DRD2 Research Articles

Pharmacogenetic aspects of the dopaminergic system in clozapine pharmacodynamics

A systematic review of association studies on the role of single nucleotide variants (SNVs) of the dopaminergic system genes on the effectiveness of clozapine in schizophrenia has been perfromed. A search of literature was conducted in PubMed, MedLine, Web of Science Core Collection (Clarivate Analytics), Web of Science, Russian Science Citation Index, Scopus, Scientific Research, Google Scholar, Oxford Press, e-Library from 1995-2019. Association studies of 53 SNPs of genes encoding dopamine receptor isoforms (DRD1), dopamine transporter (SCL6A3) and catechol-O- methyltransferase (COMT), and the nature of their association with the therapeutic response to clozapine were analyzed. The results of SNPs studies of DRD1 and COMT genes are the most controversial. This can be explained by the heterogeneity of the samples and the lack of standardization of methods for evaluating the effectiveness of treatment in the context of association studies. The clear population specificity of the association of some SNPs of DRD1, DRD2 and DRD3 genes with the response to clozapine therapy has been shown. Most of the identified associations are haplotype specific. The obtained regularities of the effect of SNPs of dopaminergic system genes on the effectiveness of clozapine therapy should be considered in an individual approach to treatment of schizophrenia.

Determination of the Relationship Between Craving and 4-repeat Allele of DRD4 Gene Polymorphism in the Early Withdrawal Period of Alcohol Use Disorders.

Alcohol use disorder (AUD) is a disease with chronic relapses. Risk factors of craving, which is thought to be one of the predictors of relapse, have been studied for a long time. The DRD4 gene is located on chromosome 11p and has a 48-base pair variable number of tandem repeat (VNTR) polymorphisms in the 3rd exon. This study aimed to investigate if a relationship existed between craving and DRD4 VNTR polymorphism and to determine the predictors of craving. A total of 125 patients with AUD were included in the study. The sociodemographic data form, the Michigan Alcoholism Screening Test (MAST), the Obsessive Compulsive Drinking Scale (OCDS), and the Penn Alcohol Craving Scale (PACS) were applied to the patients. Polymerase chain reaction (PCR) was used to determine the DRD4 VNTR variant of all participants in the peripheral blood sample. In the 4R/4R homozygous group, it was found that the age at first alcohol use was higher and the scores of the OCDS on the seventh day were lower, but this relationship could not be demonstrated in further statistical analyses. In the stepwise linear regression model, the age at first alcohol use, MAST score, duration of AUD, and delirium tremens history were found to be the predictors of craving. DRD4 VNTR polymorphism does not play a role as a predictor of craving. A decrease in age at first alcohol use, an increase in the MAST score, and the presence of delirium tremens were found to be the predictors of craving among the participants of this study.

Влияние полиморфизма генов PGC1α, АСЕ и DRD2 на развитие и течение гестационного сахарного диабета

Влияние полиморфизма генов PGC1α, АСЕ и DRD2 на развитие и течение гестационного сахарного диабета

Effect of the C1473G Polymorphic Variant of the Tryptophan Hydroxylase 2 Gene and Photoperiod Length on the Dopamine System of the Mouse Brain

A decrease in the light in autumn and winter causes depression like seasonal affective disorders (SAD) in sensitive patients, in which the serotonin (5-HT) and dopamine (DA) brain mediator systems are involved. We studied the interaction of the 5-HT and DA brain systems in an experimental SAD model in sexually mature male mice of the congenic B6-1473C and B6-1473G lines with high and low activity of tryptophan hydroxylase 2, a key enzyme of 5-HT synthesis in the brain. Mice of each line (divided into two groups of eight individuals) were kept for 30 days in standard (14 h light/10 h dark) and short (4 h light/20 h dark) daylight. The presence of the C1473G variant in the tryptophan hydroxylase 2 gene did not affect the expression of key genes of DA system: Drd1, Drd2, Scl6a3, Th, and Comt, that encode the D1 and D2 receptors, dopamine transporter, tyrosine hydroxylase, and catechol-o-methyltransferase, respectively. A decrease in the level of DA in the midbrain, as well as of its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum, was detected in B6-1473G mice. Keeping mice in short daylight did not affect expression of the Drd1 gene in all brain structures nor the expression of the Slc6a3 and Th genes in the midbrain. Drd2 expression increased in the midbrain and decreased in the hippocampus, where Comt expression increased. An increase in DA level in the midbrain and DOPAC in the striatum was detected in mice kept in short daylight. This indicates the involvement of the brain's DA system in the reaction to a decrease in daylight duration. No statistically significant effect of the interaction between the presence of the C1473G variant and daylight length on indicators of the activity of DA system was detected. No reasons were found to assert that this polymorphism determines the observed reaction of the brain DA system in keeping of animals under short daylight conditions.

