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Social stress is common among people and is considered one of the causes of the declining birth rate. Predisposition to stress and stress-induced disorders is largely determined genetically. We hypothesized that due to differences in stress resistance, carriers of different genetic variants of genes associated with stress resilience and stress-induced diseases may have dissimilar numbers of offspring under conditions of long-term social stress. To test this hypothesis, a comparative analysis of frequencies of seven common polymorphic regions [exon 3 variable number of tandem repeats (VNTR) of the DRD4 gene, rs4680 of COMT, STin2 VNTR and the 5-HTTLPR (rs774676466) insertion/deletion polymorphism of SLC6A4, rs4570625 of TPH2, rs6265 of BDNF, and rs258747 of NR3C1] was performed on standardized groups of randomly selected adolescents born before, during, and after severe socioeconomic deprivation (the crisis of the 1990s in Russia). There were significant differences in frequencies of “long” alleles of the DRD4 gene (p = 0.020, χ2 = 5.492) and rs4680 (p = 0.022, χ2 = 5.289) in the “crisis” group as compared to the combined “noncrisis” population. It is possible that the dopaminergic system had an impact on the successful adaptation of a person to social stress.

Anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED) are the three most common eating disorders (EDs). Their etiopathogenesis is multifactorial where both the environmental and genetic factors contribute to the disease outcome and severity. Several polymorphisms in genes involved in the dopaminergic pathways seem to be relevant in the susceptibility to EDs, but their role has not been fully elucidated yet. In this study, we have analyzed the association between selected common polymorphisms in the DRD2 and DRD4 genes in a large cohort of Italian patients affected by AN (n = 332), BN (n = 122), and BED (n = 132) compared to healthy controls (CTRs) (n = 172). Allelic and genotypic frequencies have been also correlated with the main psychopathological and clinical comorbidities often observed in patients. Our results showed significant associations of the DRD2-rs6277 single nucleotide polymorphism (SNP) with AN and BN, of the DRD4-rs936461 SNP with BN and BED and of DRD4 120-bp tandem repeat (TR) polymorphism (SS plus LS genotypes) with BED susceptibility. Moreover, genotyping of DRD4 48-bp variable number TR (VNTR) identified the presence of ≥7R alleles as risk factors to develop each type of EDs. The study also showed that ED subjects with a history of drugs abuse were characterized by a significantly higher frequency of the DRD4 rs1800955 TT genotype and DRD4 120-bp TR short-allele. Our findings suggest that specific combinations of variants in the DRD2 and DRD4 genes are predisposing factors not only for EDs but also for some psychopathological features often coupled specifically to AN, BN, and BED. Further functional research studies are needed to better clarify the complex role of these proteins and to develop novel therapeutic compounds based on dopamine modulation.

Background: Drug treatment is one of the most important treatments for attention deficit hyperactivity disorder (ADHD). The DRD4 gene is a transporter and receptor coding gene of dopamine and is one of the most important genes under investigation in the disorder and etiology of ADHD. In this study, the association between rs3758653 C/T and VNTR exon 3 repetition polymorphisms of the DRD4 gene and the effects of methylphenidate were investigated in patients with ADHD disorder consuming methylphenidate.Methods: The descriptive-analytical study was performed on 122 patients (5 - 18 years old) with ADHD who were treated with methylphenidate. DNA was extracted using salting out method. Subsequently, the rs3758653 polymorphism in the 5’UTR region of DRD4 gene was genotyped by PCR-RFLP method, and the VNTR fragment in exon III of DRD4 gene was investigated by electrophoresis gel on acrylamide gel method. After eight weeks from the start of drug treatment with methylphenidate, the intensity of symptoms was evaluated using the Conners scale. Finally, all data from questionnaires and information that were resulted from laboratory findings were analyzed using ANOVA and repeated measure analysis.Results: Of the 122 patients under study, 15 patients (12.3%) were responded to the drug treatment, and 107 patients (87.7%) were not responded. The significant differences were not revealed in genotype, and allele frequencies of between rs3758653 (C/T) and exon III 3’VNTR repeats polymorphisms of the DRD4 gene and responder and non-responder of ADHD groups to the drug treatment.Conclusions: The results showed that the reduction of ADHD symptoms with drug treatment is not related to DRD4 sub-types in patients with ADHD.

Attention deficit hyperactivity disorder (ADHD) is a highly heritable neurobehavioral disorder that affects children worldwide, with detrimental long-term consequences in affected individuals. ADHD-affected patients display visual–motor and visuospatial abilities and skills that depart from those exhibited by non-affected individuals and struggle with perceptual organization, which might partially explain impulsive responses. Endophenotypes (quantifiable or dimensional constructs that are closely related to the root cause of the disease) might provide a more powerful and objective framework for dissecting the underlying neurobiology of ADHD than that of categories offered by the syndromic classification. In here, we explore the potential presence of the linkage and association of single-nucleotide polymorphisms (SNPs), harbored in genes implicated in the etiology of ADHD (ADGRL3, DRD4, and FGF1), with cognitive endophenotypes related to working memory and perceptual organization in 113 nuclear families. These families were ascertained from a geographical area of the Caribbean coast, in the north of Colombia, where the community is characterized by its ethnic diversity and differential gene pool. We found a significant association and linkage of markers ADGRL3-rs1565902, DRD4-rs916457 and FGF1-rs2282794 to neuropsychological tasks outlining working memory and perceptual organization such as performance in the digits forward and backward, arithmetic, similarities, the completion of figures and the assembly of objects. Our results provide strong support to understand ADHD as a combination of working memory and perceptual organization deficits and highlight the importance of the genetic background shaping the neurobiology, clinical complexity, and physiopathology of ADHD. Further, this study supplements new information regarding an ethnically diverse community with a vast African American contribution, where ADHD studies are scarce.

Previous studies have identified variants in genes encoding proteins associated with the degree of addiction, smoking onset, and cessation. We aimed to describe thirty-one single nucleotide polymorphisms (SNPs) in seven candidate genomic regions spanning six genes associated with tobacco-smoking in a cross-sectional study from two different interventions for quitting smoking: (1) thirty-eight smokers were recruited via multimedia to participate in e-Decídete! program (e-Dec) and (2) ninety-four attended an institutional smoking cessation program on-site. SNPs genotyping was done by real-time PCR using TaqMan probes. The analysis of alleles and genotypes was carried out using the EpiInfo v7. on-site subjects had more years smoking and tobacco index than e-Dec smokers (p &lt, 0.05, both), in CYP2A6 we found differences in the rs28399433 (p &lt, 0.01), the e-Dec group had a higher frequency of TT genotype (0.78 vs. 0.35), and TG genotype frequency was higher in the on-site group (0.63 vs. 0.18), same as GG genotype (0.03 vs. 0.02). Moreover, three SNPs in NRXN1, two in CHRNA3, and two in CHRNA5 had differences in genotype frequencies (p &lt, 0.01). Cigarettes per day were different (p &lt, 0.05) in the metabolizer classification by CYP2A6 alleles. In conclusion, subjects attending a mobile smoking cessation intervention smoked fewer cigarettes per day, by fewer years, and by fewer cumulative pack-years. There were differences in the genotype frequencies of SNPs in genes related to nicotine metabolism and nicotine dependence. Slow metabolizers smoked more cigarettes per day than intermediate and normal metabolizers.

Attention deficit hyperactivity disorder (ADHD) is one of the most common neurobehavioural in the children. Genetic factor is known one of the factors which contributed in ADHD development. VNTR polymorphism in 3’UTR exon 15 of DAT1 gene and exon 3 of DRD4 gene are reported to be associated in ADHD. In this study we examine the association of ADHD with VNTR polymorphism of DAT1 and DRD4 gene in Indonesian children. Sixty-five ADHD children and 70 normal children (6- 13 years of age), were included in the study, we matched by age and gender. ADHD was diagnosed by DSM-IV. We performed a casecontrol study to found the association between ADHD and VNTR polymorphism of DAT1 and DRD4 genes. The 10-repeat allele of DAT1 and 2-repeat allele of DRD4 were higher in Indonesian children. Although the frequency of these allele was higher, but it was similar both in ADHD and control groups. Neither DAT1 nor DRD4 gene showed showed significant difference in genotype distribution and frequency allele between both groups (p > 0.05). No association between ADHD and VNTR polymorphism of DAT1 and DRD4 genes found in Indonesian children. This data suggest that DAT1 and DRD4 do not contribute to etiology of ADHD in Indonesian children. Further studies are needed to clarify association between VNTR polymorphism of DAT1 and DRD4 genetic with ADHD of Indonesian children in larger sample size and family based study.

