Dopamine D2 Receptor Gene Polymorphisms Research Articles

DRD4 gene polymorphism and impulse control disorder induced by dopamine agonists in Parkinson's disease.

Impulse control disorders and their consequences display variability among individuals, indicating potential involvement of environmental and genetic factors. In this retrospective study, we analyzed a cohort of Parkinson's disease patients treated with dopamine agonists and investigated the influence of the dopamine D4 receptor gene polymorphism, DRD4 7R+, which is linked to psychiatric disorders, impulsive traits, and addictive behaviors. We found that DRD4 7R+ is a significant genetic risk factor associated with the severity of ICD.

Influence of COMT (rs4680) and DRD2 (rs1076560, rs1800497) Gene Polymorphisms on Safety and Efficacy of Methylphenidate Treatment in Children with Fetal Alcohol Spectrum Disorders

Fetal alcohol spectrum disorders (FASD) in a course of high prenatal alcohol exposure (hPAE) are among the most common causes of developmental disorders. The main reason for pharmacological treatment of FASD children is attention deficit hyperactivity disorder (ADHD), and methylphenidate (MPH) is the drug of choice. The aim of the study was to assess whether children born of hPAE with ADHD, with or without morphological FASD, differ in terms of catechol-O-methyltransferase (COMT) and dopamine receptor D2 (DRD2) gene polymorphisms, and if genetic predisposition affects response and safety of MPH treatment. The polymorphisms of COMT (rs4680) and DRD2 (rs1076560, rs1800497) were analyzed in DNA samples. A borderline significance was found for the correlation between MPH side effects and the G allele of COMT (rs4680) (p = 0.04994) in all ADHD children. No effect of COMT (rs4680) and DRD2 (rs1076560, rs1800497) polymorphisms and the treatment efficacy was observed. The analyzed DRD2 and COMT gene polymorphisms seem to play no role in MPH efficacy in ADHD children with hPAE, while low-activity COMT (Met158) variant carriers may be more intolerant to MPH. The MPH treatment is effective in ADHD independent of FASD, although the ADHD-FASD variant requires higher doses to be successful. These results may help in optimization and individualization in child psychiatry.

Dopamine D4 receptor gene polymorphism (DRD4 VNTR) moderates real-world behavioural response to the food retail environment in children

BackgroundEvidence for the impact of the food retailing environment on food-related and obesity outcomes remains equivocal, but only a few studies have attempted to identify sub-populations for whom this relationship might be stronger than others. Genetic polymorphisms related to dopamine signalling have been associated with differences in responses to rewards such as food and may be candidate markers to identify such sub-populations. This study sought to investigate whether genetic variation of the dopamine D4 receptor gene (DRD4 exon III 48 bp VNTR polymorphism) moderated the association between local exposure to food retailers on BMI and diet in a sample of 4 to12-year-old children.MethodsData collected from a birth cohort and a community cross-sectional study conducted in Montreal, Canada, were combined to provide DRD4 VNTR polymorphism data in terms of presence of the 7-repeat allele (DRD4-7R) for 322 children aged between 4 and 12 (M (SD): 6.8(2.8) y). Outcomes were Body Mass Index (BMI) for age and energy density derived from a Food Frequency Questionnaire. Food environment was expressed as the proportion of local food retailers classified as healthful within 3 km of participants’ residence. Linear regression models adjusted for age, sex, income, cohort, and geographic clustering were used to test gene*environment interactions.ResultsA significant gene*food environment interaction was found for energy density with results indicating that DRD4-7R carriers had more energy dense diets than non-carriers, with this effect being more pronounced in children living in areas with proportionally more unhealthy food retailers. No evidence of main or interactive effects of DRD4 VNTR and food environment was found for BMI.ConclusionsResults of the present study suggest that a genetic marker related to dopamine pathways can identify children with potentially greater responsiveness to unhealthy local food environment. Future studies should investigate additional elements of the food environment and test whether results hold across different populations.

Influence of DRD2 Polymorphisms on the Clinical Outcomes of Opioiddependent Patients on Methadone Maintenance Therapy.

