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Animal personalities are stable, context-dependent behavioral differences. Associations between the personality of birds and polymorphisms in the dopamine receptor D4 (DRD4) gene have been repeatedly observed. In mammals, our understanding of the role of the dopamine (DA) system in higher cognitive functions and psychiatric disorders is improving, and we are beginning to understand the relationship between the neural circuits modulating the DA system and personality traits. However, to understand the phylogenetic continuity of the neural basis of personality, it is necessary to clarify the neural circuits that process personality in other animals and compare them with those in mammals. In birds, the DA system is anatomically and molecularly similar to that in mammals; however, the function of DRD4 remains largely unknown. In this study, we used chicks as model birds to reveal the expression regions of the DA neuron-related markers tyrosine hydroxylase (TH), dopa decarboxylase (DDC), dopamine β -hydroxylase (DBH) , and DRD4 , as well as other DRDs throughout the forebrain. We found that DRD4 was selectively expressed in the mitral cells of the olfactory bulb (OB). Furthermore, a detailed comparison of the expression regions of DA neurons and DRD4 in the OB revealed a cellular composition similar to that of mammals. Our findings suggest that the animal personality gene DRD4 is important for olfactory information processing in birds, providing a new basis for comparing candidate neural circuits for personality traits between birds and mammals. [ABSTRACT FROM AUTHOR]

Currently, there is a growing amount of evidence for the involvement of dopamine receptors and the functionally related trace amine-associated receptor, TAAR1, in upper intestinal function. In the present study, we analyzed their expression in the duodenum using publicly accessible transcriptomic data. We revealed the expression of DRD1, DRD2, DRD4, DRD5, and TAAR1 genes in different available datasets. The results of the gene ontology (GO) enrichment analysis for DRD2 and especially TAAR1 co-expressed genes were consistent with the previously described localization of D2 and TAAR1 in enteric neurons and secretory cells, respectively. Considering that co-expressed genes are more likely to be involved in the same biological processes, we analyzed genes that are co-expressed with TAAR1, DRD2, DRD4, and DRD5 genes in healthy mucosa and duodenal samples from patients with functional dyspepsia (FD) or diabetes-associated gastrointestinal symptoms. Both pathological conditions showed a deregulation of co-expression patterns, with a high discrepancy between DRDs and TAAR1 co-expressed gene sets in normal tissues and patients' samples and a loss of these genes' functional similarity. Meanwhile, we discovered specific changes in co-expression patterns that may suggest the involvement of TAAR1 and D5 receptors in pathologic or compensatory processes in FD or diabetes accordingly. Despite our findings suggesting the possible role of TAAR1 and dopamine receptors in functional diseases of the upper intestine, underlying mechanisms need experimental exploration and validation. [ABSTRACT FROM AUTHOR]

This study draws on the conservation of resources theory to explore the role of altruistic behavior in resource gain and loss spirals and the association between particular genetic markers and these spirals. Using experience sampling data and genetic analysis, we found that positive affect (T1) was directly associated with altruistic behavior. A payoff of increased positive affect resulted from such behavior (T2). Individuals who started work with an elevated level of fatigue (T1) engaged in less altruistic behavior and became more fatigued (T2). Altruistic behavior mediated the positive affect/fatigue at T1 and T2. Hence, altruistic behavior may promote a resource gain spiral by enhancing positive affect resources. Furthermore, it buffers against a resource loss spiral by preventing increased fatigue. Moreover, genetic testing showed that the 2R carriers of the DRD4 polymorphism would respond with stronger positive affect and less fatigue after performing altruistic behaviors compared to non-2R carriers. Therefore, our research revealed the moderating role of individual differences in the relationship between altruistic behavior and resource gain and loss spirals. [ABSTRACT FROM AUTHOR]

Abstract Antipsychotic drugs are the first line of treatment in schizophrenia; although antipsychotic responses indicate a wide interindividual variety in patients with schizophrenia. This study aimed to investigate the association between four polymorphisms in DRD2, DRD4 and COMT genes and their gene-gene interactions with antipsychotic treatment response in patients with schizophrenia. A total of 101 patients with schizophrenia were recruited and stratified in treatment responder and treatment resistant groups based on the published criteria of resistant to treatment using PANSS. Clinical and demographic factors were analyzed. Genomic DNA was extracted from whole blood and genotyping for the four polymorphisms were done by ARMS-PCR, PCR-RFLP and gap-PCR. Gene-gene interactions were analyzed by logistic regression. In case of DRD2 A-241G, G allele was significantly associated with resistant to treatment. Regarding DRD4 120-bp duplication, 240/240 genotype was significantly associated with resistant to treatment comparing to other genotypes in a dominant model. The genotype combination of DRD4 240/240 and COMT Val/Val was significantly associated with treatment resistant. Among DRD2 AA genotype, COMT met allele carriers which also had a 120 bp allele of DRD4 had a significantly better response to antipsychotics. Moreover, analysis of clinical and demographic factors demonstrated a significantly longer duration of hospitalization and higher chlorpromazine-equivalent daily dose in resistant to treatment patients. Discovering the polymorphisms which effect treatment response to antipsychotics will provide the possibility of genetic screening before starting an antipsychotic treatment which enhances the chance of responding to antipsychotics and decreases drugs side effects and costs.