Attention deficit hyperactivity disorder (ADHD) is one of the most common neurobehavioural in the children. Genetic factor is known one of the factors which contributed in ADHD development. VNTR polymorphism in 3’UTR exon 15 of DAT1 gene and exon 3 of DRD4 gene are reported to be associated in ADHD. In this study we examine the association of ADHD with VNTR polymorphism of DAT1 and DRD4 gene in Indonesian children. Sixty-five ADHD children and 70 normal children (6- 13 years of age), were included in the study, we matched by age and gender. ADHD was diagnosed by DSM-IV. We performed a casecontrol study to found the association between ADHD and VNTR polymorphism of DAT1 and DRD4 genes. The 10-repeat allele of DAT1 and 2-repeat allele of DRD4 were higher in Indonesian children. Although the frequency of these allele was higher, but it was similar both in ADHD and control groups. Neither DAT1 nor DRD4 gene showed showed significant difference in genotype distribution and frequency allele between both groups (p > 0.05). No association between ADHD and VNTR polymorphism of DAT1 and DRD4 genes found in Indonesian children. This data suggest that DAT1 and DRD4 do not contribute to etiology of ADHD in Indonesian children. Further studies are needed to clarify association between VNTR polymorphism of DAT1 and DRD4 genetic with ADHD of Indonesian children in larger sample size and family based study.

International audience; We examine the country-level relationship between novelty-seeking traits and applied research activities. Using DRD4 exon III allele frequencies (DRD4) to proxy for the former and per capita patent applications and grants to proxy for the latter, we find a negative relationship between the two. Our results complement the findings of recent studies about the relationship between novelty-seeking traits, innovation and comparative economic development.

I In many animals, individuals show consistent variation in activity and movement, suggesting the existence of movement-related behavioural syndromes. I assessed the relationship between exploratory behaviour (over a small spatial scale) and migration distance (over a much larger scale) in song sparrows (Melospiza melodia). I quantified exploration using a novel environment test and inferred migration distance (overwintering latitude) using stable hydrogen isotope analysis of winter-grown claw tissue. Exploration was positively related to migration distance. I also investigated candidate mechanisms that if common to both exploration and migration, could explain the correlation between these behaviours. Circulating androgen levels were not associated with either movement behaviour, but at the dopamine receptor gene DRD4 one sequence variant was linked to exploration and another to migration distance. The observed relationship between small- and large-scale movement suggests the existence of a movement syndrome and provides insight into the evolution of movements over multiple geographic scales.

Epigenetic processes that regulate gene expression, such as DNA methylation (DNAm), have been linked to individual differences in physical aggression. Yet, it is currently unclear whether: (a) DNAm patterns in humans associate with physical aggression independently of other co-occurring psychiatric and behavioral symptoms; (b) whether these patterns are observable across multiple tissues; and (c) whether they may function as a causal versus noncausal biomarker of physical aggression. Here, we used a multisample, cross-tissue design to address these questions. First, we examined genome-wide DNAm patterns (buccal swabs; Illumina 450k) associated with engagement in physical fights in a sample of high-risk youth (n = 119; age = 16-24 years; 53% female). We identified one differentially methylated region in DRD4, which survived genome-wide correction, associated with physical aggression above and beyond co-occurring symptomatology (e.g., ADHD, substance use), and showed strong cross-tissue concordance with both blood and brain. Second, we found that DNAm sites within this region were also differentially methylated in an independent sample of young adults, between individuals with a history of chronic-high versus low physical aggression (peripheral T cells; ages 26-28). Finally, we ran a Mendelian randomization analysis using GWAS data from the EAGLE consortium to test for a causal association of DRD4 methylation with physical aggression. Only one genetic instrument was eligible for the analysis, and results provided no evidence for a causal association. Overall, our findings lend support for peripheral DRD4 methylation as a potential biomarker of physically aggressive behavior, with no evidence yet of a causal relationship.

Feng-ling Xu, Xue Wu, Jing-jing Zhang, Bao-jie Wang, Jun Yao Department of Forensic, Genetic and Biology Medicine, School of Forensic Medicine, China Medical University, Shenyang, China Abstract: To explore the association between DRD4 polymorphisms and schizophrenia risk, a meta-analysis was carried out with 41 case–control articles. Specifically, we included 28 articles (5,735 cases and 5,278 controls) that pertained to the 48bp variable number tandem repeat (VNTR) polymorphism, nine articles (1,517 cases and 1,746 controls) that corresponded to the 12bp tandem repeat (TR), six articles (1,912 cases and 1,836 controls) that addressed the 120bp TR, 10 articles (2,927 cases and 2,938 controls) that entailed the −521 C>T polymorphism, six articles (1,735 cases and 1,724 controls) that pertained to the −616 C>G polymorphism, and four articles (1,191 cases and 1,215 controls) that involved the −376 C>T polymorphism. Pooled analysis, subgroup analysis, and sensitivity analysis were performed, and the data were visualized by means of forest and funnel plots. Results of pooled analysis indicated that the -521 CC variant (Pz=0.009, odds ratio [OR] =1.218, 95% confidence interval [CI] =1.050–1.413) and genotype L/L (ie, long allele) of the 120bp TR were risk factors of schizophrenia (Pz=0.004, OR=1.275, 95% CI =1.081–1.504). The 48bp VNTR, the 12bp TR, the −616 C>G polymorphism, and the −376 C>T polymorphism were not associated with schizophrenia. Additional research is warranted to explore the association between polymorphisms of DRD4 and schizophrenia risk. Keywords: DRD4, schizophrenia, meta-analysis, polymorphism

We report the first isolation of the alkaloid aaptamine from the Philippine marine sponge Stylissa sp. Aaptamine possessed weak antiproliferative activity against HCT116 colon cancer cells and inhibited the proteasome in vitro at 50 µM. These activities may be functionally linked. Due to its known, more potent activity on certain G-protein coupled receptors (GPCRs), including α-adrenergic and δ-opioid receptors, the compound was profiled more broadly at sub-growth inhibitory concentrations against a panel of 168 GPCRs to potentially reveal additional targets and therapeutic opportunities. GPCRs represent the largest class of drug targets. The primary screen at 20 µM using the β-arrestin functional assay identified the antagonist, agonist, and potentiators of agonist activity of aaptamine. Dose-response analysis validated the α-adrenoreceptor antagonist activity of aaptamine (ADRA2C, IC50 11.9 µM) and revealed the even more potent antagonism of the β-adrenoreceptor (ADRB2, IC50 0.20 µM) and dopamine receptor D4 (DRD4, IC50 6.9 µM). Additionally, aaptamine showed agonist activity on selected chemokine receptors, by itself (CXCR7, EC50 6.2 µM, CCR1, EC50 11.8 µM) or as a potentiator of agonist activity (CXCR3, EC50 31.8 µM, CCR3, EC50 16.2 µM). These GPCRs play a critical role in the treatment of cardiovascular disease, diabetes, cancer, and neurological disorders. The results of this study may thus provide novel preventive and therapeutic strategies for noncommunicable diseases (NCDs).