ABSTRACTIntroduction:Dopamine receptor D2 (DRD2) is one of the dopamine receptors that have been studied in relation to opioid dependence. It is possible, therefore, that DRD2 gene (DRD2) polymorphisms influence treatment outcomes of patients with opioid dependence. The objective of this study was to investigate the influence of DRD2 polymorphisms on the clinical outcomes of opioid-dependent patients on methadone maintenance therapy (MMT).Materials and Methods:Patients with opioid dependence (n = 148) were recruited from MMT clinics. Pain sensitivity, severity of the opiate withdrawal syndrome, and sleep quality were assessed using cold pressor test (CPT), Subjective Opiate Withdrawal Scale (SOWS-M), and Pittsburgh Sleep Quality Index (PSQI)-Malay, respectively. Deoxyribonucleic acid (DNA) was extracted from whole blood, and then was used for genotyping of Val96Ala, Leu141Leu, Val154Ile, Pro310Ser, Ser311Cys, TaqI A, -141C Ins/Del, and A-241G polymorphisms.Results:Among 148 patients, 8.1% (n = 12), 60.8% (n = 90), 27.7% (n = 41), and 29.1% (n = 43) had at least one risk allele for Ser311Cys, TaqI A, -141C Ins/Del, and A-241G polymorphisms, respectively. There were no significant differences in pain responses (pain threshold, tolerance, and intensity), SOWS, and PSQI scores between DRD2 polymorphisms.Conclusion:The common DRD2 polymorphisms are not associated with pain sensitivity, severity of the opiate withdrawal syndrome, and sleep quality in patients with opioid dependence on MMT. However, this may be unique for Malays. Additional research should focus on investigating these findings in larger samples and different ethnicity.

Association of dopamine D2 receptor gene polymorphisms with prolactin levels related to risperidone treatment: A systematic review and meta-analysis.

Dopamine D2 receptor (DRD2) polymorphisms are inconsistently associated with elevated prolactin levels related to risperidone treatment. The aim of this systematic review and meta-analysis was to investigate whether DRD2 polymorphisms could modulate prolactin levels in patients treated with risperidone. Three electronic databases (PubMed, EMBASE and the Cochrane Library) were searched for studies investigating the effect of DRD2 polymorphisms on prolactin levels in patients treated with risperidone until May 2018. Summary standard mean differences (SMDs) and 95% confidence intervals (CIs) were calculated with Hedges' g tests for effect estimates using random effects models. The heterogeneity, sensitivity, univariable meta-regression, subgroup analyses and publication biases were calculated. After initially identifying 886 studies, 772 patients from eight studies were included. Summary SMDs indicated that compared with A1 non-carriers, Taq1A A1 carriers did not have different risperidone-related prolactin levels (SMD: 0.13; 95% CI: -0.18 to 0.43; P=0.423) among patients with schizophrenia (SCZ; SMD: 0.07; 95% CI: -0.14 to 0.29; P=0.505) or among those without SCZ (SMD: 0.16; 95% CI: -0.39 to 0.71; P=0.562). There was no significant difference between Del carriers and Del non-carriers with regard to risperidone-related prolactin levels (SMD: -0.00; 95% CI: -0.59 to 0.58; P=0.996). In an Asian subgroup analysis, we also noted that compared with Taq1A A1A2 carriers, Taq1A A1A1 carriers had lower prolactin levels (SMD: -0.34; 95% CI: -0.66 to -0.02; P=0.040). However, there was no significant difference in prolactin levels between A1A1 carriers and A2A2 carriers (SMD: -0.27; 95% CI: -0.60 to 0.05; P=0.098), or between A2 carriers and A2 non-carriers (SMD: 0.29; 95% CI: -0.01 to 0.59; P=0.059). Based on univariable meta-regression analyses, the effects of publication year, study design, ethnicity, comparison groups and study quality could bias the identified association of DRD2 Taq1A with risperidone-related prolactin levels. The findings of this study suggest that there is no significant difference between Taq1A A1 carriers and non-A1 carriers with regard to risperidone-related prolactin levels. As there were few A1 homozygotes, large prospective studies with robust designs are still needed to investigate whether A1A1 could affect risperidone-related prolactin levels in the Asian population.

Potential Role of Brain-Derived Neurotrophic Factor and Dopamine Receptor D2 Gene Variants as Modifiers for the Susceptibility and Clinical Course of Wilson's Disease.