The VNTR 48 bp Polymorphism in the DRD4 Gene Is Associated with Higher Tobacco Smoking in Male Mexican Mestizo Smokers with and without COPD.

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

Effects of traumatic life events, cognitive biases and variation in dopaminergic genes on psychosis proneness.

Recent studies have provided evidence that interactions between variation in dopaminergic genes and stressful experiences might impact risk of psychosis. However, it remains unknown whether these interactions impact the development of subclinical symptoms, including psychotic-like experiences (PLEs). In this study, we aimed to test the effects of interactions between variation in dopaminergic genes and traumatic life events (TLEs) on a severity of PLEs. We assessed TLEs, cognitive biases, PLEs as well as the catechol-O-methyltransferase (COMT) rs4680 and the dopamine D2 receptor (DRD2) rs6277 gene polymorphisms in 445 university students at three urban areas. There was a significant effect of the interaction between the COMT rs4680 and a history of any type of TLEs on a severity of PLEs. Among the COMT rs4680 Met allele carriers, a severity of PLEs was higher in individuals with a history of any type of TLEs. Further stratification of the sample revealed that this effect appears only in the group of participants with a high level of cognitive biases. The DRD2 rs6277 C allele was independently associated with a higher level of PLEs. Our results indicate that decreased dopamine catabolism related to the COMT gene polymorphism might increase psychosis proneness in individuals with a history of TLEs and high levels of cognitive biases. Variation in the DRD2 gene might exert independent effects on psychosis proneness. These findings imply that there are various levels of complexity in the models of interactions between genetic and environmental factors explaining the mechanisms underlying psychosis proneness.

MicroRNA-15a, microRNA-15b and microRNA-16 inhibit the human dopamine D1 receptor expression in four cell lines by targeting 3′UTR –12 bp to + 154 bp

Background The abnormal expression Dopamine D1 receptor (DRD1) gives rise to the dysfunction of dopaminergic neurotransmitter and may be associated with the occurrence of schizophrenia. MicroRNAs (miRNAs) can regulate the DRD1 expression by binding 3’UTR and be involved in the post-transcriptional regulation. Methods We first constructed the pmirGLO-recombined vectors of series of DRD1 gene 3′UTR-truncated fragments and performed the luciferase receptor assay to screen the underlying 3′UTR sequence targeted by miRNAs. Then, we predicted the potential miRNAs binding the target sequence and confirmed their effects using luciferase receptor assay after transfection of the miRNA mimics/inhibitors. We also examined the effects of the miRNA on the endogenous DRD1 expression. Results We found that the DRD1 3′UTR ranging from –12 to +1135 bp was essential for the post-transcriptional regulation of miRNAs. The deletion of –12 to +154 bp fragment significantly increased the luciferase expression but not the mRNA expression. The miRNA-15a, miRNA-15b and miRNA 16 affected DRD1 expression in HEK293, U87, SK-N-SH and SH-SY5Y cell lines. Conclusion The miRNA-15a, miRNA-15b and miRNA-16 inhibit the human dopamine D1 receptor expression by targeting 3′UTR –12 to +154 bp. Highlights DRD1 3′UTR ranging from –12 to +1135 bp was essential for the post-transcriptional regulation of miRNAs. The deletion of –12 to +154 bp fragment significantly increased the luciferase expression but not the mRNA expression. The miRNA-15a, miRNA-15b and miRNA 16 affected DRD1 expression in different cell lines, respectively.

The influence of dopaminergic polymorphisms on selective stopping

Although the genetic influence on global stopping has been extensively investigated, little is known about the genetic contribution to other more complex forms of inhibitory control such as selective stopping. The selectivity of inhibitory control can be assessed by using the stimulus-selective stop-signal task. Notably, recent behavioural and neural evidence indicates that individuals can adopt selective but also non-selective stopping strategies to solve it. This study aimed to investigate for the first time the influence of two relevant dopaminergic polymorphisms (in COMT and DRD2 genes) on stimulus-selective stopping in a sample of 529 adults. Results showed that although none of these polymorphisms (neither individually nor in combination) modulate the latency of the stop process in each strategy (the stop-signal reaction time), the choice of strategy was influenced by their interaction. These results suggest that dopaminergic polymorphisms might influence strategy adoption in selective stopping paradigms, which constitutes a novel finding.