Cognitive or executive control is a critical mental ability, an important marker of mental illness, and among the most heritable of neurocognitive traits. Two candidate genes, catechol-O-methyltransferase (COMT) and DRD4, which both have a roles in the regulation of cortical dopamine, have been consistently associated with cognitive control. Here, we predicted that individuals with the COMT Met/Met allele would show improved response execution and inhibition as indexed by event-related potentials in a Go/NoGo task, while individuals with the DRD4 7-repeat allele would show impaired brain activity. We used independent component analysis (ICA) to separate brain source processes contributing to high-density EEG scalp signals recorded during the task. As expected, individuals with the DRD4 7-repeat polymorphism had reduced parietal P3 source and scalp responses to response (Go) compared to those without the 7-repeat. Contrary to our expectation, the COMT homozygous Met allele was associated with a smaller frontal P3 source and scalp response to response-inhibition (NoGo) stimuli, suggesting that while more dopamine in frontal cortical areas has advantages in some tasks, it may also compromise response inhibition function. An interaction effect emerged for P3 source responses to Go stimuli. These were reduced in those with both the 7-repeat DRD4 allele and either the COMT Val/Val or the Met/Met homozygous polymorphisms but not in those with the heterozygous Val/Met polymorphism. This epistatic interaction between DRD4 and COMT replicates findings that too little or too much dopamine impairs cognitive control. The anatomic and functional separated maximally independent cortical EEG sources proved more informative than scalp channel measures for genetic studies of brain function and thus better elucidate the complex mechanisms in psychiatric illness., Brain Topography, 31 (3), ISSN:0896-0267, ISSN:1573-6792

Obesity is one of the five global health risks; it is a worldwide problem. Mortality of obesity is 2.6 million per year. Recently, obesity is considered as a neurobehavioural disorder with defects appetite control. The central dopamine system regulates eating behavior. The cause of obesity is the diminished dopaminergic neurotransmission, which provokes an increase of food stimulus that leads to an increasing of the body mass index (BM1). 1n this case, the main candidate genes will be genes of dopamine type 2 receptors: dopamine receptor D2 (DRD2), D3 (DRD), D4 (DRD4). The article focuses on the DRD4 gene. The latest literature data about the relationship of various polymorphic variants of the DRD4 gene with eating disorders, overweight and obesity are analyzed. 1t has been clarified, that the 48bp VNTR is the main and most significant polymorphism. One part of the researches shows a positive correlation of the tandem repeat VNTR DRN4 gene with overweight, obesity, eating disorders, including the DRD4-S and DRD4-L alleles. The other part denies the correlation of the tandem repeat VNTR DRN4 gene with these indicators. Perhaps the contradictions are due to differences in research design, as well as ethnic, gender and age differences in cohorts, and due to the fact, that in vitro changes do not always correspond to changes in vivo.

Cigarette smoking is influenced by nicotine’s effects on dopaminergic activity, which appear to be moderated by genetic variation, particularly a variable number tandem repeat (VNTR, 48 bp) polymorphism in the third exon of the dopamine receptor gene (DRD4). Smokers with the VNTR ≥7 repeats (long, L allele) report markedly increased participation in some smoking behaviors; hence, our aim was to evaluate the association of the L allele in Mexican Mestizo smokers with and without COPD. The DRD4 VNTR 48 bp was genotyped in 492 Mexican Mestizo smokers: 164 COPD patients (≥20 cigarettes per day, cpd), 164 heavy smokers without COPD (HS, ≥20 cpd) and 164 light smokers without COPD (LS, 1–10 cpd). In the dominant model analysis (SL + LL vs. SS), men in the COPD and HS groups showed a statistical difference compared to LS (p = 0.01, OR = 2.06, CI 95% 1.17–3.64 and p = 0.05, OR = 1.88, CI 95% 1.03–3.45, respectively). In addition, by clustering smokers >20 cpd (COPD + HS) and comparing with the LS group, we found an association with increased risk of higher tobacco smoking p = 0.01, OR = 1.99, CI 95% 1.18–3.34. In conclusion, the long allele (L) in the VNTR of the DRD4 gene is associated with the risk of presenting higher tobacco smoking in male Mexican Mestizo smokers.

Background International research has emphasized that youths are at higher risk for the onset of internet addiction (IA), but studies investigating biological, psychological, and social factors associated with this condition are limited. Objective This study aims to investigate the possible association between IA and genetic polymorphisms in monoamine oxidase A (MAO-A), serotonin-transporter (5-HTTPR), dopamine receptor (DRD4), and dopamine transporter (DAT1) genes by considering the role played by the perception of young adults in their family functioning and their depression, anxiety, and avoidant personality problems. Methods In a sample of 104 male and female young adults aged between 19 and 23 years (mean age 21.87, SD 2.29 years) recruited from universities in the central southern part of Italy, we addressed the presence of IA using the Young criteria of the IA test. Moreover, the perception of young adults of their family functioning and their psychopathological symptoms were assessed through the Family Assessment Device (FAD) and the Adult Self-Report, respectively. Results We found no significant association between IA and any genetic polymorphisms, neither among males or females. Young adults with IA reported significantly higher scores in the subscale of FAD affective responsiveness (AR; P=.01) and in depressive problems (P=.02), anxiety problems (P=.009), and avoidant personality problems (P=.003) than those in the control group. Results of mediation analyses showed a mediation role played by depressive symptoms (B=0.99; 95% CI 0.22 to 1.97) and avoidant personality problems (B=1.09; 95% CI 0.32 to 2.05) of young adults on the relationship between the FAD, AR, and IA. Finally, this relationship was moderated by the genotype of the 5-HTTLPR (P Conclusions This exploratory study supports the recent evidence on the mutual relationship among biological, individual, and social risk factors associated with IA in young adulthood. Our findings may have important clinical implications for the development of prevention and treatment programs.

Cigarette smoking is influenced by nicotine&rsquo, s effects on dopaminergic activity, which appear to be moderated by genetic variation, particularly a variable number tandem repeat (VNTR, 48 bp) polymorphism in the third exon of the dopamine receptor gene (DRD4). Smokers with the VNTR &ge, 7 repeats (long, L allele) report markedly increased participation in some smoking behaviors, hence, our aim was to evaluate the association of the L allele in Mexican Mestizo smokers with and without COPD. The DRD4 VNTR 48 bp was genotyped in 492 Mexican Mestizo smokers: 164 COPD patients (&ge, 20 cigarettes per day, cpd), 164 heavy smokers without COPD (HS, &ge, 20 cpd) and 164 light smokers without COPD (LS, 1&ndash, 10 cpd). In the dominant model analysis (SL + LL vs. SS), men in the COPD and HS groups showed a statistical difference compared to LS (p = 0.01, OR = 2.06, CI 95% 1.17&ndash, 3.64 and p = 0.05, OR = 1.88, CI 95% 1.03&ndash, 3.45, respectively). In addition, by clustering smokers &gt, 20 cpd (COPD + HS) and comparing with the LS group, we found an association with increased risk of higher tobacco smoking p = 0.01, OR = 1.99, CI 95% 1.18&ndash, 3.34. In conclusion, the long allele (L) in the VNTR of the DRD4 gene is associated with the risk of presenting higher tobacco smoking in male Mexican Mestizo smokers.

Developmental conditions can impact the adult phenotype via epigenetic changes that modulate gene expression. In mammals, methylation of the glucocorticoid receptor gene Nr3c1 has been implicated as mediator of long-term effects of developmental conditions, but this evidence is limited to humans and rodents, and few studies have simultaneously tested for associations between DNA methylation, gene expression and phenotype. Adverse environmental conditions during early life (large natal brood size) or adulthood (high foraging costs) exert multiple long-term phenotypic effects in zebra finches, and we here test for effects of these manipulations on DNA methylation and expression of the Nr3c1 gene in blood. Having been reared in a large brood induced higher DNA methylation of the Nr3c1 regulatory region in adulthood, and this effect persisted over years. Nr3c1 expression was negatively correlated with methylation at 2 out of 8 CpG sites, and was lower in hard foraging conditions, despite foraging conditions having no effect on Nr3c1 methylation at our target region. Nr3c1 expression also correlated with glucocorticoid traits: higher expression level was associated with lower plasma baseline corticosterone concentrations and enhanced corticosterone reactivity. Our results suggest that methylation of the Nr3c1 regulatory region can contribute to the mechanisms underlying the emergence of long-term effects of developmental conditions in birds, but in our system current adversity dominated over early life experiences with respect to receptor expression., We thank A. Hidalgo, F.M. Miranda and E. Mulder for their assistance and training in the lab; S. Jörg for expertly running the hormone assays; M. Briga for training and assistance with the long-term experiment, and M. Driessen for assistance with sampling. We also thank M. Jordà for assistance with the interpretation of methylation data analysis, and the laboratory of ecophysiology and molecular ecology of the Estación Biológica de Doñana for technical support. This project was funded by an EMBO short-term fellowship grant (nº7178) and a Dr. J. L. Dobberke Foundation grant (n°0205510782), both awarded to B.J., who was further supported by the University of Groningen and the Max Planck Institute for Ornithology. E.G-D was funded by a Spanish Ministry of Economy and Competitiveness Ramon y Cajal fellowship and by Plan Nacional Grant BFU2015-65000-R.