Wilson's disease (WD), an inborn error of copper metabolism caused by mutations in the ATPase copper transporting beta (ATP7B) gene, manifests variable age of onset and different degrees of hepatic and neurological disturbances. This complex phenotypical outcome of a classical monogenic disease can possibly be explained by modifier loci regulating the clinical course of the disease. The brain-derived neurotropic factor (BDNF), critical for the survival, morphogenesis, and plasticity of the neurons, and the dopamine receptor D2 (DRD2), one of the most abundant dopamine receptors in the brain, have been highlighted in the pathophysiology of various neuropsychiatric diseases. This study aims to identify the potential association between BDNF and DRD2 gene polymorphisms and WD and its clinical characteristics. A total of 164 WD patients and 270 controls from India were included in this study. Two BDNF polymorphisms [p.Val66Met (c.G196A) and c.C270T] and the DRD2 Taq1A (A2/A1 or C/T) polymorphism were examined for their association with WD and some of its clinical attributes, using polymerase chain reaction, restriction fragment length digestion, and bidirectional sequencing. The C allele and CC genotype of BDNF C270T were significantly overrepresented among controls compared to WD patients. In addition, a significantly higher proportion of the allele coding for Val and the corresponding homozygous genotype of BDNF Val66Met polymorphism was found among WD patients with age of onset later than 10years. Furthermore, the A1A1 genotype of DRD2 Taq1A polymorphism was significantly more common among WD patients with rigidity. Our data suggest that both BDNF and DRD2 may act as potential modifiers of WD phenotype in the Indian context.

Dopamine D2 receptor gene polymorphisms and externalizing behaviors in children and adolescents

BackgroundDopamine is involved in several cerebral physiological processes, and single nucleotide polymorphisms (SNP) in the dopamine D2 receptor gene (DRD2) have been associated with numerous neurological and mental disorders, including those involving alterations in cognitive and emotional processes.MethodsThe aim of this study was to evaluate the association between the SNPs c.957C > T (rs6277) and c.-585A > G (rs1799978) in the DRD2 gene and behavioral characteristics of children and adolescents based on an inventory of the Child Behavior Checklist (CBCL). Children and adolescents between 8 and 20 years old who were clinically followed-up were genotyped for the SNPs c.957C > T and c.-585A > G, and related to data of the CBCL/6–18 scale assessment performed with the help of caregivers. The chi-squared test was used to assess the differences in the frequencies of the C and T alleles in the polymorphism c.957C > T and of the A and G alleles in the polymorphism c.-585A > G with respect to the grouped CBCL scores at a significance level of 5%. Multiple logistic regression models were performed, to control whether sex and/or ethnicity could influence the results.ResultsEighty-five patients were assessed overall, and the presence of the T allele (C/T and T/T) of DRD2 c.957C > T polymorphism was found to be significantly associated with the occurrence of defiant and oppositional problems and with attention and hyperactivity problems. There were no associations detected with polymorphism DRD2 c.-585A > G polymorphism. Both SNPs were in Hardy-Weinberg-equilibrium.ConclusionsAlthough the findings of this study are preliminary, due to its small number of participants, the presence of T allele (C/T, T/T) in c.957C > T SNP was associated with difficulty in impulse control, self-control of emotions, and conduct adjustment, which can contribute to improving the identification of mental and behavioral phenotypes associated with gene expression.

Dopamine receptor D2 genetic variations is associated with the risk and clinicopathological variables of urothelial cell carcinoma in a Taiwanese population.

