Dopamine D1 receptor gene polymorphism is associated with myocardial infarction

Dopamine D1 receptor (DRD1) gene is associated with the pathogenesis of myocardial infarction (MI) in aspects of plaque rupture, platelet aggregation, and neutrophil-mediated injury of cardiac myocytes. Thus, the study was designed to explore whether the A-48G polymorphism of the DRD1 gene was associated with MI. The genotype of the DRD1A-48G polymorphism was determined by polymerase chain reaction in the 602 Han Chinese participants, 255 MI patients and 347 controls without MI. A significant association was found between the A-48G polymorphism of DRD1 and MI (genotype model: χ(2)=13.2, unadjusted p=0.001; χ(2)=13.9, adjusted p=0.0002; dominant model: adjusted OR 2.05, 95%CI 1.40-3.00, p=0.0002; recessive model: adjusted OR 2.34, 95%CI 1.01-5.39, p=0.047). The G allele was a risk-increased allele for MI (unadjusted OR 1.83, 95%CI 1.34-2.50, p=0.0001; adjusted OR 1.94, 95%CI 1.40-2.68, p=0.00007). Thus, the study demonstrated the significant association between A-48G polymorphism of the DRD1 gene and MI.     

Dopamine D4 receptor oligomerization--contribution to receptor biogenesis

Dopamine D(4) receptors (D(4) Rs) are G protein-coupled receptors that play a role in attention and cognition. In the present study, we investigated the dimerization properties of this receptor. Western blot analysis of the human D(4.2)R, D(4.4)R and D(4.7)R revealed the presence of higher molecular weight immunoreactive bands, which might indicate the formation of receptor dimers and multimers. Homo- and heterodimerization of the receptors was confirmed by co-immunoprecipitation and bioluminescence resonance energy transfer studies. Although dimerization of a large number of G protein-coupled receptors has been described, the functional importance often remains to be elucidated. Folding efficiency is rate-limiting for D(4)R biogenesis and quality control in the endoplasmic reticulum plays an important role for D(4)R maturation. Co-immunoprecipitation and immunofluorescence microscopy studies using wild-type and a nonfunctional D(4.4)R folding mutant show that oligomerization occurs in the endoplasmic reticulum and that this plays a role in the biogenesis and cell surface targeting of the D(4)R. The different polymorphic repeat variants of the D(4)R display differential sensitivity to the chaperone effect. In the present study, we show that this is also reflected by bioluminescence resonance energy transfer saturation assays, suggesting that the polymorphic repeat variants have different relative affinities to form homo- and heterodimers. In summary, we conclude that D(4)Rs form oligomers with different affinities and that dimerization plays a role in receptor biogenesis.     

Suffering makes you egoist: acute pain increases acceptance rates and reduces fairness during a bilateral ultimatum game

Social preferences like interpersonal altruism, fairness, reciprocity and inequity aversion are inherently linked to departures from pure self-interest. During economic interactions, for example, defectors may be punished even if this implies a cost for the punishers. This violation of canonical assumptions in economics indicates that socially oriented decisions may predominate over self-centred stances. Here we explore whether the personal experience of pain changes the balance between self-gain and socially based choices. We used laser stimulation to induce pain or a warm sensation in subjects playing a modified version of the Ultimatum Game (UG) both in the role of responder and proposer. After each shot, responders evaluated the fairness of the offer. Moreover, responders and proposers rated the intensity and unpleasantness of the sensation evoked by the laser stimulation. Results show that suffering proposers decrease fair offers and suffering responders increase their acceptance rate irrespective of economic offer. Crucially, the intensity of painful stimulation has a predictive role on Moderately Unfair offers' acceptance rates. Thus the personal experience of pain may favour the emergence of a self-centered perspective aimed at maximizing self-gain. The results suggest that bodily states play a fundamental role in higher-order interpersonal negotiations and interactions.     

