Dopamine D4 Receptor Polymorphism Research Articles

Dopamine D4 receptor polymorphism and sex interact to predict children's affective knowledge.

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 social 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. 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.

Enhancement of gamma activity after selective activation of dopamine D4 receptors in freely moving rats and in a neurodevelopmental model of schizophrenia

Dopamine D4 receptor (D4R) mechanisms have been implicated in several psychiatric diseases, including schizophrenia, attention-deficit hyperactivity disorder (ADHD), and autism, which are characterized by cognitive deficits. The cellular mechanisms are poorly understood but impaired neuronal synchronization within cortical networks in the gamma frequency band has been proposed to contribute to these deficits. A D4R polymorphism was recently linked to variations in gamma power in both normal and ADHD subjects, and D4R activation was shown to enhance kainate-induced gamma oscillations in brain slices in vitro. The goal of this study was to investigate the effect of D4R activation on gamma oscillations in freely moving rats during natural behavior. Field potentials were recorded in the frontal, prefrontal, parietal, and occipital cortex and hippocampus. Gamma power was assessed before and after subcutaneous injection of a D4R agonist, A-412997, in several doses between 0.3 and 10.0mg/kg. The experiments were also repeated in a neurodevelopmental model of schizophrenia, in which rats are prenatally treated with methylazoxymethanol (MAM). We found that the D4R agonist increased gamma power in all regions at short latency and lasted for ~2h, both in normal and MAM-treated rats. The effect was dose dependent indicated by the significant difference between the effects after 3 and 10mg/kg in pair-wise comparison, whereas 0.3 and 1.0mg/kg injections were ineffective. This study demonstrates the involvement of D4R in cortical gamma oscillations in vivo and identifies this receptor as potential target for pharmacological treatment of cognitive deficits.

Association between dopamine D4 receptor polymorphism and age related changes in brain glucose metabolism.

Aging is associated with reductions in brain glucose metabolism in some cortical and subcortical regions, but the rate of decrease varies significantly between individuals, likely reflecting genetic and environmental factors and their interactions. Here we test the hypothesis that the variant of the dopamine receptor D4 (DRD4) gene (VNTR in exon 3), which has been associated with novelty seeking and sensitivity to environmental stimuli (negative and positive) including the beneficial effects of physical activity on longevity, influence the effects of aging on the human brain. We used positron emission tomography (PET) and [18F]fluoro-D-glucose (18FDG) to measure brain glucose metabolism (marker of brain function) under baseline conditions (no stimulation) in 82 healthy individuals (age range 22–55 years). We determined their DRD4 genotype and found an interaction with age: individuals who did not carry the 7-repeat allele (7R−, n = 53) had a significant (p<0.0001) negative association between age and relative glucose metabolism (normalized to whole brain glucose metabolism) in frontal (r = −0.52), temporal (r = −0.51) and striatal regions (r = −0.47, p<0.001); such that older individuals had lower metabolism than younger ones. In contrast, for carriers of the 7R allele (7R+ n = 29), these correlations with age were not significant and they only showed a positive association with cerebellar glucose metabolism (r = +0.55; p = 0.002). Regression slopes of regional brain glucose metabolism with age differed significantly between the 7R+ and 7R− groups in cerebellum, inferior temporal cortex and striatum. These results provide evidence that the DRD4 genotype might modulate the associations between regional brain glucose metabolism and age and that the carriers of the 7R allele appear to be less sensitive to the effects of age on brain glucose metabolism.

Evidence for epistasis between the 5-HTTLPR and the dopamine D4 receptor polymorphisms in externalizing behavior among 15-year-olds

The present study aimed to clarify the functional role of genes in the dopamine and serotonin systems by examining whether polymorphisms in these genes are related to adolescent externalizing behavior either alone or in interaction with each other. Participants were selected from an ongoing prospective study of the outcome of early risk factors. At age 15 years, 298 adolescents (144 males, 154 females) completed the Youth Self Report, 296 primary caregivers the Child Behavior Checklist and 253 teachers the Teacher Report Form. DNA was genotyped for the DRD4 exon III VNTR and the 5-HTTLPR polymorphisms. Results revealed that individuals with the DRD4 7r allele reported significantly more externalizing behavior than carriers of other variants. In addition, a significant interaction emerged, indicating that adolescents carrying two copies of the 5-HTTLPR short allele and the DRD4 7r variant scored highest on aggressive and/or delinquent behavior compared to other genotypes. This result suggests an effect of 5-HTTLPR on externalizing behavior in the presence of DRD4 7r but no effect in its absence.