Dopamine receptor D2 (DRD2) is overexpressed in several kinds of cancers and was correlated with the prognosis of these cancers. Polymorphisms within the DRD2 gene were shown to be associated with lung and colon cancers. The purpose of this study was to explore effects of DRD2 gene polymorphisms on the susceptibility to and clinicopathological characteristics of urothelial cell carcinoma (UCC). In total, 369 patients diagnosed with UCC and 738 healthy controls were enrolled to analyze DRD2 genotypes at four loci (rs1799732, -141C>del; rs1079597, TaqIB; rs6277, 957C>T; and rs1800497, TaqIA) using a TaqMan-based real-time polymerase chain reaction (PCR). We found a significantly lower risk for UCC in individuals with the DRD2 rs6277 CT genotype compared to those with the wild-type CC genotype (adjusted odds ratio (AOR)=0.405, 95% confidence interval (CI): 0.196~0.837, p=0.015). In 124 younger patients (aged < 65 years) of the recruited UCC cohort, patients who carried at least one T allele of DRD2 rs1800497 were at higher risk (AOR=2.270, 95% CI: 1.060~4.860, p=0.033) of developing an invasive stage (pT2~pT4). In 128 female patients of the recruited UCC cohort, patients who carried at least one deletion allele of DRD2 rs1799732 showed a higher incidence of having an invasive stage (AOR=2.585, 95% CI: 1.066~6.264, p=0.032) and a large tumor (AOR=2.778, 95% CI: 1.146~6.735, p=0.021). Further analyses of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets revealed correlations of the expression of DRD2 with an invasive tumor, tumor metastasis, and the lower survival rate in patients with UCC. Our findings suggest that DRD2 levels might affect the progression of UCC, and the polymorphisms rs6277, rs1800497, and rs1799732 of DRD2 are probably associated with the susceptibility and clinicopathologic development of UCC in a Taiwanese population.

P.3.d.046 - Effect of dopamine D2 receptor and serotonin 2A receptor gene polymorphisms on response to risperidone in schizophrenia

P.3.d.046 - Effect of dopamine D2 receptor and serotonin 2A receptor gene polymorphisms on response to risperidone in schizophrenia

Associations Between Dopamine D2 Receptor (DRD2) Gene, Maternal Positive Parenting and Trajectories of Depressive Symptoms from Early to Mid-Adolescence.

Using data from the Longitudinal Study of Chinese Children and Adolescents (LSCCA), this study is the first to examine the roles of the dopamine D2 receptor (DRD2) gene polymorphisms (i.e., TaqIA and A241G) and maternal positive parenting at ages 10 and 11years in the trajectories of depressive symptoms from early to mid-adolescence (ages 11 to 16years). In a sample of 1090 Chinese adolescents (50% girls), three trajectories of depressive symptoms were identified: (i) low-stable (36.1%), (ii) moderate-increasing (44.5%), and (iii) high-increasing (19.4%). A241G AA homozygotes and youth exposed to lower levels of maternal positive parenting were both at increased odds to follow the high-increasing vs. low-stable trajectory. Moreover, the A241G polymorphism interacted with maternal positive parenting to distinguish the moderate-increasing trajectory from the high-increasing and the low-stable trajectories. For A241G G-allele carriers, but not AA homozygotes, exposure to high quality of maternal parenting decreased the odds to follow the high-increasing vs. moderate-increasing trajectory of depressive symptoms. For AA homozygotes, but not G-allele carriers, high quality of maternal parenting increased the odds to follow the low-stable vs. moderate-increasing trajectory. The DRD2 TaqIA polymorphism had neither a direct nor an interactive effect with maternal positive parenting on trajectory membership. The current findings highlight the importance of investigating gene-by-environment interactions (G×E) in trajectories of depressive symptoms over adolescence, and support a developmental versus static nature of G×E effects.

The impact of common dopamine D2 receptor gene polymorphisms on D2/3 receptor availability: C957T as a key determinant in putamen and ventral striatum

Dopamine function is broadly implicated in multiple neuropsychiatric conditions believed to have a genetic basis. Although a few positron emission tomography (PET) studies have investigated the impact of single-nucleotide polymorphisms (SNPs) in the dopamine D2 receptor gene (DRD2) on D2/3 receptor availability (binding potential, BPND), these studies have often been limited by small sample size. Furthermore, the most commonly studied SNP in D2/3 BPND (Taq1A) is not located in the DRD2 gene itself, suggesting that its linkage with other DRD2 SNPs may explain previous PET findings. Here, in the largest PET genetic study to date (n=84), we tested for effects of the C957T and -141C Ins/Del SNPs (located within DRD2) as well as Taq1A on BPND of the high-affinity D2 receptor tracer 18F-Fallypride. In a whole-brain voxelwise analysis, we found a positive linear effect of C957T T allele status on striatal BPND bilaterally. The multilocus genetic scores containing C957T and one or both of the other SNPs produced qualitatively similar striatal results to C957T alone. The number of C957T T alleles predicted BPND in anatomically defined putamen and ventral striatum (but not caudate) regions of interest, suggesting some regional specificity of effects in the striatum. By contrast, no significant effects arose in cortical regions. Taken together, our data support the critical role of C957T in striatal D2/3 receptor availability. This work has implications for a number of psychiatric conditions in which dopamine signaling and variation in C957T status have been implicated, including schizophrenia and substance use disorders.