3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is a recreational substance also investigated as medication for posttraumatic stress disorder. Dopamine (DA) system stimulation likely contributes to the acute mood effects of amphetamines, including MDMA. Genetic variants, such as single-nucleotide polymorphisms (SNPs), and polymorphic regions of the DA system genes may in part explain interindividual differences in the acute responses to MDMA in humans. We characterized the effects of common genetic variants within genes coding for key players in the DA system including the dopamine D2 receptor (DRD2/ANKK1 rs1800497, DRD2 rs6277, and rs107959), the dopamine transporter (DAT1 rs28363170, rs3836790, rs6347, rs11133767, rs11564774, rs460000, and rs463379), and dopamine D4 receptor [DRD4, variable-number tandem repeat (VNTR)] on the subjective and autonomic response to MDMA (125 mg) in pooled data from randomized, placebo-controlled, crossover studies in a total of 149 healthy subjects. Plasma concentrations of MDMA were used as covariate in the analysis to control for individual pharmacokinetic (metabolic and weight) differences. None of the tested genetic polymorphisms within the DA system altered effects of MDMA when adjusting for multiple comparisons. Genetic variations in genes coding for players of the DA system are unlikely to explain interindividual variations in the acute effects of MDMA in humans.

Multiple subtypes of dopamine receptors within the GPCR superfamily regulate neurological processes through various downstream signaling pathways. A crucial question about the dopamine receptor family is what structural features determine the subtype-selectivity of potential drugs. Here, we report the 3.5-angstrom crystal structure of mouse dopamine receptor D4 (DRD4) complexed with a subtype-selective antagonist, L745870. Our structure reveals a secondary binding pocket extended from the orthosteric ligand-binding pocket to a DRD4-specific crevice located between transmembrane helices 2 and 3. Additional mutagenesis studies suggest that the antagonist L745870 prevents DRD4 activation by blocking the relative movement between transmembrane helices 2 and 3. These results expand our knowledge of the molecular basis for the physiological functions of DRD4 and assist new drug design.

Intelligence as an ability to reason, think abstractly and adapt effectively to the environment is a subject of research in the field of psychology, neurobiology, and in the last twenty years genetics as well. Genetical testing of twins carried out from XX century indicated heritebility of intelligence, therefore confirmed an influence of genetic factor on cognitive processes. Studies on genetic background of intelligence focus on dopaminergic (DRD2, DRD4, COMT, SLC6A3, DAT1, CCKAR) and adrenergic system (ADRB2, CHRM2) genes as well as, neutrofins (BDNF) and oxidative stress genes (LTF, PRNP). Positive effect of investigated gene polymorphism was indicated by variation c.957C>T DRD2 gene (if in polymorphic site is thymine), polymorphism c.472G>A COMT gene (presence of adenine) and also gene ADRB2 c.46A->G (guanine), CHRM2 (thymine in place c.1890A>T) and BDNF (guanine in place c.472G>A) Obtained results indicate that intelligence is a feature dependent not only on genetic but also an environmental factor.

Aim. To study prevalence rates of vital exhaustion and its effects on 14-year risk of cardiovascular disease (CVD) (arterial hypertension (AH), myocardial infarction (MI), and stroke) development and genetic traits in open population of 25–64-yearold men in Russia/Siberia (West Siberia metropolis, Novosibirsk). Material and methods. Random representative sample of 25–64-year-old men was studied in a framework of WHO MONICA-Psychosocial Program (MOPSY) in 1994. Maastricht Questionnaire (MQ) was used to assess vital exhaustion. Genotyping for variable number of tandem repeats (VNTR) polymorphisms in DRD4 and DAT genes was performed. All new cases of AH, MI, and stroke were registered among people without CVD for 14 years (from 1994 to 2008). Statistical analysis was done by using software package SPSS 11.5. Cox proportional hazards regression model was used for evaluation of risk coefficient (hazard ratio (HR) taking into account time-adjusted control. Х2 test was used to assess statistical significance of differences between the groups. Results. In the study population, the vital exhaustion rate was 66,8%. Hazard ration was significantly increased (AH: HR=3,2; MI: HR=2,7; stroke: HR=3,2) in men with vital exhaustion compared with vital exhaustion-free individuals in open population during the first five years of observation. Multifactorial modeling showed that vital exhaustion together with concomitant social gradient determined development of AH, MI, and stroke in open population of 25–64-year-old men. Allele 7 of DRD4 and genotype 9/9 of DAT gene were associated with high level of vital exhaustion. Conclusion: Open population of 25–64-year-old men (Russia/Siberia, Novosibirsk) showed high level of vital exhaustion, a predictor for risk of developing CVD. Vital exhaustion is significantly associated with certain VNTR polymorphisms of DRD4 and DAT gens.

Objective: We aimed to understand the impact of dopamine receptor D4 (DRD4) polymorphisms on neurodegeneration in patients with dementia. We hypothesized that DRD4 dampened-variants with reduced functional potency would be associated with greater atrophy in regions with higher receptor density. Given that DRD4 is concentrated in anterior regions of the limbic and cortical forebrain we anticipated genotype effects in patients with a more rostral pattern of neurodegeneration. Methods: 337 subjects, including healthy controls, patients with Alzheimer's disease (AD) and frontotemporal dementia (FTD) underwent genotyping, structural MRI, and cognitive/behavioral testing. We conducted whole-brain voxel-based morphometry to examine the relationship between DRD4 genotypes and brain atrophy patterns within and across groups. General linear modeling was used to evaluate relationships between genotype and cognitive/behavioral measures. Results: DRD4 dampened-variants predicted gray matter atrophy in disease-specific regions of FTD in anterior cingulate, ventromedial prefrontal, orbitofrontal and insular cortices on the right greater than the left. Genotype predicted greater apathy and repetitive motor disturbance in patients with FTD. These results covaried with frontoinsular cortical atrophy. Peak atrophy patterned along regions of neuroanatomic vulnerability in FTD-spectrum disorders. In AD subjects and controls, genotype did not impact gray matter intensity. Conclusions: We conclude that DRD4 polymorphisms with reduced functional potency exacerbate neuronal injury in sites of higher receptor density, which intersect with syndrome-specific regions undergoing neurodegeneration in FTD. Keywords: Frontotemporal dementia, DRD4, Apathy, Insula, Anterior cingulate cortex, Salience network

Objective: Genetic variation, especially polymorphism of the dopamine D4 receptor gene (DRD4), has been linked to deficits in self-regulation and executive functions and to attention deficit hyperactivity disorder (ADHD), and is related to the structural and functional integrity of the default mode network (DMN), the executive control network (ECN) and the sensorimotor network (SMN). The aim of this study was to explore the effects of the 2-repeat allele of the DRD4 gene on brain network connectivity and behaviors in children with ADHD. Methods: Using independent component analysis (ICA) and dimension analyses, we examined resting-state functional magnetic resonance imaging (fMRI) data obtained from 52 Asian medicine-naive children with ADHD (33 2-repeat absent and 19 2-repeat present). Results: We found that individuals with 2-repeat absent demonstrated increased within-network connectivity in the right precuneus of the DMN, the right middle frontal gyrus (MFG) of the SMN compared with individuals with 2-repeat present. Within the ECN, 2-repeat absent showed decreased within-network connectivity in the left inferior frontal gyrus (IFG) and the left anterior cingulate cortex. A deeper study found that connectivity strength of the left IFG was directly proportional to the Stroop reaction time in 2-repeat absent group, and as well as the right MFG in 2-repeat present group. Conclusion: Polymorphisms of the DRD4 gene, specifically 2-repeat allele, had effects on the ECN, the SMN and the DMN, especially in the prefrontal cortex (PFC) circles. ADHD children with DRD4 2-repeat allele have aberrant resting-state within-network connectivity patterns in the left IFG and the right MFG related to dysfunction in inattention symptom. This study provided novel insights into the neural mechanisms underlying the effects of DRD4 2-repeat allele on ADHD.