Genes of dopamine receptors and transporter in patients with schizophrenia: associations with the clinical characteristics of the disorder

Genotyping of 28 polymorphisms of 5 dopamine receptor genes and 12 polymorphisms of dopamine transporter gene was performed in 475 schizophrenia patients and 135 healthy individuals. Associations of several polymorphisms of the DRD2, DRD3 and SLC6A3 genes were identified with leading symptoms and late debut of schizophrenia.

Effects of the 5-HT2A and DRD3 genotypes on cortical morphology and functional connectivity density in drug-naïve first episode schizophrenia

The 5-hydroxytryptamine 2A receptor (5-HT2A) and dopamine D3 receptor (DRD3) have been extensively studied as promising candidate genes for schizophrenia. Magnetic resonance imaging studies have demonstrated that schizophrenia is associated with widespread structural and functional abnormalities in the brain. Serotonin and dopamine receptors play crucial roles in the development of the human cerebral cortex and brain activity. However, how the 5-HT2A and DRD3 genes impact brain structure and function in schizophrenia remains unknown. In the present study, we investigated the main effect of disease state and the interaction effect between disease state and genotype of these two genes on cortical volume, thickness, surface area and functional connectivity density (FCD) in fifty-five drug-naïve first episode schizophrenia patients and fifty-three healthy controls. We found that the differences in local FCD (lFCD) and global FCD (gFCD) between patients and healthy controls were predominantly located in brain hub regions. The significant interaction effects of disease state and 5-HT2A and DRD3 genes on brain structure and function were mainly located in the temporal cortex. Our findings may help to improve the understanding of the relationship between 5-HT2A and DRD3 genotypes and schizophrenia pathogenesis.

Association of the DRD4 exon III and 5-HTTLPR VNTR polymorphisms with substance abuse in Jordanian Arab population

Genetic variations in the dopamine D4 receptor (DRD4) gene and the serotonin transporter (SLC6A4) gene are involved in the aetiology of substance abuse disorder (SUD). The main aim of this study is to evaluate the genetic association of DRD4 (48 bp-VNTR) and SLC6A4 (rs25531 and 5-HTTLPR VNTR) gene polymorphisms with SUD susceptibility among the Jordanian Arab population. This study included 500 SUD patients and 500 healthy matched controls. The VNTR Genetic polymorphisms of DRD4 and SLC6A4 genes were genotyped using conventional polymerase chain reaction (PCR). While, the rs25531 SNP was genotyped using PCR-restriction fragment length polymorphism (PCR-RFLP) technique. The genetic association was analysed using different statistical analyses including chi-square, Fisher exact test and one way ANOVA test. The DRD4 exon III VNTR polymorphism was associated with SUD significantly in case of alleles 4, 7 and genotype 7/7 (P = 0.004, 0.0005 and 0.01, respectively). While, there was no genetic association between the 5-HTTLPR (LL, LS, SS), rs25331 (AA, AG, GG) and tri-allelic (SASA, LASG, LASA, LALG, LALA) genotypes (P = 0.26, 0.71 and 0.52, respectively) and SUD. Moreover, using multinomial regression analysis, the homozygous 7/7 and 2/2 VNTR genotypes of DRD4 gene were nominally significantly associated with a lower risk of addiction (OR = 0.285 with P = 0.003 and OR = 0.447 with P = 0.031, respectively) after adjusting for other covariates. Our findings showed that 4 and 7 repeats and the genotype 7/7 of DRD4 exon III VNTRs polymorphism are involved in the aetiology of SUD among Jordanian population in compared to the 5-HTTLPR polymorphisms.