Acute kidney injury (AKI) is a life-threatening health condition associated with increasing morbidity and mortality. Despite extensive research on the mechanisms underlying AKI, effective clinical tools for prediction and treatment remain scarce. Oxidative stress and mitochondrial damage play a critical role in AKI and dopamine D4 receptor (DRD4) has been confirmed to be associated with oxidative stress. In this study, we hypothesized that DRD4 could attenuate AKI through its antioxidative and antiapoptotic effects. In vivo, DRD4 was remarkably decreased in the kidneys of mice subjected to ischemia/reperfusion injury (IRI) or cisplatin treatment. Notably, DRD4 significantly attenuated nephrotoxicity by suppressing oxidative stress and enhancing mitochondrial bioenergetics through the downregulation of reactive oxygen species (ROS) generation and NADPH oxidase 4 (NOX4) expression. In vitro, DRD4 demonstrated the ability to ameliorate oxidative stress-induced apoptosis in HK-2 cells subjected to hypoxia/reoxygenation- or cisplatin treatment. Transcriptome sequencing revealed that, mechanistically, DRD4 reduced the expression of its downstream target, interferon-stimulated gene 15 (ISG15), suppressing NOX4 ISGylation, enhancing the ubiquitination of NOX4, leading to its degradation, and ultimately counteracting oxidative stress-induced AKI. Altogether, these findings underscore the significance of DRD4 in AKI and elucidate DRD4 as a potential protectant against IRI or cisplatin-induced nephrotoxicity.

The prevalence of mental disorders and how they are diagnosed represent some of the major problems in psychiatry. Modern genetic tools offer the potential to reduce the complications concerning diagnosis. However, the vast genetic diversity in the world population requires a closer investigation of any selected populations. In the current research, four polymorphisms, namely rs6265 in BDNF, rs10835210 in BDNF, rs6313 in HTR2A, and rs1800955 in DRD4, were analyzed in a case–control study of 2393 individuals (1639 patients with mental disorders (F20-F29, F30-F48) and 754 controls) from the European part of Russia using the TaqMan SNP genotyping method. Significant associations between rs6265 BDNF and rs1800955 DRD4 and mental impairments were detected when comparing the general group of patients with mental disorders (without separation into diagnoses) to the control group. Associations of rs6265 in BDNF, rs1800955 in DRD4, and rs6313 in HTR2A with schizophrenia in patients from the schizophrenia group separately compared to the control group were also found. The obtained results can extend the concept of a genetic basis for mental disorders in the Russian population and provide a basis for the future improvement in psychiatric diagnostics. [ABSTRACT FROM AUTHOR]

Currently, there is a growing amount of evidence for the involvement of dopamine receptors and the functionally related trace amine-associated receptor, TAAR1, in upper intestinal function. In the present study, we analyzed their expression in the duodenum using publicly accessible transcriptomic data. We revealed the expression of DRD1, DRD2, DRD4, DRD5, and TAAR1 genes in different available datasets. The results of the gene ontology (GO) enrichment analysis for DRD2 and especially TAAR1 co-expressed genes were consistent with the previously described localization of D2 and TAAR1 in enteric neurons and secretory cells, respectively. Considering that co-expressed genes are more likely to be involved in the same biological processes, we analyzed genes that are co-expressed with TAAR1, DRD2, DRD4, and DRD5 genes in healthy mucosa and duodenal samples from patients with functional dyspepsia (FD) or diabetes-associated gastrointestinal symptoms. Both pathological conditions showed a deregulation of co-expression patterns, with a high discrepancy between DRDs and TAAR1 co-expressed gene sets in normal tissues and patients’ samples and a loss of these genes’ functional similarity. Meanwhile, we discovered specific changes in co-expression patterns that may suggest the involvement of TAAR1 and D5 receptors in pathologic or compensatory processes in FD or diabetes accordingly. Despite our findings suggesting the possible role of TAAR1 and dopamine receptors in functional diseases of the upper intestine, underlying mechanisms need experimental exploration and validation.

Antipsychotic drugs are the first line of treatment in schizophrenia; although antipsychotic responses indicate a wide interindividual variety in patients with schizophrenia. This study aimed to investigate the association between four polymorphisms in DRD2, DRD4 and COMT genes and their gene-gene interactions with antipsychotic treatment response in patients with schizophrenia. A total of 101 patients with schizophrenia were recruited and stratified in treatment responder and treatment resistant groups based on the published criteria of resistant to treatment using PANSS. Clinical and demographic factors were analyzed. Genomic DNA was extracted from whole blood and genotyping for the four polymorphisms were done by ARMS-PCR, PCR-RFLP and gap-PCR. Gene-gene interactions were analyzed by logistic regression. In case of DRD2 A-241G, G allele was significantly associated with resistant to treatment. Regarding DRD4 120-bp duplication, 240/240 genotype was significantly associated with resistant to treatment comparing to other genotypes in a dominant model. The genotype combination of DRD4 240/240 and COMT Val/Val was significantly associated with treatment resistant. Among DRD2 AA genotype, COMT met allele carriers which also had a 120 bp allele of DRD4 had a significantly better response to antipsychotics. Moreover, analysis of clinical and demographic factors demonstrated a significantly longer duration of hospitalization and higher chlorpromazine-equivalent daily dose in resistant to treatment patients. Discovering the polymorphisms which effect treatment response to antipsychotics will provide the possibility of genetic screening before starting an antipsychotic treatment which enhances the chance of responding to antipsychotics and decreases drugs side effects and costs. [ABSTRACT FROM AUTHOR]