Experimental evidence for differential susceptibility: Dopamine D4 receptor polymorphism (DRD4 VNTR) moderates intervention effects on toddlers' externalizing behavior in a randomized controlled trial.

In a randomized controlled trial we tested the role of genetic differences in explaining variability in intervention effects on child externalizing behavior. One hundred fifty-seven families with 1- to 3-year-old children screened for their relatively high levels of externalizing behavior participated in a study implementing Video-feedback Intervention to promote Positive Parenting and Sensitive Discipline (VIPP-SD), with six 1.5-hr intervention sessions focusing on maternal sensitivity and discipline. A moderating role of the dopamine D4 receptor (DRD4) variable-number tandem repeat (VNTR) exon III polymorphism was found: VIPP-SD proved to be effective in decreasing externalizing behavior in children with the DRD4 7-repeat allele, a polymorphism that is associated with motivational and reward mechanisms and Attention Deficit Hyperactivity Disorder (ADHD) in children. VIPP-SD effects were largest in children with the DRD4 7-repeat allele whose parents showed the largest increase in the use of positive discipline. The findings of this first experimental test of (measured) gene by (observed) environment interaction in human development indicate that children may be differentially susceptible to intervention effects depending on genetic differences.

The dopamine D4 receptor polymorphism affects the canine fearfulness

The canine fearfulness is a behavioral trait known to have a genetic basis. This research analyzed genetic effects of the dopamine D4 receptor polymorphism on this behavior by postulating a mixed model of inheritance. Genotyping for the three different repeat polymorphism found in the third exon of the receptor gene was carried out for the population of the Korean native dogs. Four hundred fifty eight dogs with known pedigree were genotyped, and 264 individuals were tested for their fear responses to an experimenter, in which four different behavioral paradigms were adopted. Since the results assessed by principal factor analysis revealed a major factor explaining 69% of the total phenotypic variance, the subsequent analyses were conducted for this quantity. Analyses of the factor scores by estimating their posterior means indicated that there is a fixed effect exerted by the three different repeat polymorphism found in the D4 receptor as well as sex, in addition to unidentified polygenic effects. The phenotypic contribution of the D4 genotype was roughly estimated to be about 2%, which is a fraction of the total genetic effects responsible for more than 20% of the total phenotypic variance.

A gene × gene interaction between DRD2 and DRD4 is associated with conduct disorder and antisocial behavior in males

BackgroundAntisocial behaviors are complex polygenic phenotypes that are due to a multifactorial arrangement of genetic polymorphisms. Little empirical research, however, has been undertaken that examines gene × gene interactions in the etiology of conduct disorder and antisocial behavior. This study examined whether adolescent conduct disorder and adult antisocial behavior were related to the dopamine D2 receptor polymorphism (DRD2) and the dopamine D4 receptor polymorphism (DRD4).MethodsA sample of 872 male participants from the National Longitudinal Study of Adolescent Health (Add Health) completed self-report questionnaires that tapped adolescent conduct disorder and adult antisocial behavior. DNA was genotyped for DRD2 and DRD4.ResultsMultivariate regression analysis revealed that neither DRD2 nor DRD4 had significant independent effects on conduct disorder or antisocial behavior. However, DRD2 interacted with DRD4 to predict variation in adolescent conduct disorder and in adult antisocial behavior.ConclusionThe results suggest that a gene × gene interaction between DRD2 and DRD4 is associated with the development of conduct disorder and adult antisocial behavior in males.

DRD4 7-repeat polymorphism moderates the association between maternal unresolved loss or trauma and infant disorganization

Previous studies have related attachment disorganization in children to either dopamine D4 receptor polymorphisms or maternal unresolved loss or trauma and frightening or anomalous parenting. In this study it was examined whether the interaction between genetic (DRD4 7-repeat and -521 C/T) and environmental risk factors (maternal unresolved loss/trauma and maternal frightening behavior) was associated with infant disorganization. A moderating role of the DRD4 gene was found. Maternal unresolved loss or trauma was associated with infant disorganization, but only in the presence of the DRD4 7-repeat polymorphism. The increase in risk for disorganization in children with the 7-repeat allele exposed to maternal unresolved loss/trauma compared to children without these combined risks was 18.8 fold. Similar moderating effects were not found for maternal frightening behavior. Our findings indicate that children are differentially susceptible to unresolved loss or trauma dependent on the presence of the 7-repeat DRD4 allele.