The peer environment is among the most important factors for children’s behavioral development. However, not all children are equally influenced by their peers, which is potentially due to their genetic make-up. The dopamine receptor D4 gene (DRD4) is a potential candidate gene that may influence children’s susceptibility to the peer environment. In the present study, we explored whether variations in the DRD4 gene moderated the association between children’s social standing in the peer group (i.e., social preference among classmates) with subsequent conduct problems and prosocial behavior among 405 (51 % females) elementary school children followed annually throughout early adolescence (ages 9–12 years). The behavioral development of children with and without the DRD4 7-repeat allele was compared. The results indicated that children who had higher positive social preference scores (i.e., who were more liked relative to disliked by their peers) showed less conduct problem development in subsequent years relative to children who had lower positive social preference scores. In contrast, children who had more negative preference scores (i.e., who were more disliked relative to liked among peers) showed more conduct problem development in subsequent years, relative to children who had less negative preference scores. However, these effects only occurred when children had a 7-repeat allele. For children who did not have a 7-repeat allele, the level of social preference was not associated with subsequent conduct problems. No evidence for gene–environment interaction effects for prosocial behavior was found. The implications for our understanding of conduct problem development and its prevention are discussed.

DNA methylation is one of the main epigenetic mechanisms that can regulate gene expression and is an important means for creating phenotypic variation. In the present study, we performed methylation profiling of 2 candidate genes for personality traits, namely DRD4 and SERT, in the great tit Parus major to ascertain whether personality traits and behavior within different habitats have evolved with the aid of epigenetic variation. We applied bisulphite PCR and strand-specific sequencing to determine the methylation profile of the CpG dinucleotides in the DRD4 and SERT promoters and also in the CpG island overlapping DRD4 exon 3. Furthermore, we performed pyrosequencing to quantify the total methylation levels at each CpG location. Our results indicated that methylation was ∼1–4% higher in urban than in forest birds, for all loci and tissues analyzed, suggesting that this epigenetic modification is influenced by environmental conditions. Screening of genomic DNA sequence revealed that the SERT promoter is CpG poor region. The methylation at a single CpG dinucleotide located 288 bp from the transcription start site was related to exploration score in urban birds. In addition, the genotypes of the SERT polymorphism SNP234 located within the minimal promoter were significantly correlated with novelty seeking behavior in captivity, with the allele increasing this behavior being more frequent in urban birds. As a conclusion, it seems that both genetic and methylation variability of the SERT gene have an important role in shaping personality traits in great tits, whereas genetic and methylation variation at the DRD4 gene is not strongly involved in behavior and personality traits., The present study was funded by research project CGL2012–38262 to JCS from the Ministry of Science and Innovation, Spanish Research Council. Birds were handled and kept in captivity with the permission of the Environment Department of the Generalitat de Catalunya (licenses number 2012-SF/518, 2013-SF/677 and 2014-SF/090).

To explore the association between DRD4 polymorphisms and schizophrenia risk, a meta-analysis was carried out with 41 case–control articles. Specifically, we included 28 articles (5,735 cases and 5,278 controls) that pertained to the 48 bp variable number tandem repeat (VNTR) polymorphism, nine articles (1,517 cases and 1,746 controls) that corresponded to the 12 bp tandem repeat (TR), six articles (1,912 cases and 1,836 controls) that addressed the 120 bp TR, 10 articles (2,927 cases and 2,938 controls) that entailed the −521 C>T polymorphism, six articles (1,735 cases and 1,724 controls) that pertained to the −616 C>G polymorphism, and four articles (1,191 cases and 1,215 controls) that involved the −376 C>T polymorphism. Pooled analysis, subgroup analysis, and sensitivity analysis were performed, and the data were visualized by means of forest and funnel plots. Results of pooled analysis indicated that the −521 CC variant (Pz=0.009, odds ratio [OR] =1.218, 95% confidence interval [CI] =1.050–1.413) and genotype L/L (ie, long allele) of the 120 bp TR were risk factors of schizophrenia (Pz=0.004, OR =1.275, 95% CI =1.081–1.504). The 48 bp VNTR, the 12 bp TR, the −616 C>G polymorphism, and the −376 C>T polymorphism were not associated with schizophrenia. Additional research is warranted to explore the association between polymorphisms of DRD4 and schizophrenia risk.

Das Erzeugen einer stabilen und kohärenten Wahrnehmung unserer externen Umwelt stellt eine Herausforderung für unser visuelles System dar. Die uneindeutigen und verrauschten sensorischen Signale (bottom-up) werden hierbei mit Vorhersagen (top-down) integriert. Dieser, als perzeptuelle Inferenz bezeichnete Prozess, kann mittels bistabiler Wahrnehmungsexperimente untersucht werden. Bistabile Reize weisen uneindeutige physikalische Eigenschaften zweier sich ausschließenden Interpretationen auf und erzeugen persistierende Wahrnehmungswechsel. Die vorliegende Dissertation untersucht die interindividuelle Variabilität bistabiler Wahrnehmung hinsichtlich verschiedener genetischer, neurobiologischer und kognitiver Einflussfaktoren, um zu einem besseren Verständnis von perzeptuellen Inferenzmechanismen als zentralem Bestandteil in Pathogenesemodellen der bipolaren affektiven Störung und der Schizophrenie beizutragen. In der ersten Studie wurden funktionelle dopaminassoziierte Varianten zweier Kandidatengene der bipolaren Störung (DRD4, DAT1) mit perzeptueller Stabilität in Verbindung gebracht, wobei das Risiko-Allel DRD4-2R mit einer stabileren Perzeption einherging. In der zweiten Arbeit wurde die funktionelle Magnetresonanztomographie (fMRT) genutzt um neuronale Korrelate kognitiver Erwartungen in der perzeptuellen Inferenz zu bestimmen und diese mit Wahnsymptomatik zu verbinden. Hierbei ging eine verringerte perzeptuelle Stabilität mit verstärkten wahnhaften Überzeugungen und einem größeren Erwartungseffekt auf die visuelle Wahrnehmung einher, der als stärkere topdown Modulation präfrontaler Gehirnareale auf den primären visuellen Kortex identifiziert wurde. In der dritten Arbeit wurde die dopaminerge Bioverfügbarkeit mittels funktioneller Genvarianten der Catechol-O-Methyltransferase (COMT) mit der Tendenz zu wahnhaften Überzeugungen und dem Erwartungseffekt auf die Wahrnehmung in Verbindung gesetzt. Dabei zeigte sich, dass höhere Dopaminspiegel mit Wahnsymptomatik korrelierten und dieser Zusammenhang durch den perzeptuellen Erwartungseffekt vermittelt wurde. In der abschließenden Studie wurden mittels fMRT neuronale Korrelate kognitiver Flexibilität mit interindividuellen Unterschieden der perzeptuellen Inferenz in Beziehung gesetzt. Die gefundene Korrelation von perzeptueller Stabilität mit kognitiver, flexibilitäts-abhängiger neuronaler Aktivität in den Basalganglien deutet darauf hin, dass fronto-striatale Gehirnareale auch bei der visuellen Wahrnehmung von Relevanz sind. Zusammenfassend etabliert die vorliegende Arbeit eine Beteiligung des Dopaminsystems bei perzeptuellen Inferenzmechanismen und impliziert über den Zusammenhang mit Wahnsymptomatik eine wichtige Rolle in der Pathogenese der Schizophrenie. Zudem konnten erstmalig die bisher separat betrachteten Inferenzprozesse in Kognition und Perzeption als zusammenhängende und generelle integrative Mechanismen unseres Gehirns etabliert werden., Maintaining a stable and unique experience of the world is a constant challenge to our visual system. As sensory data are often noisy, visual perception can be described as an inferential process that combines bottom-up sensory input with top-down predictions. This process of perceptual inference can be assessed using ambiguous stimuli that cause our perception to continuously switch between two mutually exclusive interpretations. The current dissertation investigated the impact of several genetic, neurobiological and cognitive factors on interindividual differences in visual perception, in order to broaden the understanding of perceptual inference as a central feature in the pathogenesis of bipolar affective disorder and schizophrenia. In the first study we tested the association of two dopamine-associated candidate genes for bipolar disorder with functional impact on dopaminergic neurotransmission (DRD4, DAT1) with perceptual stability. We found the risk-allel DRD4-2R to be significantly associated with a more stable perception. In the second study functional magnetic resonance imaging (fMRI) was used to identify the neural correlates of top-down predictions on visual perception and to relate effects of learned expectations of perception to individuals’ tendency towards unfounded beliefs. Participants with decreased perceptual stability had higher delusion scores and their perception was more strongly influenced by experimentally induced beliefs that were identified as increased prefrontal top-down modulation on primary visual areas. The third study investigated whether the tendency towards delusional conviction depended on dopaminergic neurotransmission by assessing a functional haplotype of Catechol-O-Methyltransferase (COMT). It was shown that substantially increased synaptic dopamine levels are not only associated with stronger delusion conviction, but also correlated with the degree of belief-induced bias on perception. The correlation between dopamine-levels and delusion conviction was shown to be mediated by the degree of the belief-induced bias on perception. In the last study fMRI was used to interrelate the neural correlates of cognitive flexibility with inter-individual differences in perceptual inference. Perceptual flexibility correlated with cognitive flexibility-associated activity in the right putamen as part of the basal ganglia. This points towards a relevance of fronto-striatal brain areas in visual perception. Taken together, this thesis proves the involvement of the dopaminergic system in the inferential processes of visual perception. The associations of delusional ideations with perceptual inference suggests an important role of the latter in the pathogenesis of schizophrenia. Further empirical support is provided for the general notion of shared mechanisms between perception and cognition.