The "paradox of the great speciators" has puzzled evolutionary biologists for over half a century. A great speciator requires excellent dispersal propensity to explain its occurrence on multiple islands, but reduced dispersal ability to explain its high number of subspecies. A rapid reduction in dispersal ability is often invoked to solve this apparent paradox, but a proximate mechanism has not been identified yet. Here, we explored the role of six genes linked to migration and animal personality differences (CREB1, CLOCK, ADCYAP1, NPAS2, DRD4, and SERT) in 20 South Pacific populations of silvereye (Zosterops lateralis) that range from highly sedentary to partially migratory, to determine if genetic variation is associated with dispersal propensity and migration. We detected genetic associations in three of the six genes: (i) in a partial migrant population, migrant individuals had longer microsatellite alleles at the CLOCK gene compared to resident individuals from the same population; (ii) CREB1 displayed longer average microsatellite allele lengths in recently colonized island populations (<200 years), compared to evolutionarily older populations. Bayesian broken stick regression models supported a reduction in CREB1 length with time since colonization; and (iii) like CREB1, DRD4 showed differences in polymorphisms between recent and old colonizations but a larger sample is needed to confirm. ADCYAP1, SERT, and NPAS2 were variable but that variation was not associated with dispersal propensity. The association of genetic variants at three genes with migration and dispersal ability in silvereyes provides the impetus for further exploration of genetic mechanisms underlying dispersal shifts, and the prospect of resolving a long‐running evolutionary paradox through a genetic lens. [ABSTRACT FROM AUTHOR]

Background. It is known that some genes regulate neurochemical metabolism, and their polymorphisms affect cognitive performance, including the ability to categorize emotionally significant information. Objective. The aim of our study was to analyze the recognition of emotional and neutral visual scenes in carriers of different polymorphic variants of the MAOA, COMT, DRD4, and 5HT2A genes. Design. The study sample consisted of 87 university students (Caucasians, women 63%, average age 20.4±2.6 years). The genotypes of the COMT, 5HT2A, and DRD4 genes were determined by polymerase chain reaction. Agarose gel electrophoresis was used to determine the number of tandem repeats of the MAOA gene. Three hundred sixty (360) photographic images of scenes of different emotional valence (positive, negative, and neutral – 120 images for each category) were used as stimuli. These images were classified by expert assessments. The images were presented in a random sequence. The exposure time was 700 ms. The research participants were asked to determine the emotional valence of each scene. Results. We found that only the COMT gene genotype affected the recognition of emotional and neutral visual scenes. Carriers of the COMT Val/Val genotype, which causes dopamine to stay in the synaptic space for a shorter time, are better in recognizing and demonstrate higher sensitivity to the emotional content of scenes. Carriers of the Val/Met genotype demonstrated the worst ability to differentiate the emotional valence of visual scenes. Conclusion. This study has shown that the length of stay of monoamines in the synaptic space regulated by the COMT gene affects the recognition of emotional visual information.

Background. Attention deficit hyperactivity disorder (ADHD) is one of the most common psychiatric disorders starting at an early age with symptoms of attention deficit hyperactivity disorder and impulsivity. This study aimed to investigate the molecular alterations of the DRD4 gene, which have been linked to ADHD in previous studies with respect to the dose of methylphenidate. Methods. The study population included all ADHD patients needing drug therapy aged 5-18 years referred to Bozorgmehr psychiatric clinic in Tabriz in 2017 for one year. After diagnosis, symptoms severity was assessed using the Conners Scale for ADHD Assessment. Then, 4 ml of blood was collected from each individual and DNA was extracted using salting out method. After performing polymerase chain reaction (PCR), the products were separated using specific restriction enzymes and then polymorphisms of Ex3 VNTR and rs3758653 of DRD4 gene were analyzed in 2% agarose gel. The last dose to achieve the therapeutic response was recorded in mg/kg. Then, we investigated the relationship between the doses of drug used to achieve the therapeutic response and the existence of the mentioned polymorphisms. Results. There was no significant relationship between treatment response and type of polymorphism. Also, there was no significant relationship between the average dose of drug and the polymorphisms of three replicates, four replicates, six replicates, and more than six replicates in EX3VNTR in DRD4 gene. In addition, we witnessed no statistically significant relationship between the mean drug dose and CC, TC, and TT genotypes in DRD4rs3758653. Conclusion. There was no significant relationship between treatment response and type of polymorphism. There was no significant relationship between the average dose of drug and the polymorphisms of three replicate, four replicates, six replicates and more than six replicates in EX3VNTR in DRD4 gene. Between mean drug dose and CC, TC and TT genotypes in DRD4rs3758653, there was no statistically significant relationship. Practical Implications. Determining the reduction of ADHD symptoms by taking methylphenidate and evaluating the relationship between presence or absence of DRD4 polymorphisms and the dosage of drug to achieve a better response to treatment can collect enough evidence to determine the dose of methylphenidate according to the molecular analysis of DRD4 gene in patients with ADHD. This can reduce doctor visits, save time, and decrease the drug side effects.