Gene-environment interaction of the dopamine D4 receptor (DRD4) and observed maternal insensitivity predicting externalizing behavior in preschoolers

Previous studies have related aggression and other externalizing problems in children to either dopamine D4 receptor polymorphisms or harsh and insensitive parenting. In this study it was determined whether the combination of the DRD4 7-repeat polymorphism and maternal insensitivity predicted significantly more externalizing behavior in preschoolers. The results pointed to a gene-environment interaction effect: maternal insensitivity was associated with externalizing (oppositional, aggressive) behaviors, but only in the presence of the DRD4 7-repeat polymorphism. The increase in externalizing behaviors in children with the 7-repeat allele exposed to insensitive care compared to children without these combined risks was sixfold. The data indicate that children are differentially susceptible to insensitive parenting dependent on the presence of the 7-repeat DRD4 allele.

Plasticity of Dopamine D4 Receptors in Rat Forebrain: Temporal Association with Motor Hyperactivity Following Neonatal 6-Hydroxydopamine Lesioning

Genetic studies suggest that dopamine D4 receptor polymorphism is associated with attention deficit hyperactivity disorder (ADHD). We recently reported that motor hyperactivity in juvenile male rats with neonatal 6-hydroxydopamine lesions of the central dopamine system can be reversed by dopamine D4 receptor-selective antagonists. In this study, effects of such lesions on D4 as well as other dopamine receptors (D1 and D2) were autoradiographically quantified at selected developmental stages. Neonatal lesions resulted in motor hyperactivity at postnatal day (PD) 25, but not at PD 37 or 60. Correspondingly, D4 receptor levels in lesioned rats were substantially increased in caudate-putamen and decreased in nucleus accumbens at PD 25, but not at PD 37 or 60. Neonatal lesions also led to relatively minor changes in D1 and D2 receptor binding in various forebrain regions. However, the time-course of lesion-induced motor hyperactivity correlated only with changes in D4, but not D1 and D2 receptors. These results further support the hypothesis that D4 receptors may play a pivotal role in lesion-induced hyperactivity, and possibly in clinical ADHD.

Idiopathic environmental intolerance: Increased prevalence of panic disorder–associated cholecystokinin B receptor allele 7

Background: A growing body of evidence suggests that idiopathic environmental intolerance (IEI) is a psychophysiologic disorder with prominent features of anxiety/panic and somatization, although proponents of a toxicogenic explanation claim, despite a lack of convincing evidence, that symptoms arise from exposure to otherwise nonnoxious environmental agents. Patient behaviour is characterized by strenuous avoidance of perceived triggers to the point of severe impairment of normal social and vocational functioning. IEI proponents claim that previous studies showing a high prevalence of psychopathology in patients with IEI and studies showing panic responses to known panicogenic challenges merely reflect the anxiety-producing result of living with IEI. Objective: We explored whether IEI and panic disorder, personality traits, or both shared an underlying neurogenetic basis that would predate the anxiety of IEI symptomatology. The DNA of patients with IEI was examined for the presence of known panic disorder–associated cholecystokinin B (CCK-B) receptor alleles and for personality trait–associated dopamine D4 receptor polymorphisms. Methods: Eleven patients with typical IEI symptoms were recruited and were individually matched to normal control subjects from an existing bank for age, sex, and ethnic background. Genomic DNA was extracted from peripheral blood samples. CCK-B and dopamine D4 receptor polymorphisms were examined by using standard PCR-based techniques. Results: There was a significantly higher prevalence of the panic disorder–associated CCK-B receptor allele 7 in subjects with IEI (9/22 [40.9%]) compared with control subjects (2/22 [9.1%], P = .037). There was no difference in personality trait–associated polymorphisms of the gene encoding dopamine D4 receptor between patients and control subjects. Conclusions: These findings provide preliminary evidence that IEI and panic disorder share a common neurogenetic basis, which would predate the anxiety-producing effects of IEI symptoms. Further studies with larger samples are warranted, but these results support previous studies that suggest that panic disorder may account for much of the symptomatology in at least some cases of IEI and provide a basis for rational treatment strategies. (J Allergy Clin Immunol 2001;107:887-90.)