The aim of the work was to assess prevalence of the frequencies of the DRD4 gene alleles in nomadic and urban residents of the north of West Siberia. The study was performed in the boarding schools of Purovsky district of Yamal-Nenets Autonomous Area (YaNAA) where were both the children of nomadic people (ChNP) and the children whose parents permanently lived (ChPLP) in a settlement. The samples of buccal epithelial cells for the polymerase chain reaction (PCR) were obtained from 178 of the ChNP and 140 of the ChPLP. Found that the children of the nomadic parents who are reindeer herders and the urban residents of YaNAA are significantly distinguished by the frequency of DRD4*7R allele., Цель этой работы заключалась в оценке распространенности частот аллелей гена DRD4 у кочевых и городских жителей севера Западной Сибири. Исследование было проведено в школах-интернатах Пуровского района Ямало-Ненецкого автономного округа (ЯНАО), где были дети кочевых народов (ДК) и дети, чьи родители постоянно жили (ДО) в поселке. У 178 ДК и 140 ДО были получены образцы клеток буккального эпителия для цепной реакции полимеразы (PCR). Установлено, что дети кочевых родителей, которые являются оленеводами и городские жители YaNAA, значительно отличаются по частоте DRD4 * 7R аллелей.

A remarkable finding in recent research in psychopathology is that not every child is equally susceptible to interventions. Research showed that genetic differences, and in particular a dopamine-related gene, DRD4, predict who will benefit from interventions, and who will not. In the project "What Works for Whom", this theory was tested, on a large-scale, in the field of early literacy. More than 180 schools spread over the Netherlands were involved in the experiments. We tested the hypothesis that children who were carrier of the DRD4 7-repeat allele, were more receptive to digital educational interventions; one program aimed at understanding the alphabetic principle, and the other program included digital storybooks with animated illustrations. Results for the book reading program were in line with the differential susceptibility theory. The carriers of the DRD4 7-repeat allele, about one-third of the children, benefitted extra from digital storybooks and outperformed their non-carrier peers. For non-carriers the digital books added nothing to the experience children already had with book reading in school and at home. For carriers of the DRD4 7-repeat allele the digital storybooks are a new essential in the curriculum in kindergarten.

Objective: to study the association of the DRD4, DAT genes with vital exhaustion in an open 25—64-old-year male population. A random representative sample of 657 men aged 25—64 years, living in one of the Novosibirsk districts was examined within the WHO MONICA project in 1994. The MONICA-MOPSY test was used to estimate the level of vital exhaustion. The examined DRD4, DAT gene Polymorphisms were genotypes in the Laboratory of Molecular Genetic Studies, Therapy Research Institute, Siberian Branch, Russian Academy of Medical Sciences (Novosibirsk). Results. The genotype containing allele 7 in the dopamine receptor subtype 4 (DRD4) gene, as well as genotype 9/9 in the dopamine-transporter protein (DAT) gene are significantly associated with the high level of vital exhaustion. Conclusion. The vital exhaustion is significantly associated with certain DRD4, DAT gene polymorphisms in the open 25—64-year-old male population of Novosibirsk.

The polymorphism of variable number of tandem repeat (VNTR) in dopamine receptor D4 (DRD4) gene exon III has been linked to various neuro-psychiatric conditions with disinhibition/impulsivity as one of the core features. This study examined the modulatory effects of long-allele variant of DRD4 VNTR on the regional neural activity as well as inter-regional neural interactions in a young female population. Blood sample and resting state eyes-closed EEG signals were collected in 233 healthy females, stratified into two groups by polymerase chain reaction: long-allele carriers (>4- repeat) and non-carriers (

To study the origin of Polynesians and the gene flow from Polynesian ancestors to indigenous Melanesians, a 48-bp variable number of tandem repeats (VNTR) in exon 3 of the dopamine D4 receptor (DRD4) gene was investigated for six Austronesian (AN)-speaking populations—two in Tonga (Nuku’alofa and Ha’apai), three in Solomon Islands (Munda, Paradise, and Rawaki, of whom Rawaki was a Micronesian migrant group), and one in Papua New Guinea (Balopa), and one Non-Austronesian (NAN)-speaking population in Papua New Guinea (Gidra). In these Oceanic populations, six VNTR alleles with 2 (2R) to 11 (7R) repeats were observed. The most frequent DRD4 VNTR allele was the 4R allele, although the allele frequencies of 2R and 7R varied markedly among them, characterized by high frequencies of 7R and lack of 2R in NAN-speaking Melanesians (Gidra), and high frequencies of 2R and low or null frequencies of 7R in AN-speaking Polynesians (Nuku’alofa and Ha’apai) and Micronesians (Rawaki). The allele frequency distribution of DRD4 VNTR in Polynesians was similar to that in Aboriginal Taiwanese (Ami and Atayal), supporting the hypothesis that Polynesian ancestors were derived from Southeast Asians (probably Taiwanese). A principal component analysis for Southeast Asian and Oceanic populations based on the DRD4 VNTR allele frequencies revealed that AN-speaking Melanesian populations were genetically placed between two AN-speaking Polynesian and one NAN-speaking Melanesian populations. These results provide evidence of gene flow from Polynesian ancestors to indigenous Melanesians while Polynesian ancestors passed through Melanesia., 論文