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.

[Display omitted] Allergic asthma develops from allergen exposure in early childhood and progresses into adulthood. The central mediator of progressive allergic asthma is allergen-specific, T H 2–resident memory cells (TRMs). Although the crosstalk between nerves and immune cells plays an established role in acute allergic inflammation, whether nerves facilitate the establishment of T H 2-TRMs in the immature lung following early life allergen exposure is unknown. The aim of this study was to identify nerve-derived signals that act in T H 2 effector cells to regulate the tissue residency in the immature lung. Following neonatal allergen exposure, allergen-specific T H 2-TRMs were tracked temporally and spatially in relationship to developing sympathetic nerves in the lung. Functional mediators of dopamine signaling in the establishment of T H 2-TRMs were identified by in vitro bulk RNA-sequencing of dopamine-treated T H 2 cells followed by in vivo assessment of candidate genes using adoptive transfer of T H 2 cells with viral gene knockdown. This study found that sympathetic nerves produce dopamine and reside in proximity to T H 2 effector cells during the contraction phase following neonatal allergen exposure. Dopamine signals via DRD4 on T H 2 cells to elevate IL2RA and epigenetically facilitate type 2 cytokine expression. Blockade of dopamine-DRD4 signaling following neonatal allergen exposure impairs lung residence of T H 2 cells and ameliorates anamnestic inflammation in adults. These results demonstrate that maturing sympathetic nerves enable a dopamine-enriched lung environment in early life that promotes the establishment of allergen-specific T H 2-TRMs. The dopamine-DRD4 axis may provide a therapeutic target to modify allergic asthma progression from childhood to adulthood. [ABSTRACT FROM AUTHOR]

Biological and genetic factors, as well as contextual influences, contribute to the etiology of externalizing behaviors in children and adolescents. The current project used a longitudinal design to examine how individual vulnerability for externalizing behavior is influenced by the interplay among biological/genetic and environmental factors, and how this occurs across development. We investigated the influence of dopamine receptor D4 genotype (DRD4), child temperament, and household chaos on children's externalizing behaviors using a sample of twins/triplets tested at the ages of 4 and 5 years (n = 229), including a subset of these who were tested again in middle childhood (ages 7–13 years; n = 174). Multilevel linear regression modeling demonstrated that the DRD4‐7repeat genotype, 4‐year‐old negative affectivity, and household chaos at the age of 4 years were related to 5‐year‐old externalizing behaviors. Stability in externalizing behaviors from the age of 5 years to middle childhood was demonstrated. A significant interaction between DRD4 and household chaos showed that children with no 7‐repeat DRD4 alleles had significantly higher levels of externalizing in homes with extremely low levels of parent‐reported chaos, suggesting a "goodness‐of‐fit" pattern of gene–environment interaction. These findings suggest that risk for childhood externalizing behaviors is likely multifaceted and differs across developmental periods. [ABSTRACT FROM AUTHOR]

The African Sacred Ibis Threskiornis aethiopicus is an invasive bird species in Taiwan and has expanded its distribution range rapidly over the past three decades. There is limited information available on the invasion process of African Sacred Ibises in Taiwan and its genetic consequences. We investigated whether genetic factors reflected the expansion of African Sacred Ibises and determined the extent to which two behaviour‐associated genes may have facilitated invasion. The dopamine receptor gene (DRD4) and the serotonin transporter gene (SERT) have both been found to be associated with novel‐seeking and bold behaviour in birds. We hypothesized that: (1) selection on temperament traits may determine the polymorphisms in these two genes and (2) the likelihood of dispersal of African Sacred Ibis populations can be explained by the intraspecific variation at these two genes. To detect the signals of population expansion and natural selection, we compared intra‐population variation and inter‐population differentiation of DRD4 and SERT with those of a mitochondrial gene (COX1) and an additional intron. We recovered contrasting patterns of nucleotide variation between the mitochondrial and nuclear genes with no single nucleotide polymorphisms detected in COX1 compared with allelic polymorphism in DRD4 and SERT. Populations showed decreasing genetic diversity at DRD4 as their distance to the initial invasive locality increased, consistent with a rapid expansion from one founder population. However, we found little evidence of selection on DRD4 or SERT, suggesting that these behaviour‐related genes are unlikely to have played a significant role in the successful invasion of the African Sacred Ibises in Taiwan. We detected high levels of genetic variation at these two behaviour‐related genes despite the effects of inbreeding in these invasive birds. [ABSTRACT FROM AUTHOR]

ObjectiveWe aimed to understand the impact of dopamine receptor D4 (DRD4) polymorphisms on neurodegeneration in patients with dementia. We hypothesized that DRD4dampened-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.Methods337 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.ResultsDRD4 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.ConclusionsWe 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.

ObjectiveWe aimed to understand the impact of dopamine receptor D4 (DRD4) polymorphisms on neurodegeneration in patients with dementia. We hypothesized that DRD4dampened-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.Methods337 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.ResultsDRD4 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.ConclusionsWe 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.

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.