Dopamine D4 receptor polymorphism and idiopathic Parkinson's disease.

Patients with idiopathic Parkinson's disease (IPD) are described as having markedly decreased novelty seeking characteristics. Since recent publications suggest an association between the dopamine D4 receptor polymorphism and novelty seeking, we investigated this polymorphism in a group of 122 patients with IPD and 127 healthy control subjects. We found similar allele and genotype frequencies in both groups and no association with the age of onset of symptoms. Therefore, the dopamine D4 receptor polymorphism does not confer genetic susceptibility to IPD and cannot explain the decreased novelty seeking in IPD patients.

Human novelty‐seeking personality traits and dopamine D4 receptor polymorphisms: a twin and genetic association study

Human novelty‐seeking personality traits and dopamine D4 receptor polymorphisms: a twin and genetic association study

Human novelty-seeking personality traits and dopamine D4 receptor polymorphisms: a twin and genetic association study

Although it is well-established that genetic variation is important in causing individual differences in many human personality traits or based on family, twin, and adoption studies, the first reports that specific genetic polymorphisms might influence a normal dimension of personality were only recently published. Specifically, two studies have described significant associations between a dopamine D4 receptor (D4DR) exon III 48-base pair (bp) insertion/deletion polymorphism and the personality traits of novelty-seeking and positive emotional experience [Benjamin et al. (1996): Nat Genet 12: 81-84; Ebstein et al. (1996): Nat Genet 12:78-80]. The present study was undertaken to attempt to replicate these important and heuristic initial findings. Personality questionnaires measuring novelty-seeking and positive emotional experience were administered to 306 male and female young adult twins (monozygotic 92 pairs, dizygotic 61 pairs) from the general population, 281 of whom were genotyped for D4DR exon I and III polymorphisms. No significant associations were observed between novelty-seeking or positive emotional experience and these D4DR polymorphisms. This failure to replicate the initial reports seems unlikely to represent measurement or genetic differences across studies, although environmental differences may be possible. Adequate statistical power in the present study suggests that these results are unlikely to be statistical "false negatives" and instead may reduce confidence in the generality of the initial positive findings.

Lack of evidence for allelic association between personality traits and the dopamine D4 receptor gene polymorphisms.

Personality traits in human subjects have shown considerable heritable components. Recently, two research groups reported associations between dopamine D4 receptor genotypes and the personality trait known as novelty seeking. This study was an attempt to replicate these findings. Three different exonic dopamine D4 receptor polymorphisms were genotyped in 126 healthy Swedish subjects. Personality traits of the subjects were assessed with the Karolinska Scales of Personality. Although there was a tendency in the direction hypothesized, no significant association between genotype constellations and personality traits was found. The previously reported association between dopamine D4 receptor alleles and novelty seeking was not replicated. Possible reasons for this include differences in personality inventories, ethnicity, and type I or type II errors.

O-16-7 - Positive association between dopamine D4 receptor polymorphism and schizophrenia

O-16-7 - Positive association between dopamine D4 receptor polymorphism and schizophrenia

Positive Associations between Dopamine D4 Receptor Polymorphism and Schizophrenia. A Study on Two Schizophrenic Groups with Genetic Loading and Unloading.

We studied the allelic distributions of 48-base pair repeat polymorphism of the dopamine D4 receptor (DRD4) gene in two groups of schizophrenic patients, one with any schizophrenic member in the family (L(+) group) and the other without schizophrenic family histories (L(-) group), and healthy controls. The frequency of the sum of the alleles of 4, 5, and 6 repeats in the L(+) group was significantly higher than the controls. The frequency of the allele of 4 repeats in the L(-) group was significantly higher than the controls. These results show positive allelic associations between DRD4 polymorphism and each of the two groups of schizophrenic patients.

No association between dopamine D4 receptor polymorphism and manic depressive illness.

No association between dopamine D4 receptor polymorphism and manic depressive illness.