Aims: The aims of the present study were to determine the direct effect of DRD2 and DRD4, as well as their interaction with parenting (i.e. rejection, overprotection and emotional warmth), on the development of regular alcohol and cannabis use in 1192 Dutch adolescents from the general population.Methods: Information was obtained by self-report questionnaires. Perceived rejection, overprotection and emotional warmth were assessed at age 10-12. Regular alcohol and cannabis use were determined at age 15-18 and defined as the consumption of alcohol on 10 or more occasions in the past four weeks, and the use of cannabis on 4 or more occasions in the past four weeks. Models were adjusted for age, sex, parental alcohol or cannabis use, and externalizing behavior.Results: Carrying the A1 allele of the DRD2 TaqIA polymorphism, or the 7 repeat DRD4, was not directly related to regular alcohol or cannabis use. In addition, adolescent carriers of these genetic risk markers were not more susceptible to the influence of less optimal parenting. Main effects for parenting indicated that overprotection increased the risk of regular alcohol use, whereas the risk of cannabis use was enhanced by parental rejection and buffered by emotional warmth.Conclusions: Our findings do not support an association between DRD2/DRD4 and regular alcohol and cannabis use in adolescents. Given the substance-specific influences of rejection, overprotection and emotional warmth, these parenting factors might be promising candidates for prevention work. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

Attention Deficit Hyperactivity Disorder (ADHD) is one of the most common neuropsychiatric disorders of childhood. Due to studies reporting that the effects of ADHD diagnosis on functioning may last throughout life, this disorder, which has great importance for child and adolescent psychiatry, started to attract greater attention recently in terms of adult psychiatry. A review, evaluating the results of studies conducted on the genetic basis of ADHD, which started to attract increasing attention both in our country and the world, was thought to help clinicians working in this field. PubMed and Turkish Psychiatry Index online search engines were screened using “attention deficit hyperactivity disorder”, “ADHD”, “genetics” as key words. The data obtained were combined with information gleaned from several textbooks. Based on previous studies, it could easily be concluded that ADHD is one of the most common heritable psychiatric disorder with distinguished genetic features. Despite its importance for diagnosis and treatment, the etiology of ADHD is still not clear and the disorder seems to be a complex problem arising from the effects of both genetic and environmental factors. Although previous studies revealed that ADHD displayed familial and hereditary transmission, stable patterns of Mendelian inheritance could not be discriminated by evaluation of pedigrees. Therefore, many studies have been conducted on the molecular genetic basis of ADHD recently. The previous studies did not report consistent results in identification of the genes responsible for ADHD which has been partially linked to heterogeneity of the disorder. Grouping relevant patients according to comorbidities and persistence in adolescence rather than DSM-IV subtypes could be an important alternative method for overcoming this limitation in the research studies.

Polymorphisms in the dopamine receptor D4 gene (DRD4) have been related to individual variation in novelty-seeking or exploratory behaviour in a variety of animals, including humans. Recently, the human DRD4 orthologue was sequenced in a wild bird, the great tit (Parus major) and a single nucleotide polymorphism in exon 3 of this gene (SNP830) was shown to be associated with variation in exploratory behaviour of lab-raised individuals originating from a single wild population. Here we test the generality of this finding in a large sample of free-living individuals from four European great tit populations, including the originally sampled population. We demonstrate that the association between SNP830 genotype and exploratory behaviour also exists in free-living birds from the original population. However, in the other three populations we found only limited evidence for an association: in two populations the association appeared absent; while in one there was a nonsignificant tendency. We could not confirm a previously demonstrated interaction with another DRD4 polymorphism, a 15 bp indel in the promoter region (ID15). As yet unknown differences in genetic or environmental background could explain why the same genetic polymorphism (SNP830) has a substantial effect on exploratory behaviour in one population, explaining 4.5-5.8% of the total variance-a large effect for a single gene influencing a complex behavioural trait-but not in three others. The confirmation of an association between SNP830 genotype and personality-related behaviour in a wild bird population warrants further research into potential fitness effects of the polymorphism, while also the population differences in the strength of the association deserve further investigation. Another important future challenge is the identification of additional loci influencing avian personality traits in the wild.

Alleles frequencies and polymorphisms genotypes frequencies of gene DRD4 (VNTR), gene DAT (VNTR), gene 5-HTT (VNTR and ID) and gene OPRM1 (SNP) were investigated at Russian males taking narcotic substances. It was determined that genotype 4/3 occurs only at persons taking narcotic substances, the most often occurring polymorphism of gene DRD4 is genotype 4/4 in all groups. It was detected that the polymorphism of gene DAT at narcotized persons is presented by the high enough part of genotypes 9/10 and 10/10, but in the rest of groups the distribution is the same. At narcotized persons and in the control group, the carriers’ part of genotype I/D of gene 5НТ2А is high. The genotype D/D occurs only at persons taking narcotic substances. The genotype10/10 of gene 5НТ2А occurs more often than in population group, which conforms to the literature data.

The subject of the current work is a highly polymorphic region on the gene coding for D4 type dopamine receptors (DRD4) consisting of a variable number of tandem repeats (VNTR) of a 48 base pair sequence. Convergent evidence from psychology, population genetics and animal behavior research support the important role the DRD4 VNTR polymorphism plays in promoting exploratory behavior. Awe is an emotion felt in the presence of vast stimuli that are not accounted for by existing mental schema (Keltner & Haidt, 2003). In the current work I made the claim that awe signals the opportunity for exploration. Given the demonstrated relationship between the DRD4 VNTR polymorphism and exploratory behavior, the main aim of the current work is to test the relationship between this polymorphism and emotional reactivity to awe-eliciting situations. Specifically, I hypothesized that people with DRD4 VNTR variants that have been associated with exploratory behavior (carriers) would experience more awe than people who do not have those variants (non-carriers) across a range of situations. Study 1 used a college sample to test this hypothesis, both in a controlled laboratory environment and in people’s daily lives using diary methodology. Specifically, in a laboratory setting, carriers reported more awe than non-carriers in response to a film clip that had been validated as a reliable elicitor or awe, but no differences were found between groups in response to film clips that elicited compassion and amusement. Furthermore, analyses of daily diary data showed a trend such that carriers reported more awe across a 14-day diary period than non-carriers. Study 2, an ecologically valid test of my hypothesis, found that in a sample of adolescents from underserved communities who went white-water rafting, carriers reported more awe than non-carriers. Importantly, DRD4 VNTR did not have a consistent effect on any of the other emotions measured across these three contexts. I discussed the implications these findings have for our understanding of the emotion of awe and programs that aim to increase well-being through the experience of awe.

Polymorphisms in several neurotransmitter-associated genes have been associated with variation in human personality traits. Among the more promising of such associations is that between the human dopamine receptor D4 gene ( Drd4 ) variants and novelty-seeking behaviour. However, genetic epistasis, genotype–environment interactions and confounding environmental factors all act to obscure genotype–personality relationships. Such problems can be addressed by measuring personality under standardized conditions and by selection experiments, with both approaches only feasible with non-human animals. Looking for similar Drd4 genotype–personality associations in a free-living bird, the great tit ( Parus major ), we detected 73 polymorphisms (66 SNPs, 7 indels) in the P. major Drd4 orthologue. Two of the P. major Drd4 gene polymorphisms were investigated for evidence of association with novelty-seeking behaviour: a coding region synonymous single nucleotide polymorphism (SNP830) and a 15 bp indel (ID15) located 5′ to the putative transcription initiation site. Frequencies of the three Drd4 SNP830 genotypes, but not the ID15 genotypes, differed significantly between two P. major lines selected over four generations for divergent levels of ‘early exploratory behaviour’ (EEB). Strong corroborating evidence for the significance of this finding comes from the analysis of free-living, unselected birds where we found a significant association between SNP830 genotypes and differing mean EEB levels. These findings suggest that an association between Drd4 gene polymorphisms and animal personality variation predates the divergence of the avian and mammalian lineages. Furthermore, this work heralds the possibility of following microevolutionary changes in frequencies of behaviourally relevant Drd4 polymorphisms within populations where natural selection acts differentially on different personality types.