An epistasis between dopaminergic and oxytocinergic systems confers risk of post-traumatic stress disorder in a traumatized Chinese cohort

Post-traumatic stress disorder (PTSD) is a psychiatric syndrome that occurs after trauma exposure. Neurotransmitters such as dopamine and oxytocin have been reported to be involved in neuropathology of PTSD. Previous studies indicated that the dopamine–oxytocin interaction may contribute to behavioral disorders. Thus, exploring the epistasis (gene–gene interaction) between oxytocinergic and dopaminergic systems might be useful to reveal the genetic basis of PTSD. In this study, we analyzed two functional single nucleotide polymorphisms (SNPs), rs2268498 for oxytocinergic gene OXTR and rs1801028 for dopaminergic gene DRD2 based on putative oxytocin receptor–dopamine receptor D2 (OTR–DR2) heterocomplex in a Chinese cohort exposed to the 2008 Wenchuan earthquake (156 PTSD cases and 978 controls). Statistical analyses did not find any single variant or gene–environment interaction (SNP × earthquake-related trauma exposure) associated with provisional PTSD diagnosis or symptoms. An OXTR–DRD2 interaction (rs2268498 × rs1801028) was identified to confer risk of provisional PTSD diagnosis (OR = 9.18, 95% CI = 3.07–27.46 and P = 7.37e-05) and further subset analysis indicated that rs2268498 genotypes controlled the association directions of rs1801028 and rs1801028 genotypes also controlled the association directions of rs2268498. Rs2268498 × rs1801028 is also associated with PTSD symptoms (P = 0.043). Our study uncovered a genetic and putative function-based contribution of dopaminergic–oxytocinergic system interaction to PTSD.

Study of the association between DRD2 Gene Ser311Cys and GSTM1 Gene Polymorphism in Schizophrenia

Introduction: Schizophrenia is a mental disorder affecting 1% of the world's population. Two of genes have been recognized to be involved in development of this disease: DRD2 and GSTM1. Methods: This case-control study included 100 patients suffering from schizophrenia who referred to Yazd Neuropsychiatry Hospital. Also, 100 healthy patients without schizophrenia were selected as the control group. After DNA extraction, it was genotyped 100 schizophrenic and 100 healthy controls by use of restricted fragment of length polymorphism (RFLP) for Ser311Cys polymorphism and multiplex PCR for GSTM1. After performing relevant experiments and gaining some results, statistical analysis was performed using SPSS software16. In this study, Chi-square and logistic regression tests were used to investigate the relation between genotype of polymorphism and schizophrenia. Results: Data analysis showed that frequency distribution of Ser311Cys polymorphism genotypes between the patients and healthy participants was not significant (P: 0.121). Also, for GSTM1, there was no association between the polymorphism and schizophrenia. In general, the frequency distribution of the deleting gene between the patients and the control group was not significant (P= 0.089). And this polymorphism was significantly associated with symptoms (P = 0.012). Conclusion: The results of this study show that Ser311Cys polymorphism and GSTM1 polymorphism is not common among the studied patients, therefore it indicates its non-effectiveness in the study population. However, because the study population is not representative of the entire Iranian population, further studies with larger population are needed.

Genetic and psychological underpinnings of motivation and satisfaction of industrial salespeople

We investigate the effects of genetic polymorphisms of salespeople on their motivation and job satisfaction. We hypothesize that psychological attachment styles (anxious, avoidance, and secure) and role conflict interact with variants of three genes (dopamine DRD4, COMT and OXTR) to influence motivation and satisfaction. Our approach follows the spirit of the emerging subfield of organizational neuroscience and biological foundations of social behavior recently introduced into the literature and is one of the first studies to uncover complex dependence of behavior on genes and to employ a large enough sample to reduce false positive inferences. Variants of the DRD4 and COMT genes are found to interact with avoidance and secure attachment style, respectively, to influence motivation, under conditions of felt role conflict. Variants of OXTR have main effects on job satisfaction, as do anxious attachment styles and felt role conflict. Hypotheses are tested on a sample of 334 salespersons selling goods and services to business customers. The role of genetic endowment represents untapped origins for research into the behavior of salespeople and has a number of managerial implications that we discuss.

Effects of the Interaction of the ANKK1/DRD2 TaqIA and HTR2C Cys23Ser Polymorphisms on Approach Motivation in Schizophrenia Patients and Healthy People