The functional and pharmacological significance of dopamine receptor D4 (DRD4) in psychiatric and neurological disorders is well elucidated. However, the roles of DRD4 in colorectal cancer (CRC) remain unclear. This study observes a significant upregulation of DRD4 expression in clinical samples, which is negatively correlated with patient prognosis. In vitro, overexpression of DRD4 causes a constitutive activation of β-Arrestin2/PP2A/AKT independent of dopamine. Interestingly, this classical signaling pathway is not associated with the phenotype of DRD4-promoted migration and invasion in CRC cells. Instead, DRD4 interacts with transforming growth factor beta receptors (TGFBR1 and TGFBR2) to activate Smad2 phosphorylation and promote Smad2/Smad4 complex nucleus translocation. Then, SNAI1 and JAG1 are transcriptionally activated to induce epithelial-mesenchymal transition and enhance the metastatic potential of CRC. Notably, the COOH-terminal domain is identified as the key intracellular region for the pro-metastatic roles of DRD4. Furthermore, treatment with a TGFBR1 inhibitor combined with a BMP inhibitor effectively counteracts the pro-metastatic effects induced by DRD4 both in vitro and in vivo. In conclusion, these findings uncover an unconventional role for DRD4 beyond its classic function as a neurotransmitter receptor. The intracellular signaling of DRD4 interacting with TGFBR1 can be targeted pharmacologically for CRC therapy., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Most studies examining gene-environment effects on self-regulation focus on outcomes early childhood or adulthood. However, only a few studies investigate longitudinal effects during middle childhood and adolescence and compare two domains of early caregiving. In a longitudinal follow-up with a sample of N = 87, we studied the effects of differences in the DRD4 tandem repeat polymorphisms and two domains of early maternal caregiving quality on children's personality development using Block's California Child Q-Set (CCQ) at age six and age 12 and on problem behavior at ages six and seven. Early maternal regulation quality predicted later ego-resiliency and aggressiveness. In addition, significant gene-environment interactions revealed that children with the 7+ DRD4 tandem repeat polymorphism and poor maternal regulation quality in infancy showed lower scores in ego-resiliency and higher scores in ego-undercontrol and CCQ aggressiveness. In contrast, children who had experienced effective maternal regulation in infancy showed a comparable level in personality traits and problem behavior as the DRD4 7- group independent of the levels of maternal regulatory behavior. Similarly, longitudinal caregiving × DRD4 interactions were found for behavior problems in middle childhood, especially for oppositional-aggression, inattentive-hyperactivity, and social competence. Early caregiving effects were only found for maternal regulation quality, but not for maternal responsiveness. Effective early maternal regulation in infancy can moderate the negative effect of DRD4 7+ on children's self-regulation in middle childhood and adolescence. However, maternal responsiveness has no comparable effects. It seems relevant to consider several dimensions of early caregiving and to also measure the environment in more detail in gene-environment studies. [ABSTRACT FROM AUTHOR]

Most studies examining gene-environment effects on self-regulation focus on outcomes early childhood or adulthood. However, only a few studies investigate longitudinal effects during middle childhood and adolescence and compare two domains of early caregiving. In a longitudinal follow-up with a sample of N = 87, we studied the effects of differences in the DRD4 tandem repeat polymorphisms and two domains of early maternal caregiving quality on children’s personality development using Block’s California Child Q-Set (CCQ) at age six and age 12 and on problem behavior at ages six and seven. Early maternal regulation quality predicted later ego-resiliency and aggressiveness. In addition, significant gene-environment interactions revealed that children with the 7+ DRD4 tandem repeat polymorphism and poor maternal regulation quality in infancy showed lower scores in ego-resiliency and higher scores in ego-undercontrol and CCQ aggressiveness. In contrast, children who had experienced effective maternal regulation in infancy showed a comparable level in personality traits and problem behavior as the DRD4 7- group independent of the levels of maternal regulatory behavior. Similarly, longitudinal caregiving × DRD4 interactions were found for behavior problems in middle childhood, especially for oppositional-aggression, inattentive-hyperactivity, and social competence. Early caregiving effects were only found for maternal regulation quality, but not for maternal responsiveness. Effective early maternal regulation in infancy can moderate the negative effect of DRD4 7+ on children’s self-regulation in middle childhood and adolescence. However, maternal responsiveness has no comparable effects. It seems relevant to consider several dimensions of early caregiving and to also measure the environment in more detail in gene-environment studies.

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.

Objective: To investigate whether single nucleotide polymorphisms (SNPs) in the ADGRL3, DRD4, and SNAP25 genes are associated with and predict ADHD severity in families from a Caribbean community. Method: ADHD severity was derived using latent class cluster analysis of DSM-IV symptomatology. Family-based association tests were conducted to detect associations between SNPs and ADHD severity latent phenotypes. Machine learning algorithms were used to build predictive models of ADHD severity based on demographic and genetic data. Results: Individuals with ADHD exhibited two seemingly independent latent class severity configurations. SNPs harbored in DRD4, SNAP25, and ADGRL3 showed evidence of linkage and association to symptoms severity and a potential pleiotropic effect on distinct domains of ADHD severity. Predictive models discriminate severe from non-severe ADHD in specific symptom domains. Conclusion: This study supports the role of DRD4, SNAP25, and ADGRL3 genes in outlining ADHD severity, and a new prediction framework with potential clinical use. [ABSTRACT FROM AUTHOR]