Associations between dopamine D2 receptor gene polymorphisms and schizophrenia risk: a PRISMA compliant meta-analysis.

ObjectiveTo determine the relationships between dopamine D2 receptor gene polymorphisms and the risk of schizophrenia using meta-analysis.MethodThe PubMed, Embase, and China National Knowledge Infrastructure databases were searched to identify relevant literature published up to February 2016. The allele contrast model was used. Stata software was used for statistical analysis, with odds ratios (ORs) and 95% confidence intervals (CIs) calculated to evaluate the associations between dopamine D2 receptor gene polymorphisms and the risk of schizophrenia. Meta-regression and publication bias, trim-and-fill, subgroup, sensitivity, cumulative, and fail-safe number analyses were also performed.ResultsThis meta-analysis included 81 studies. The rs1801028 and rs1799732 were associated with schizophrenia risk among Asians (P=0.04, OR =1.25, 95% CI =1.01–1.55; P<0.01, OR =0.76, 95% CI =0.63–0.92, respectively), while the rs6277 was associated with schizophrenia risk in Caucasians (P<0.01, OR=0.72, 95% CI =0.66–0.79). The rs1800497 was also associated with schizophrenia risk in population-based controls (P<0.01, OR =0.84, 95% CI =0.72–0.97). The rs6275, rs1079597, and rs1800498 were not associated with schizophrenia risk. In addition, meta-regression indicated that the controls may be sources of heterogeneity for the rs1801028 single-nucleotide polymorphism (SNP), while ethnicity may be sources of heterogeneity for the rs6277 SNP. Publication bias was significant for the rs1801028 SNP, and this result changed after the publication bias was adjusted using the trim-and-fill method.ConclusionThis meta-analysis demonstrated that the rs1801028 may be a risk factor for susceptibility to schizophrenia among Asians, while the rs1799732 may be a protective factor for that population. Large-sample studies are necessary to verify the results of this meta-analysis.

Dopamine receptor D2 and catechol-O-methyltransferase gene polymorphisms associated with anorexia nervosa in Chinese Han population: DRD2 and COMT gene polymorphisms were associated with AN

Dopamine receptor D2 (DRD2) and catechol-O-methyltransferase (COMT) are important in dopamine system which is proved to be associated with food-anticipatory behavior, food restriction, reward and motivation. This has made them good candidates for anorexia nervosa (AN). The aim of this work is to explore the roles of DRD2 (rs1800497) and COMT (rs4680, rs4633, rs4818) gene polymorphisms in the susceptibility of AN within the Chinese Han population. We recruited 260AN patients with DSM-IV diagnosis criteria, and 247 unrelated, normal weight controls. DRD2 (rs1800497) and COMT (rs4680, rs4633, rs4818) were genotyped in all subjects. We found rs1800497 and rs4633 were associated with the susceptibility of AN within the Chinese Han sample, and allele C of rs1800497 was a protective factor. There was a gene–gene interaction between rs1800497 of DRD2 gene and rs4633 of COMT gene. We concluded that rs1800497 and rs4633 play important roles in the AN susceptibility with respect to the Chinese Han population. The gene–gene interaction between DRD2 and COMT contributes to the risk of AN.

Association between dopamine D2 receptor gene polymorphisms and the risk of heroin dependence.

Heroin dependence is a chronic relapsing brain disease. Researchers have reported that the dopamine D2 receptor (DRD2) is involved in the development of opiate dependence. To identify markers that contribute to the genetic susceptibility to heroin addiction, we examined the potential association between heroin dependence and six polymorphisms of the DRD2 gene using the MassARRAY system. Three hundred and thirty-four patients with heroin dependence and 299 healthy controls participated in the research. Compared with the healthy controls, heroin-dependent patients had a significantly lower frequency of the AA genotype of rs6275 (P = 0.038), and a significantly higher frequency of the C allele of rs1125394 (P = 0.030). Statistically significant differences were observed in the genotypic and allelic frequencies of rs17115583 (P = 0.005 and P = 0.001, respectively) and rs1079597 (P = 0.03 and P = 0.02, respectively). Haplotype analysis revealed that the T-G-A (block 1) haplotype of the DRD2 gene conferred a protective effect (P = 0.020). These findings point to a role for DRD2 polymorphism in heroin dependence in the Chinese Han population, and may be informative for future genetic or neurobiological studies on heroin dependence.