酒精依赖综合征患者DRD2、DRD4和DAT基因多态性的研究

目的:探讨云南地区人群中DRD2(TaqIA、-141C)、DRD4和DAT基因多态性与酒精依赖的相关性.方法:采用聚合酶链式反应-限制性片断长度多态性(PCR-RFLP)分析技术以及聚合酶链式反应-可变数目串联重复序列多态性(PCR-VNTR)分析技术检测酒依赖组(80例)和对照组(70例)在3个候选基因中的基因型和等位基因频率.结果:上述三个基因多态性的基因型和等位基因频率在酒依赖组和对照组中差异均无统计学意义(P>0.05),对DRD2基因中的TaqIA和-141C进行单倍型分析时发现,Del/Al是一种保护单倍型,能抑制酒依赖综合征的发生.结论:在云南地区人群中,携带有Del/Al单倍型基因的人不易形成酒依赖.     

Dopamine D2 and D4 receptor heteromerization and its allosteric receptor-receptor interactions

Dopamine D₂ and D₄ receptors partially codistribute in the dorsal striatum and appear to play a fundamental role in complex behaviors and motor function. The discovery of D₂R–D_4.xR (D_4.2R, D_4.4R or D_4.7R) heteromers has been made in cellular models using co-immunoprecipitation, in situ Proximity Ligation Assays and BRET¹ techniques with the D₂R and D_4.7R receptors being the least effective in forming heteromers. Allosteric receptor–receptor interactions in D₂R–D_4.2R and D₂R–D_4.4 R heteromers were observed using the MAPK assays indicating the existence of an enhancing allosteric receptor–receptor interaction in the corresponding heteromers between the two orthosteric binding sites. The bioinformatic predictions suggest the existence of a basic set of common triplets (ALQ and LRA) in the two participating receptors that may contribute to the receptor–receptor interaction interfaces.     

Vitamin D receptor gene polymorphism is associated with chronic periodontitis

Chronic periodontitis (CP) is caused by enhanced resorption of the alveolar bone supporting the teeth and is associated with intraoral inflammation after infection with certain bacteria. The VDR gene polymorphism was reported recently to be deeply related to the occurrence of tuberculosis and infection of chronic hepatitis B virus. This may be interpreted to indicate a close relationship between VDR gene polymorphism and the immunological action, because vitamin D activates monocytes, stimulates cell-mediated immunity, and suppresses lymphocyte proliferation. The purpose of the present study was to clarify whether polymorphisms in VDR gene exons are associated with the incidence of CP. A case-controlled study was performed on a group of 168 unrelated Japanese subjects whose ages ranged from 35 to 65 years. The Taq I polymorphism in the VDR gene was found to be associated significantly with CP (X2=4.48, P=0.034). We performed multiple logistic regression analyses on the TT genotype, which was found to be associated with CP, and on well-recognized risk factors, smoking and diabetes. The odds ratio (OR) for the genotype (TT/Tt) was 2.73 (95% CI 1.11-6.68, P=0.028), being larger than the unadjusted value. This indicates that the VDR gene polymorphism (TT genotype) is a risk factor for CP, independently of smoking and diabetes.     

Fluctuating asymmetry and behavior in the ultimatum game in Jamaica

The ultimatum game measures cooperative tendencies in humans under experimental conditions. One individual can split money between oneself and another, while the other has the option of accepting or rejecting the offer, with each player receiving the accepted split or nothing if the split is rejected. We studied the association of players' degree of symmetry [fluctuating asymmetry (FA)] with behavior in the ultimatum game. Symmetrical males were expected to be less cooperative and, thus, make lower offers (while being more likely to reject unfair offers). In a population of young adult Jamaicans, who are well-characterized for bodily symmetry, we found that symmetrical males made significantly lower offers than asymmetrical ones (p<.001), but found no effect on rejection rates (perhaps due to a very small sample size). No significant association of symmetry and game playing was found in women, but women with a higher body mass index made less generous offers (p<.05).     

