浓度。结果　DRD4基因第 3外显子 4 8bp可变重复序列多态性的 5等位基因的纯合子基因型 (DRD4 5 / 5 )和 5等位基因 (DRD4 5 )的频率在氯氮平有效组和无效组之间有显著性差异。氯氮平治疗精神分裂症阳性症状、阴性症状的有效组和无效组间基因型及等位基因的频率相比无显著性差异。结论　氯氮平治疗精神分裂症的总疗效个体差异与DRD4基因第 3外显子 4 8bp可变重复序列相关 ,携带DRD4 5等位基因者和DRD4 5 / 5基因型者疗效好     

Dopamine receptor 3(DRD3) polymorphism and risk for migraine

Background/objectives: Dopamine has been implicated in the pathogenesis of migraine. We investigated the possible association between the polymorphism 312G>A (rs6280) in the DRD3 gene(essential tremor 1‐ETM1‐ locus, chromosome 3q13) and the risk for migraine and for triggering migraine attacks by alcohol. Methods: We studied the frequency of the DRD3 genotypes and allelic variants in 197 patients with migraine and 282 healthy controls using a polymerase chain reaction and MlsI‐restriction fragment length polymorphisms method. Results: The frequencies of the DRD3 genotypes and DRD3Gly9 were similar in patients with migraine and controls and were unrelated to the age of onset of migraine, gender, family history of migraine and triggering of migraine attacks by alcohol. The frequency of the genotype DRD3Gly9Gly9 was significantly higher in patients with migraine with aura when compared with patients with migraine without aura, but not with controls. Conclusion: DRD3 genotype and allelic variants were not related to the risk for migraine in Caucasian Spanish people.     

D4受体基因与精神分裂症的关联研究

目的 探讨上海地区汉族人D4受体基因与精神分裂症的易感性、患者的性别、发病年龄、家族史以及症状严重度之间的关系。方法 抽取38例精神分裂症病人作研究,以76例正常人作对照。用聚合酶链式反应（PCR）扩增技术测定所有研究对象的D4基因型和等位基因。结果 发现D4受体基因与精神分裂症的易感性相关联,而与患者的性别、发病年龄、家族史以及症状严重度均无关联;发现正常对照组D4受体基因与性别相关联。结论 D4受体基因可影响精神分裂症患者的易感性,但不改变患者的发病年龄以及症状严重度,D4受体基因多态性的频率分布不受患者的性别及家族聚集性的影响;正常人群中D4受体基因多态性的频率分布存在性别差异。     

多巴胺D5受体基因多态性与精神分裂症的关联研究

目的　探讨昆明地区汉族人群多巴胺D5受体 (DRD5 )基因多态性与精神分裂症的关系。方法　对 79例精神分裂症患者 (患者组 )和 75名正常对照者 (对照组 )采用聚合酶链反应 (PCR)扩增DRD5基因二核苷酸多态性片段 ,并通过聚丙烯酰胺凝胶电泳对PCR扩增产物进行多态性分型鉴定。比较患者组与对照组DRD5基因各等位基因分布频率。结果　 ( 1)患者组与对照组之间等位基因分布的差异无显著性 ( χ2 =12 2 6 ,P >0 0 5 )。 ( 2 )女性患者比男性患者及对照组 14 0bp等位基因有更高的分布频率 ;与男性患者比较 ,相对危险度 (RR) =2 73( χ2 =5 33,P <0 0 5 ) ;与对照组比较 ,RR =2 0 1( χ2 =4 5 9,P <0 0 5 )。结论　未发现汉族人群中DRD5基因多态性与精神分裂症存在明显关联 ,但该基因多态性可能影响不同性别间的疾病易感性     

Dopamine D(3) receptor deficiency sensitizes mice to iron deficiency-related deficits in motor learning

Iron deficiency is a widespread form of malnutrition and is known to interfere with cognitive performance and development. To elucidate the role of dopamine D3 and iron deficiency (ID) in inducing cognitive deficits, we studied wildtype and D3 knockout mice on normal or iron-deficient diets subjected to a running wheel-based motor skill sequence. Surprisingly, ID alone had no effect on motor learning in this study, whereas combined ID and dopamine D(3) receptor (D3R)-deficiency significantly interfered with the acquisition of motor skills. Reduced D3R function may serve as a predisposing factor towards ID-related effects on motor learning.     

多巴胺D2受体基因的TaqI A多态性与迟发性运动障碍的关联分析

目的　研究多巴胺D2受体 (DRD2 )基因TaqIA多态性与精神分裂症伴迟发性运动障碍 (TD)的相关性。方法　使用异常不自主运动量表 (AIMS)评定精神分裂症患者有无TD及TD严重程度 ,并采用简明精神病评定量表 (BPRS)评定患者精神症状 ;应用聚合酶链反应 (PCR)—限制性片段长度多态性 (RFLP)法分析TD组和非TD组的DRD2基因的TaqIA等位基因频率和基因型分布。结果　DRD2基因TaqIA的等位基因频率和基因型分布在TD组与非TD组之间均无显著性差异 ,且不同基因型间的AIMS总分值也无显著性差异。结论　在中国汉族男性精神分裂症患者中DRD2基因的TaqIA多态性可能不是影响TD发生的主要危险因素。     