Searching for genetic causes of depressive and anxiety disorders has been going on for about three decades. However, the accumulated experimental data do not allow us to come to a final conclusion about the influence of certain genes on the risk of the disease and the severity of its course. Most studies of candidate genes were carried out using samples of patients with different nosological forms of depression. The aim of our work was to check whether the previously found associations are common for all depressive spectrum disorders or there are loci that specifically affect the risk of developing a certain disease. The study involved patients with disorders characterized by severe depressive symptoms (n = 357). Patients were divided into three samples according to the diagnosis: depressive episode (DE), recurrent depression (RD), and mixed anxiety and depressive disorder (MADD). The polymorphic locus 40 bp VNTR of gene SLC6A3 was associated with all studied disorders; the LL genotype was less common in patients and was associated with a low risk of disease. The polymorphism 120 bp VNTR in gene DRD4 was associated with RD and MADD. The rs6311 locus of gene HTR2A was associated with DE and MADD. A specific genetic risk factor for RD in the studied samples was the rs53576 polymorphism of gene OXTR. The genotype homozygous for the minor allele (AA) was associated with a low risk of RD. None of the studied polymorphic loci influenced the severity of depression symptoms. The loci rs6311 of gene HTR2A and 120 bp VNTR of gene DRD4 were associated with symptoms of situational and personality anxiety. The severity of situational anxiety symptoms was also influenced by the loci rs53576 of gene OXTR and 16–17 bp VNTR of gene SLC6A4. [ABSTRACT FROM AUTHOR]

Genetic variability is being discussed as a source of inter‐individual differences in Theory of Mind development. Previous studies documented an association between variations in DRD4 VNTR 48 bp, OXTR rs53576, COMT rs4680, and Theory of Mind task performance. As empirical evidence on these associations is sparse, we conducted a preregistered replication attempt of a study reporting a link between DRD4 VNTR 48 bp and false belief understanding in 50‐month‐old children [Lackner, C., Sabbagh, M. A., Hallinan, E., Liu, X., & Holden, J. J. (2012). Developmental Science, 15(2), 272–280.]. Additionally, we attempted a replication of studies on the role of OXTR rs53576 and COMT rs4680 in Theory of Mind. In both replication attempts, we did not find any evidence for associations between the sampled genetic markers and Theory of Mind ability in a series of analyses. Extending the replication attempt of Lackner et al., we employed longitudinal data from several tasks and measurement points, which allowed us to run follow‐up robustness checks with more reliable scores. These extensive analyses corroborated our null finding. This comprehensive non‐replication is important to balance current research on genetic markers of Theory of Mind. In a combined evaluation of our own and previous studies, we point to substantial methodological issues that research on the genetic basis of Theory of Mind development faces. We conclude that these limitations currently prevent firm conclusions on genetic influences on Theory of Mind development. [ABSTRACT FROM AUTHOR]

BackgroundWe 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.MethodThe 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)].ResultsBarring 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.ConclusionRightward 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.

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.

Depression is characterized by extremely high clinical heterogeneity. Only a few of the many symptoms of depression may overlap in different people with major depressive disorder. The search for molecular genetic markers of depression often yields conflicting results, which may be due to the heterogeneity of the samples. The aim of this work was to identify genetic risk factors for three diseases characterized by severe depressive symptoms. All participants were of East Slavic origin from Moscow and the regions of Central Russia. The polymorphisms of the genes of the dopamine transporter (SLC6A3/DAT1), dopamine receptors (DRD4 and DRD2), and the enzyme catechol-O-methyltransferase (COMT) were studied in patients with three diagnoses: depressive episode, recurrent depression, and mixed anxiety and depressive disorder. We observed statistically significant differences in the distribution of alleles for the SLC6A3 (DAT1) 40 bp VNTR locus in patients with mixed anxiety and depressive disorder. The short allele (8R and 9R) was more common in patients than in the control group (p = 0.005); significant differences were also observed in the distribution of genotypes of this locus (p = 0.025). No associations were found between the loci of the dopaminergic system and the risk of depressive episode and recurrent depression. [ABSTRACT FROM AUTHOR]

Introduction: Opioid and amphetamine type stimulant (ATS) exert their rewarding effects by stimulating the dopaminergic system in the mesolimbic area. It has been suggested that dopamine system in peripheral blood lymphocytes reflect the central dopamine system's activity and pathology, especially in neuropsychiatric diseases including drug addiction. The present study aimed to assess the effect of co-occurring opioid and ATS (COATS) addiction towards mRNA expression of dopamine receptors DRD4 and DRD5 in peripheral blood lymphocytes (PBLs) of drug dependent subjects (n=36) undergoing methadone maintenance therapy in comparison to control subjects (n=36). Materials and methods: Ten mL blood were obtained from the subjects followed by lymphocyte isolation, RNA extraction and reverse transcription. DRD4 and DRD5 mRNA expression in peripheral lymphocytes was assessed using real-time PCR. The DRD4 mRNA expression but not DRD5 was significantly reduced in the peripheral lymphocytes of COATS subjects. Results: Mean expression value for DRD4 was 14.0+0.24 among patients and 13.3+0.25 among control subjects. For DRD5 it was 12.87 + 0.75 among patients and 12.59 + 1.24 among controls. Conclusion: Inconclusion, co-occurring opioid and ATS addiction was associated with persistent deficiency of DRD4 but not DRD5 in PBLs. [ABSTRACT FROM AUTHOR]