Dopamine D1 receptor interaction with arrestin3 in neostriatal neurons

Dopamine D1 receptor interactions with arrestins have been characterized using heterologously expressed D1 receptor and arrestins. The purpose of this study was to investigate the interaction of the endogenous D1 receptor with endogenous arrestin2 and 3 in neostriatal neurons. Endogenous arrestin2 and 3 in striatal homogenates bound to the C-terminus of the D1 receptor in a glutathione-S-transferase (GST) pulldown assay, with arrestin3 binding more strongly. The D1 C-terminus and, to a lesser extent, the third cytoplasmic loop also bound purified arrestin2 and 3. In neostriatal neurons, 2, 5, and 20 min agonist treatment increased the colocalization of the D1 receptor and arrestin3 immunoreactivity without altering the colocalization of the D1 receptor and arrestin2. Further, agonist treatment for 5 and 20 min caused translocation of arrestin3, but not arrestin2, to the membrane. The binding of arrestin3, but not arrestin2, to the D1 receptor was increased as assessed by coimmunoprecipitation after agonist treatment for 5 and 20 min. Agonist treatment of neurons induced D1 receptor internalization (35-45%) that was maximal within 2-5 min, a time-course similar to that of the increase in colocalization of the D1 receptor with arrestin3. These data indicate that the D1 receptor preferentially interacts with arrestin3 in neostriatal neurons.     

Dopamine receptor antagonism disrupts social preference in zebrafish: a strain comparison study

Zebrafish form shoals in nature and in the laboratory. The sight of conspecifics has been found reinforcing in zebrafish learning tasks. However, the mechanisms of shoaling, and those of its reinforcing properties, are not known. The dopaminergic system has been implicated in reward among other functions and it is also engaged by drugs of abuse as shown in a variety of vertebrates including zebrafish. The ontogenetic changes in dopamine levels and, to a lesser degree, in serotonin levels, have been found to accompany the maturation of shoaling in zebrafish. Thus, we hypothesized that the dopaminergic system may contribute to shoaling in zebrafish. To test this we employed a D1-receptor antagonist and quantified behavioral responses of our subjects using a social preference (shoaling) paradigm. We found significant reduction of social preference induced by the D1-R antagonist, SCH23390, in the AB strain of zebrafish, an alteration that was not accompanied by changes in motor function or vision. We also detected D1-R antagonist-induced changes in the level of dopamine, DOPAC, serotonin and 5HIAA, respectively, in the brain of AB zebrafish as quantified by HPLC with electrochemical detection. We found the antagonist-induced behavioral changes to be absent and the levels of these neurochemicals to be lower in another zebrafish population, SF, demonstrating naturally occurring genetic variability in these traits. We conclude that this variability may be utilized to unravel the mechanisms of social behavior in zebrafish, a line of research that may be extended to other vertebrates including our own species.     

Dopamine receptor genes are associated with age at first sexual intercourse

The dopaminergic system in the brain seems to play an important role in the regulation of sexual behaviour. The relationship between genes for the D1, D2 and D4 dopamine receptors and age at first sexual intercourse (AFSI) was examined in a sample of 414 non-Hispanic, European-American men and women. A significant association was observed between a DRD2 allele and AFSI and an even stronger association when the DRD2 allele was interacted with a DRD1 allele. A constrained regression model was constructed predicting AFSI using sex and a group of nine psychosocial variables as predictors. Adding the DRD2 and the DRD2-by-DRD1 predictors to this model increased the explained variance by 23 and 55%, respectively. Although these findings suggest a stronger association among males than among females, further research will be necessary to clarify this question, as well as to establish whether the observed association holds in other racial/ethnic groups.     

Fairness evolution in the ultimatum game is a function of reward size

I formulate a simple model of the ultimatum game, in which a proposer and a responder can receive a reward if they agree on how to divide this reward between them. The model is easy to analyse and shows that strong tendencies to fair division are expected when evolution of strategy frequencies follow the traditional gradient dynamics assumed in evolutionary models. The mean stable offer is typically around 20-40% although this depends on the maximum payoff and if rejection thresholds can evolve independently from proposals. The stable proportion offered at evolutionary equilibrium increases with the maximum payoff, if proposal and acceptance thresholds are dictated by the same strategy and cannot evolve independently. If proposal and acceptance evolve independently, the stable proportion instead decreases with the maximum payoff. The stable outcome may also show substantial variation.     