精神分裂症患者多巴胺D1受体基因-48A/G多态性与认知功能的关系

目的探讨精神分裂症患者多巴胺D1受体基因-48A／G多态性与认知功能的关系。方法应用聚合酶链反应-限制性片段长度多态性方法(PCR-RFLP),检测103例精神分裂症患者多巴胺D1受体基因-48A／G多态性。采用威斯康星卡片分类测验(Wiscosin Card Sorting Test,WCST)和韦氏成人智力量表修订版(Wechsler Adult Intelligence Scale-RC,WAIS-RC)评估患者的认知功能。结果其中分类数、错误应答数、持续应答数、非持续错误数、算术、数字广度(顺)、数字符号及木块图得分在AA基因型和AG+GG基因型两组患者间均无显著性差异(P>0．05),但持续错误数(t=2．321,P<0．05)和数字广度(逆)(t=3．042,P<0．01)在两组间有显著性差异,AA基因型患者持续错误数和数字广度(逆)得分明显高于AG+GG基因型患者。结论精神分裂症患者D1受体基因-48A／G多态性与持续性错误数及数字广度(逆)相关,AA基因型精神分裂症患者较AG+GG基因型患者工作记忆受损更严重,但短时记忆能力要强于后者。     

Dopamine D4 receptor (DRD4) gene polymorphism is associated with attachment disorganization in infants

About 15% of one-year-old infants in non-clinical, low-risk and up to 80% in high-risk (eg maltreated) populations show extensive disorganized attachment behavior(1,2) in the Strange Situation Test.(3) It has also been reported that disorganization of early attachment is a major risk factor for the development of childhood behavior problems.(4) The collapse of organized attachment strategy has been explained primarily by inappropriate caregiving, but recently, the contribution of child factors such as neurological impairments and neonatal behavioral organization(6) has also been suggested. Here we report an association between the DRD4 III exon 48-bp repeat polymorphism and attachment disorganization. Attachment behavior of 90 infants was tested in the Strange Situation and they were independently genotyped for the number of the 48-bp repeats by polymerase chain reaction (PCR). The 7-repeat allele was represented with a significantly higher frequency in infants classified as disorganized compared to non-disorganized infants: 12 of 17 (71%) vs 21 of 73 (29%) had at least one 7-repeat allele (chi2 = 8.66, df = 1, P < 0.005). The estimated relative risk for disorganized attachment among children carrying the 7-repeat allele was 4.15. We suggest that, in non-clinical, low-social-risk populations, having a 7-repeat allele predisposes infants to attachment disorganization.     

Interactive effects of a DRD4 polymorphism, lead, and sex on executive functions in children.

BACKGROUND: Prior studies have examined independent effects of a dopamine receptor D4 polymorphism (DRD4-7) and lead exposure on executive functions but not their interaction or the role of sex as a modifier of their effects. METHODS: Multivariable analyses were used to examine effects of DRD4-7 genotype, 60-month blood lead level, and sex on spatial working memory, rule learning and reversal, spatial span, and planning for 174 children. RESULTS: DRD4-7 was associated with poorer spatial working memory, and increasing blood lead levels were associated with impaired rule learning and reversal, spatial span, and planning. Adverse effects of lead on planning and rule learning and reversal were seen primarily for boys. In addition, the effect of lead on rule learning and reversal was evident predominately for those lacking DRD4-7. CONCLUSIONS: We observed independent effects of DRD4-7 and lead on various executive functions and modifications of lead effects by DRD4 genotype and sex.     

Dopamine D(4) receptor activation decreases the expression of mu-opioid receptors in the rat striatum

The dopaminergic and opioid peptide systems interact in many nuclei of the brain. In the striatum, dopamine/opioid peptide interactions modulate locomotor and motivated behaviors as well as reward, motivational, and tolerance processes in opiate dependence. Dopamine D(4) receptors (D(4) R) and mu-opioid receptors (MOR) are highly concentrated in the striosomes (islands) of the striatum, suggesting the existence of receptor-receptor interactions between them. In the present work we studied the role of D(4) R in modulating MOR expression in the islands by using immunohistochemistry and image analysis. The activation of D(4) R by the agonist PD168,077 (1 mg/kg) decreased MOR immunoreactivity (IR) in the striosomes 6 hours after drug treatment. MOR IR levels had recovered 12 hours later. Treatment with a D(4) R antagonist (L745,870, 1mg/kg) blocked downregulation of MOR IR, showing that the D(4) R agonist effects observed were specific. Furthermore, treatment with the D(2)/D(3) receptor agonist quinpirol (1 mg/kg) and D(2)/D(3) receptor antagonist raclopride (1 mg/kg) had no effect in MOR IR, suggesting that D(4) R is the only D2-like receptor producing an MOR downregulation in the islands. The decreases of MOR IR in the striosomes suggest that D(4) R activation may reduce MOR signaling. Increasing evidence has demonstrated that the islands in the striatum play a critical role in habit acquisition during drug addiction. D(4) R/MOR interactions could be crucial in such processes.