Smokers (≥10 cigarettes per day, N=331) of European ancestry taking part in a double-blind placebo-controlled randomized trial of 12 weeks of treatment with bupropion along with counseling for smoking cessation were genotyped for a variable number of tandem repeats polymorphism in exon III of the dopamine D4 receptor gene. Generalized estimating equations predicting point-prevalence abstinence at end of treatment and 2, 6 and 12 months after the end of treatment indicated that bupropion (vs placebo) predicted increased odds of abstinence. The main effect of Genotype was not significant. A Genotype × Treatment interaction (P=0.005) showed that bupropion predicted increased odds of abstinence in long-allele carriers (odds ratios (OR)=1.31, P

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.

Objective: We investigated the interaction effect between the methylation of dopamine receptor D4 (DRD4) and phthalate exposure in ADHD on continuous performance test (CPT) variables. Method: Urine concentrations of mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono-n-butyl phthalate (MBP) were tested. The methylation status was analyzed for CpG sites of DRD4. Multivariable linear regression models were applied to investigate the interaction effects of methylation and phthalate levels. Results: There was a significant interaction effect of the methylation of CpG26 and CpG28 with the MEHHP level on omission errors in ADHD patients, but not in controls. The post hoc analysis revealed a significant correlation between the MEHHP concentration and omission errors in the methylated group, but not in the unmethylated group. Conclusion: The interaction between the methylation status of CpG sites of DRD4, particularly CpG26 and CpG28, and phthalate metabolite levels affects the attention level in ADHD patients. [ABSTRACT FROM AUTHOR]

Avian migration is a widespread, complex behavior that has long fascinated both scientists and the general public. Nonetheless, we have not identified the genetic and environmental controls of migration. Comparisons of migratory strategies within and among species suggest that these differences are associated with genetic and personality variation. Recently, studies have identified possible candidate genes for personality and migration in several avian taxa. Partially migratory species—those in which only some individuals migrate, while others remain resident year round—provide good study systems to test whether variation at candidate loci covaries with variation in migratory behavior. Using both a population genetic and a linear model approach, we tested whether genetic variation at 2 candidate genes (adenylate cyclase activating polypeptide 1, ADCYAP1, and dopamine receptor, DRD4) underlies variation in migratory behavior in the Western Bluebird (Sialia mexicana), a partial migrant, and the closely related Mountain Bluebird (S. currucoides), an obligate migrant, breeding in the Okanagan Valley, British Columbia. Our analyses suggested that DRD4, a gene usually associated with personality, might explain some of the propensity to migrate, but provided no evidence that ADCYAP1, a gene usually associated with the propensity to migrate, explained variation in migratory behavior in these species. Our results join a growing body of literature suggesting the effects of candidate genes are not generalizable across species or populations. [ABSTRACT FROM AUTHOR]

Prior work shows that people respond more plastically to environmental influences, including cultural influences, if they carry the 7 or 2‐repeat (7/2R) allelic variant of the dopamine D4 receptor gene (DRD4). The 7/2R carriers are thus more likely to endorse the norms and values of their culture. So far, however, mechanisms underlying this moderation of cultural acquisition by DRD4 are unclear. To address this gap in knowledge, we tested the hypothesis that DRD4 modulates the processing of reward cues existing in the environment. About 72 young adults, preselected for their DRD4 status, performed a gambling task, while the electroencephalogram was recorded. Principal components of event‐related potentials aligned to the Reward‐Positivity (associated with bottom‐up processing of reward prediction errors) and frontal‐P3 (associated with top‐down attention) were both significantly more positive following gains than following losses. As predicted, the gain‐loss differences were significantly larger for 7/2R carriers than for noncarriers. Also, as predicted, the cultural backgrounds of the participants (East Asian vs. European American) did not moderate the effects of DRD4. Our findings suggest that the 7/2R variant of DRD4 enhances (a) the detection of reward prediction errors and (b) controlled attention that updates the context for the reward, thereby suggesting one possible mechanism underlying the DRD4 × Culture interactions. Is there a genetic basis for cultural learning? Recent work suggests carriers of 7‐ or 2‐repeat allele of the dopamine DRD4 are more likely than non‐carriers to acquire their culture's beliefs and practices. We show carriers are more closely attuned to reward signals compared to non‐carriers. This finding offers a possible missing link in the analysis of the co‐evolutionary dynamic between genes and culture. [ABSTRACT FROM AUTHOR]