-141C insertion/deletion polymorphism of the dopamine D2 receptor gene is associated with schizophrenia in Chinese Han population: Evidence from an ethnic group-specific meta-analysis.

Accumulate evidence has implicated dopamine D2 receptor gene polymorphisms in the etiology of schizophrenia. A single nucleotide polymorphism, -141C insertion/deletion (Ins/Del) (rs1799732), in the promoter region of the dopamine D2 receptor gene has been linked to schizophrenia; however, the data are inconclusive. This study investigated whether the -141C polymorphism is associated with the risk of schizophrenia in different ethnic groups by performing a meta-analysis. A total of 24 case-control studies examining the association between -141C Ins/Del polymorphism and schizophrenia were identified according to established inclusion criteria. Significant association was revealed between -141C Ins/Del polymorphism and schizophrenia risk in dominant genetic model (Ins/Ins + Ins/Del versus Del/Del) (odds ratio = 0.33, 95% confidence interval = 0.14-0.81, z = 2.41, P = 0.02) in Chinese Han but not in Caucasian, Japanese or India populations. Our results indicate that -141C Ins/Del polymorphism might be a susceptibility factor for schizophrenia in Chinese Han population.

Sleep Attacks in Patients With Parkinson's Disease on Dopaminergic Medications: A Systematic Review

Dopaminergic medications are used as first-line treatment for Parkinson's disease (PD). In 1999, a case series was published describing 9 patients who took dopamine agonists (pramipexole or ropinirole) and experienced sudden irresistible sleep attacks. Sleep attacks have subsequently been reported with other dopaminergic medications, including levodopa. Because these symptoms might not be rare and can affect health-related quality of life, we set out to review the prevalence and clinical characteristics of sleep attacks in patients with PD on dopaminergic medications. We conducted a systematic literature review using the terms parkinson* AND dopamine* AND narcolep* OR sleep attack in multiple databases (PubMed, Embase, and PsycINFO). The systematic literature review yielded 23 relevant articles, including nine case reports or case series and 14 original studies. According to the pooled data from the five studies reporting prevalence figures (n=10,084), sleep attacks occur in 13.0% of patients with PD on dopaminergic medications. Our analysis failed to show significant differences in the Epworth Sleepiness scores between patients with and without sleep attacks (mean difference: 2.92; 95% confidence interval: -0.47-6.31). The I2 value of 76% indicated high heterogeneity among the studies. Sleep attacks are not a rare occurrence in patients with PD on dopamine agonist treatment. We found conflicting results on whether sleep attacks in PD resemble narcolepsy. The pathophysiology of these symptoms might be related to dopamine D2 and D4 receptor gene polymorphisms. The most effective management strategies were dose reduction and discontinuation of the offending drugs.

Hatching the behavioral addiction egg: Reward Deficiency Solution System (RDSS)™ as a function of dopaminergic neurogenetics and brain functional connectivity linking all addictions under a common rubric

Background: Following the first association between the dopamine D2 receptor gene polymorphism and severe alcoholism, there has been an explosion of research reports in the psychiatric and behavioral addiction literature and neurogenetics. With this increased knowledge, the field has been rife with controversy. Moreover, with the advent of Whole Genome-Wide Studies (GWAS) and Whole Exome Sequencing (WES), along with Functional Genome Convergence, the multiple-candidate gene approach still has merit and is considered by many as the most prudent approach. However, it is the combination of these two approaches that will ultimately define real, genetic allelic relationships, in terms of both risk and etiology. Since 1996, our laboratory has coined the umbrella term Reward Deficiency Syndrome (RDS) to explain the common neurochemical and genetic mechanisms involved with both substance and non-substance, addictive behaviors. Methods: This is a selective review of peer-reviewed papers primary listed in Pubmed and Medline. Results: A review of the available evidence indicates the importance of dopaminergic pathways and resting-state, functional connectivity of brain reward circuits. Discussion: Importantly, the proposal is that the real phenotype is RDS and impairments in the brain’s reward cascade, either genetically or environmentally (epigenetically) induced, influence both substance and non-substance, addictive behaviors. Understanding shared common mechanisms will ultimately lead to better diagnosis, treatment and prevention of relapse. While, at this juncture, we cannot as yet state that we have “hatched the behavioral addiction egg”, we are beginning to ask the correct questions and through an intense global effort will hopefully find a way of “redeeming joy” and permitting homo sapiens live a life, free of addiction and pain.