The study considered individual differences in children's ability to adjust to hospitalization and found the length of hospitalization to be related to serious emotional and behavioral problems for some and to adaptive psychological functioning for others. Applying the theoretical framework of three competing models of gene X environment interactions (diathesis-stress, differential susceptibility and vantage sensitivity), the study examined the moderating effect of genetic (DRD4) on the relationship between the length of hospitalization and internalizing and externalizing problems. Mothers reported on children’s hospitalization background and conduct problems (externalizing) and emotional symptoms (internalizing), using subscales of the 25-item Strength and Difficulties Questionnaire (1). Data on both hospitalization and genetics were available for 65 children, 57% of whom were females, with an average age of 61.4 months (SD=2.3). The study found length of hospitalization did not predict emotional and behavior problems per se, but the interaction with genetics was significant; the length of hospitalization was related to diminished levels of internalizing and externalizing problems only for children with 7R allele (the sensitive variant). The vantage sensitivity model best accounted for how the length of hospitalization and genetics related to children's internalizing and externalizing problems. Longer periods of hospitalization appeared to benefit children with sensitive genetic makeup.

Affective knowledge, the ability to understand others’ emotional states, is considered to be a fundamental part in efficient social interaction. Affective knowledge can be seen as related to cognitive empathy, and in the framework of Theory of Mind (ToM) as affective ToM. Previous studies found that cognitive empathy and ToM are heritable, yet little is known regarding the specific genes involved in individual variability in affective knowledge. Investigating the genetic basis of affective knowledge is important for understanding brain mechanisms underlying socio-cognitive abilities. The 7-repeat (7R) allele within the third exon of the Dopamine D4 receptor gene (DRD4-III) has been a focus of interest, due to accumulated knowledge regarding its relevance to individual differences in prosocial behavior. A recent study suggests that an interaction between the DRD4-III polymorphism and sex is associated with cognitive empathy among adults. We aimed to examine the same association in two childhood age groups. Children (N = 280, age 3.5 years, N = 283, age 5 years) participated as part of the Longitudinal Israel Study of Twins (LIST). Affective knowledge was assessed through children’s responses to an illustrated story describing different emotional situations, told in a laboratory setting. The findings suggest a significant interaction between sex and the DRD4-III polymorphism, replicated in both age groups. Boy carriers of the 7R allele had higher affective knowledge scores than girls, whereas in the absence of the 7R there was no significant sex effect on affective knowledge. The results support the importance of DRD4-III polymorphism and sex differences to social development. Possible explanations for differences from adult findings are discussed, as are pathways for future studies.

Affective knowledge, the ability to understand others’ emotional states, is considered to be a fundamental part in efficient social interaction. Affective knowledge can be seen as related to cognitive empathy, and in the framework of Theory of Mind (ToM) as affective ToM. Previous studies found that cognitive empathy and ToM are heritable, yet little is known regarding the specific genes involved in individual variability in affective knowledge. Investigating the genetic basis of affective knowledge is important for understanding brain mechanisms underlying socio-cognitive abilities. The 7-repeat (7R) allele within the third exon of the Dopamine D4 receptor gene (DRD4-III) has been a focus of interest, due to accumulated knowledge regarding its relevance to individual differences in prosocial behavior. A recent study suggests that an interaction between the DRD4-III polymorphism and sex is associated with cognitive empathy among adults. We aimed to examine the same association in two childhood age groups. Children (N = 280, age 3.5 years, N = 283, age 5 years) participated as part of the Longitudinal Israel Study of Twins (LIST). Affective knowledge was assessed through children’s responses to an illustrated story describing different emotional situations, told in a laboratory setting. The findings suggest a significant interaction between sex and the DRD4-III polymorphism, replicated in both age groups. Boy carriers of the 7R allele had higher affective knowledge scores than girls, whereas in the absence of the 7R there was no significant sex effect on affective knowledge. The results support the importance of DRD4-III polymorphism and sex differences to social development. Possible explanations for differences from adult findings are discussed, as are pathways for future studies.

© 2015 Hale, Wiley, Smalley, Tung, Kaminsky, McGough, Jaini and Loo. Background: We previously hypothesized that poor task-directed sensory information processing should be indexed by increased weighting of right hemisphere (RH) biased attention and visuo-perceptual brain functions during task operations and have demonstrated this phenotype in ADHD across multiple studies, using multiple methodologies. However, in our recent distributed effects model of ADHD, we surmised that this phenotype is not ADHD specific, but rather more broadly reflective of any circumstance that disrupts the induction and maintenance of an emergent task-directed neural architecture. Under this view, increased weighting of RH-biased attention and visuo-perceptual brain functions is expected to generally index neurocognitive sets that are not optimized for task-directed thought and action, and when durable expressed, liability for ADHD.Method: The current study tested this view by examining whether previously identified rightward parietal EEG asymmetry in ADHD was associated with common ADHD characteristics and comorbidities [i.e., ADHD risk factors (RFs)].Results: Barring one exception (non-right handedness), we found that it was. Rightward parietal asymmetry (RPA) was associated with carrying the DRD4-7R risk allele, being male, having mood disorder, and having anxiety disorder. However, differences in the specific expression of RPA were observed, which are discussed in relation to possible unique mechanisms underlying ADHD liability in different ADHD RFs.Conclusion: Rightward parietal asymmetry appears to be a durable feature of ADHD liability, as predicted by the Distributed Effects Perspective Model of ADHD. Moreover, variability in the expression of this phenotype may shed light on different sources of ADHD liability.

© 2015 Benish-Weisman, Kerem, Knafo-Noam and Belsky. The study considered individual differences in children's ability to adjust to hospitalization and found the length of hospitalization to be related to adaptive psychological functioning for some children. Applying the theoretical framework of three competing models of gene-X-environment interactions (diathesis-stress, differential susceptibility, and vantage sensitivity), the study examined the moderating effect of genetics (DRD4) on the relationship between the length of hospitalization and internalizing and externalizing problems. Mothers reported on children's hospitalization background and conduct problems (externalizing) and emotional symptoms (internalizing), using subscales of the 25-item Strength and Difficulties Questionnaire (1). Data on both hospitalization and genetics were available for 65 children, 57% of whom were females, with an average age of 61.4 months (SD = 2.3). The study found length of hospitalization did not predict emotional and behavior problems per se, but the interaction with genetics was significant; the length of hospitalization was related to diminished levels of internalizing and externalizing problems only for children with the 7R allele (the sensitive variant). The vantage sensitivity model best accounted for how the length of hospitalization and genetics related to children's internalizing and externalizing problems.

The behaviour of beef cattle is important for the safety and welfare of stockmen and animals. Ten microsatellites spanning BTA29 and, in addition, the candidate gene, dopamine receptor D4 gene, were analysed in 545 German Angus calves of six sires and included in a quantitative trait locus (QTL) study on the basis of three different behaviour tests. A putative QTL for the score while entering the scale (ScE) was detected at BMS764. The DRD4 fragment was mapped in the distal region of BTA29 15.3 cM distal of ILSTS081. The results clearly indicate that BTA29 with a putative QTL in the proximal part and the candidate gene, DRD4, in the distal part plays an important role in the regulation of temperament. During the study one of the sires was detected to be a blood chimera.

Two classic strategic orientations have been found to pervade the behavior of modern salespersons: a sales orientation where salespersons use deception or guile to get customers to buy even if they do not need a product, and a customer orientation where salespersons first attempt to discover the customer’s needs and adjust their product and selling approach to meet those needs. Study 1 replicates recent research and finds that the Taq A1 variant of the DRD2 gene is not related to either sales or customer orientation, whereas the 7-repeat variant of the DRD4 gene is related to customer orientation but not sales orientation. Study 2 investigates gene × phenotype explanations of orientation of salespersons, drawing upon recent research in molecular genetics and biological/psychological attachment theory. The findings show that attachment style regulates the effects of DRD2 on customer orientation, such that greater avoidant attachment styles lead to higher customer orientation for persons with the A2/A2 variant but neither the A1/A2 nor A1/A1 variants. Likewise, attachment style regulates the effects of DRD4 on customer orientation, such that greater avoidant attachment styles lead to higher customer orientation for persons with the 7-repeat variant but not other variants. No effects were found on a sales orientation, and secure and anxious attachment styles did not function as moderators.