Genetics account for moderate variation of individual differences in developing alcohol use disorder (AUD), but it is unclear which genetic variations contribute to AUD risk. One candidate gene investigated due to its association with AUD is the dopamine D4 receptor gene (DRD4), which contains a 48-base pair variable number tandem repeat (VNTR) in exon 3 of its coding region. To date, no quantitative synthesis of the published literature on the effects of DRD4 VNTR variation on alcohol-related phenotypes has been conducted. MEDLINE, Embase, Web of Science, and PsycInfo were searched for studies that reported on alcohol craving, alcohol consumption, severity of AUD, and case-control (AUD versus no diagnosis of AUD) studies in DRD4L (seven repeats or more) carriers compared with DRD4S (six repeats or less) homozygotes. Random-effects meta-analysis was used for all analyses. A pooled sample size of 655 to 13,360 of 28 studies were included. Compared with DRD4S homozygotes, DRD4L carriers had increased number of drinking days (SMD: 0.205; 95% CI: 0.008 to 0.402), binge drinking days (SMD: 0.217; 95% CI: 0.0532 to 0.380), and severity of AUD (SMD: 0.143; 95% CI: 0.028 to 0.259). There was no difference between DRD4 VNTR genotypes on drinks per drinking day, largest number of drinks per day/occasion, and case-control analysis. It was not possible to conduct a meta-analysis of the craving data, but a systematic review of this literature found mixed results on DRD4 VNTR genotype effect. The present meta-analysis suggests DRD4 VNTR variation may be a risk factor for problematic alcohol use. Our findings are limited, however, by the absence of ancestry data from studies included in our analysis, precluding our ability to adjust for population stratification. Due to the likelihood of type I error in candidate gene approaches, our work highlights the critical need for studies with larger and more inclusive samples that account for sex and genetic ancestry to fully understand this relationship. [ABSTRACT FROM AUTHOR]

Three dopamine genes (DAT1, DRD2, and DRD4) have been associated with interpersonal delinquency, aggression, and violence when individuals experience adverse environmental exposures. Guided by the catalyst model of aggression, risk alleles identified in previous studies were hypothesized to be associated with intimate partner violence (IPV) perpetration in the presence of financial stressors, a possible environmental trigger. This hypothesis was tested using weighted, clustered logistic regression with data from the National Longitudinal Study of Adolescent to Adult Health. The direct effects DAT1, DRD2, and DRD4 on IPV perpetration, and the interaction of DAT1, DRD2, and DRD4 and financial stressors on IPV perpetration were assessed. Due to cell size, only White men and women were included in this analysis. Increasing number of financial stressors was associated with increased odds of IPV perpetration, regardless of DAT1, DRD2, and DRD4 alleles. As predicted, increasing number of financial stressors was more strongly associated with IPV perpetration among individuals with high-risk DAT1 alleles, than individuals with low-risk alleles. However, this relationship was inverted for DRD2. Although there was still a significant interaction between DRD2 and financial stressors, individuals with low-risk alleles had higher odds of IPV perpetration in the presence of financial stressors. A similar, nonsignificant relationship was found for DRD4. These findings indicate that these genes may interact differently with environmental exposures and types of violent behavior. In addition, the findings may, if replicated, suggest dopamine plays a different role in IPV perpetration compared with other forms of aggression and violence. [ABSTRACT FROM AUTHOR]

Associations have been reported of the 7-repeat (7R) allele of the human dopamine receptor D4 (DRD4) gene with both the personality trait of novelty seeking and attention-deficit/hyperactivity disorder (ADHD). The increased prevalence of the 7R allele in ADHD probands is consistent with the common variant-common disorder hypothesis, which proposes that the high frequency of many complex genetic disorders is related to common DNA variants. Recently, based on the unusual DNA sequence organization and strong linkage disequilibrium surrounding the DRD4 7R allele, we proposed that this allele originated as a rare mutational event, which nevertheless increased to high prevalence in human populations by positive selection. We have now determined, by DNA resequencing of 250 DRD4 alleles obtained from 132 ADHD probands, that most ADHD 7R alleles are of the conserved haplotype found in our previous 600 allele worldwide DNA sample. Interestingly, however, half of the 24 haplotypes uncovered in ADHD probands were novel (not one of the 56 haplotypes found in our prior population studies). Over 10 percent of the ADHD probands had these novel haplotypes, most of which were 7R allele derived. The probability that this high incidence of novel alleles occurred by chance in our ADHD sample is much less than 0.0001. These results suggest that allelic heterogeneity at the DRD4 locus may also contribute to the observed association with ADHD.

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 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. 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).

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.

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.

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.

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.

Prior work shows that compared to European Americans, East Asians show an enhanced propensity to take the perspective of another person. In the current work, we tested whether this cultural difference might be reflected in the gray matter (GM) volume of the temporoparietal junction (TPJ), a brain region selectively implicated in perspective taking and mentalizing. We also explored whether the cultural difference in the TPJ GM volume might be moderated by dopamine D4 receptor gene (DRD4) exon 3 variable-number tandem repeat polymorphism. Structural magnetic resonance imaging of 66 European Americans and 66 East Asian-born Asians were subjected to voxel-based morphometry. It was observed that the GM volume of the right TPJ was greater among East Asians than among European Americans. Moreover, this cultural difference was significantly more pronounced among carriers of the 7- or 2-repeat allele of DRD4 than among the non-carriers of these alleles. Our findings contribute to the growing evidence that culture can shape the brain. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Anorexia nervosa (AN) is a severe debilitating eating disorder. To date, only very few genes that predispose to AN have been identified. An alternative to association studies is to characterize ultra-rare variants in familial forms of AN. Here, we have implemented this approach to identify pathways that contribute to the development of AN through the analysis of a family with three members suffering from AN by exome analysis. We identified three ultra-rare deleterious variants in three genes (DRD4, CCKAR, NMS), already connected to the reward pathway, that co-segregate with AN, suggesting that this pathway might be playing a predisposing role in AN at least in familial forms. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]