Dopamine D4 receptors: beyond schizophrenia

Dopamine D4 receptors mediate a wide range of neuronal signal transduction cascades. Malfunctions of these mechanisms may contribute to the pathophysiology of neuropsychiatric disorders, and their modification underlies the actions of many psychotropic drugs. Postmortem neuropathological and genetic studies provide inconclusive associations between D4 receptors and schizophrenia. Clinical trials of partially selective lead D4 antagonists have proved them to be ineffective against psychotic symptoms in patients diagnosed with schizophrenia. However, associations are emerging between D4 receptors and other neuropsychiatric disorders, including attention-deficit hyperactivity disorder as well as specific personality traits such as novelty seeking. Preclinical studies indicate that D4 receptors play a pivotal role in the cellular mechanisms of hyperactivity, impulsivity, and working memory. Accordingly, D4 receptors have broader implications for human illnesses than has been suggested by early focus on psychotic illness as a clinical target, and selective D4 agents may yield clinically useful drugs for several neuropsychiatric disorders that require improved treatments.     

Dopamine D4 Receptors: Beyond Schizophrenia

Dopamine D₄ receptors mediate a wide range of neuronal signal transduction cascades. Malfunctions of these mechanisms may contribute to the pathophysiology of neuropsychiatric disorders, and their modification underlies the actions of many psychotropic drugs. Postmortem neuropathological and genetic studies provide inconclusive associations between D₄ receptors and schizophrenia. Clinical trials of partially selective lead D₄ antagonists have proved them to be ineffective against psychotic symptoms in patients diagnosed with schizophrenia. However, associations are emerging between D₄ receptors and other neuropsychiatric disorders, including attention-deficit hyperactivity disorder as well as specific personality traits such as novelty seeking. Preclinical studies indicate that D₄ receptors play a pivotal role in the cellular mechanisms of hyperactivity, impulsivity, and working memory. Accordingly, D₄ receptors have broader implications for human illnesses than has been suggested by early focus on psychotic illness as a clinical target, and selective D₄ agents may yield clinically useful drugs for several neuropsychiatric disorders that require improved treatments.     

Melanocortin-4 receptor gene variant I103 is negatively associated with obesity

Several rare mutations in the melanocortin-4 receptor gene (MC4R) predispose to obesity. For the most common missense variant V103I (rs2229616), however, the previously reported similar carrier frequencies in obese and nonobese individuals are in line with in vitro studies, which have not shown a functional implication of this variant. In the present study, we initially performed a transmission/disequilibrium test on 520 trios with obesity, and we observed a lower transmission rate of the I103 allele (P=.017), which was an unexpected finding. Therefore, we initiated two large case-control studies (N=2,334 and N=661) and combined the data with those from 12 published studies, for a total of 7,713 individuals. The resulting meta-analysis provides evidence for a negative association of the I103 allele with obesity (odds ratio 0.69; 95% confidence interval 0.50-0.96; P=.03), mainly comprising samples of European origin. Additional screening of four other ethnic groups showed comparable I103 carrier frequencies well below 10%. Genomic sequencing of the MC4R gene revealed three polymorphisms in the noncoding region that displayed strong linkage disequilibrium with V103I. In our functional in vitro assays, the variant was indistinguishable from the wild-type allele, as was the result in previous studies. This report on an SNP/haplotype that is negatively associated with obesity expands the successful application of meta-analysis of modest effects in common diseases to a variant with a carrier frequency well below 10%. The respective protective effect against obesity implies that variation in the MC4R gene entails both loss and gain of function.     

Dopamine D4 receptor expression in rat kidney: evidence for pre- and postjunctional localization.