Moderator effects of working memory on the stability of ADHD symptoms by dopamine receptor gene polymorphisms during development

We tested the hypothesis that dopamine D1 and D2 receptor gene (DRD1 and DRD2, respectively) polymorphisms and the development of working memory skills can interact to influence symptom change over 10 years in children with attention-deficit/hyperactivity disorder (ADHD). Specifically, we examined whether improvements in working memory maintenance and manipulation from childhood to early adulthood predicted the reduction of ADHD symptoms as a function of allelic variation in DRD1 and DRD2. Participants were 76 7-11-year-old children with ADHD who were genotyped and prospectively followed for almost 10 years. ADHD symptoms were rated using the Attention Problems scale on the Child Behavior Checklist, and verbal working memory maintenance and manipulation, measured by Digit Span forward and backward, respectively, were assessed at baseline and follow-up. After correction for multiple testing, improvements in working memory manipulation, not maintenance, predicted reduction of symptomatology over development and was moderated by major allele homozygosity in two DRD1 polymorphisms (rs4532 and rs265978) previously linked with variation in D1 receptor expression. Depending on genetic background, developmental factors including age-dependent variation in DRD1 penetrance may facilitate the link between improvements in higher-order working memory and the remission of symptoms in individuals with childhood-diagnosed ADHD. Furthermore, the current findings suggest that DRD1 might contribute minimally to the emergence of symptoms and cognitive difficulties associated with ADHD in childhood, but may act as a modifier gene of these clinical features and outcome during later development for those with ADHD.

Restoration of Glutamatergic Transmission by Dopamine D4 Receptors in Stressed Animals

The prefrontal cortex (PFC), a key brain region for cognitive and emotional processes, is highly regulated by dopaminergic inputs. The dopamine D4 receptor, which is enriched in PFC, has been implicated in mental disorders, such as attention deficit-hyperactivity disorder and schizophrenia. Recently we have found homeostatic regulation of AMPA receptor-mediated synaptic transmission in PFC pyramidal neurons by the D4 receptor, providing a potential mechanism for D4 in stabilizing cortical excitability. Because stress is tightly linked to adaptive and maladaptive changes associated with mental health and disorders, we examined the synaptic actions of D4 in stressed rats. We found that neural excitability was elevated by acute stress and dampened by repeated stress. D4 activation produced a potent reduction of excitatory transmission in acutely stressed animals and a marked increase of excitatory transmission in repeatedly stressed animals. These effects of D4 targeted GluA2-lacking AMPA receptors and relied on the bi-directional regulation of calcium/calmodulin kinase II activity. The restoration of PFC glutamatergic transmission in stress conditions may enable D4 receptors to serve as a synaptic stabilizer in normal and pathological conditions.

The role of parenting and dopamine D4 receptor gene polymorphisms in children's inhibitory control

Temperamental effortful control has important implications for children's development. Although genetic factors and parenting may influence effortful control, few studies have examined interplay between the two in predicting its development. The current study investigated associations between parenting and a facet of children's effortful control, inhibitory control (IC), and whether these associations were moderated by whether children had a 7-repeat variant of the DRD4 exon III VNTR. A community sample of 409 3-year-olds completed behavioural tasks to assess IC, and observational measures of parenting were also collected. Negative parenting was associated with lower child IC. The association between children's IC and positive parenting was moderated by children's DRD4 7-repeat status, such that children with at least one 7-repeat allele displayed lower IC than children without this allele when positive parenting was lower. These effects appeared to be primarily influenced by parent support and engagement. Results extend recent findings suggesting that some genetic polymorphisms may increase vulnerability to contextual influences.