Dopamine D4 receptors mediate inhibition of vasopressin-dependent sodium reabsorption by dopamine in collecting tubules. At present, the distribution of D4 receptors in other renal districts remains an open issue. The renal distribution of D4 receptor was assessed in normally innervated and denervated male Sprague-Dawley rats by quantitative immunohistochemistry using an anti-dopamine D4 receptor rabbit polyclonal antibody. D4 receptor protein immunoreactivity was observed perivascularly in the adventitia and the adventitia-media border. The density of perivascular dopamine D4 receptor was higher in afferent and efferent arterioles than in other segments of the renal vascular tree. Renal denervation abolished perivascular dopamine D4 receptor protein immunoreactivity. In renal tubules, the epithelium of collecting tubules showed the highest dopamine D4 receptor protein immunoreactivity, followed by the epithelium of proximal and distal tubules. No dopamine D4 receptor protein immunoreactivity was observed in the epithelium of the loop of Henle. Denervation did not change dopamine D4 receptor protein immunoreactivity in renal tubules. These results indicate that rat kidney expresses dopamine D4 receptors located both prejunctionally and nonprejunctionally in collecting, proximal, and distal tubules. This suggests that the dopamine D4 receptor may be involved in the control of neurotransmitter release and in renal hemodynamic and tubule function.     

Theft in an ultimatum game: chimpanzees and bonobos are insensitive to unfairness

Humans, but not chimpanzees, punish unfair offers in ultimatum games, suggesting that fairness concerns evolved sometime after the split between the lineages that gave rise to Homo and Pan. However, nothing is known about fairness concerns in the other Pan species, bonobos. Furthermore, apes do not typically offer food to others, but they do react against theft. We presented a novel game, the ultimatum theft game, to both of our closest living relatives. Bonobos and chimpanzee ‘proposers’ consistently stole food from the responders'' portions, but the responders did not reject any non-zero offer. These results support the interpretation that the human sense of fairness is a derived trait.     

Statistical fluctuations in population bargaining in the ultimatum game: Static and evolutionary aspects

We explore the emergent behavior in heterogeneous populations where players negotiate via an ultimatum game: two players are offered a gift, one of them (the proposer) suggests how to divide the offer while the other player (the responder) can either accept or reject the deal. Rejection is detrimental to both players as it results in no earnings. In this context, our contribution is twofold: (i) we consider a population where the distribution of used strategies is constant over time and properties of the random payoff received by the players (average and higher moments) are reported from simple exact methods and corroborated by computer simulations; (ii) the evolution of a population is analyzed via Monte Carlo simulations where agents may change independently the proposing and accepting parameters of their strategy depending on received payoffs. Our results show that evolution leads to a stationary state in which wealth (accumulated payoff) is fairly distributed. As time evolves, an increase in average payoff and a simultaneous variance decrease is observed when we use a dynamics based on a probabilistic version of the saying: “One should not comply with small earnings, but one's greed must be limited.”     

The BsmI vitamin D receptor gene polymorphism is associated with ulcerative colitis in Jewish Ashkenazi patients

Susceptibility to inflammatory bowel disease (IBD) has a strong genetic component. The vitamin D receptor (VDR) gene maps to a region on chromosome 12 shown to be associated with IBD in some studies. In this case-control study we determined the association between the BsmI VDR gene polymorphism and IBD in patients with Crohn's disease (CD) and ulcerative colits (UC). Three hundred seventy-nine Jewish Israeli patients with IBD, 228 with CD (129 Ashkenazi and 99 non-Ashkenazi), and 151 patients with UC (72 Ashkenazi, 79 non-Ashkenazi) were studied. The control group included 495 healthy blood donors (352 non-Ashkenazi and 143 Ashkenazi). All subjects were genotyped for the BsmI VDR gene polymorphism. The frequency of the BB genotype was higher in Ashkenazi patients with UC compared to Ashkenazi controls (0.21 vs. 0.11, p = 0.042, odds ratio 2.27, 95% confidence interval [CI] 1.06-4.9). There were no differences in the prevalence of the BB genotype or the B allele between ethnically matched patients with CD and UC. Nor were there differences in the BB genotype or B allele frequencies between CD patients and ethnically matched controls. The BsmI VDR gene polymorphism is associated with increased susceptibility to UC in Israeli Ashkenazi patients with UC.