Objective. To assess the association of the DRD2 gene and its interaction with the HTR2C gene with the characteristics of the hedonistic and activatory aspects of approach motivation in schizophrenia. Materials and methods. Genotypes at the polymorphic loci rs1800497 of DRD2 and rs6318 (Cys23Ser) of HTR2C were identified in a cohort including 174 patients with schizophrenia spectrum disorders and 268 healthy subjects. Subjects completed scales assessing approach motivation (BIS/BAS) and the Temporal Experience of Pleasure Scale (TEPS). Results and conclusions. Analysis taking account of sex and age identified an effect of the interaction between the DRD2 and HTR2C genes and diagnosis (p = 0.033) on assessments on the BAS scales. The effect was significant on the Fun-Seeking and Drive subscales. Among patients, the highest scores on both scales were seen with the combination of the DRD2 TT/CT and HTR2C GG/G genotypes and the lowest in carriers of the diplotypes with the minor alleles at both loci. Differences between these group were nominally significant for both scales, but were not significant after correction for multiple comparisons. Among healthy subjects, the highest levels of motivation were seen in people lacking the minor alleles. They were significantly different from those in carriers of the DRD2 TT/CT and HTR2C GG/G diplotype on the Fun-Seeking subscale (pcorr = 0.008). DRD2 and HTR2C were not found to have any effect on TEPS evaluations. Our results can be interpreted as indicating a role for the interaction of the DRD2 and HTR2C genes in the variation of the activatory aspects of approach motivation in both schizophrenia patients and healthy subjects. However, the absence of highly significant (persisting after the Bonferroni correction) differences between groups with different diplotypes makes it difficult to interpret this effect.

DNA-methylation of the dopamin receptor 2 gene is altered during alcohol withdrawal

The dopaminergic neurotransmission is known to be of crucial importance in addictive behavior. Epigenetic regulation like methylation of DNA influences the function of dopaminergic transmission. The present study investigated alterations of DNA methylation in the dopamine D2 receptor (DRD2)-gene in patients suffering from alcohol dependence. The study sample consists of 99 alcohol dependent males admitted for alcohol withdrawal treatment and a control group of 33 healthy participants. Blood samples underwent bisulfite sequencing to determine levels of DNA-methylation of the promoter region of the DRD2 gene. Mixed linear modeling was used to test differences between patients and controls, course of methylation during detoxification. While DRD2-gene methylation did not differ significantly between patients and controls, we found a significant increase of DRD2-gene methylation during alcohol withdrawal/early abstinence. Craving, measured with the Obsessive Compulsive Drinking Scale (OCDS), was significantly associated with DRD2-gene methylation. Furthermore, smoking significantly influenced DRD2-gene methylation in both, patients and controls. As in other types of addictive disorders, DRD2-gene methylation is altered during alcohol withdrawal/early abstinence. The findings regarding an association with alcohol craving and tobacco consumption point towards a crucial role of DRD2-gene methylation in the neurobiology of addictive behavior.

DRD2 genotype-based variants modulates D2 receptor distribution in ventral striatum

Dopaminergic signaling within the striatum is crucial for motor planning and mental function. Neurons within the striatum contain two dopamine D2 receptor isoforms-D2 long and D2 short. The amount of expression for these receptor isoforms is affected by the genotype within two single nucleotide polymorphisms (SNPs), rs2283265 and rs1076560 (both are in high linkage disequilibrium; C > A), found in the DRD2 gene. However, it is unclear how these SNPs affect the distribution of D2 receptors in vivo within the nigrostriatal dopaminergic system. We aim to elucidate this with PET imaging in healthy young adults using [11C]-(+)-PHNO. Participants were genotyped for the DRD2 rs2283265 SNP and a total of 20 enrolled: 9 with CC, 6 with CA, and 5 with AA genotype. The main effect of genotype on [11C]-(+)-PHNO binding was tested and we found significant group effect within the ventral striatum. Specifically, CC and CA carriers had higher binding in this region compared to AA carriers. There were no observed differences between genotypes in other regions within the basal ganglia. Our preliminary results implicate that the polymorphism genotype affects the dopaminergic signaling by controlling either the quantity of D2 receptors, D2 affinity, or a combination thereof within the ventral striatum.

Association between the DRD2 TaqIA gene polymorphism and Parkinson disease risk: an updated meta-analysis.

Background:DRD2 TaqIA polymorphism may be associated with an increased risk of developing Parkinson disease (PD). However, the individual study's results are still inconsistent.Methods:A meta-analysis of 4232 cases and 4774 controls from 14 separate studies were performed to explore the possible relationship between the DRD2 TaqIA gene polymorphism and PD. Pooled odds ratios (ORs) for the association and the corresponding 95% confidence intervals (CIs) were evaluated by a fixed-effect model.Results:The pooled results revealed a significant association between DRD2 gene TaqIA polymorphism under recessive genetic model (OR: 0.91, 95% CI:0.83,0.99, P = .031) and additive genetic models (OR:0.93,95%CI:0.87,0.99, P = .032), but not associated with PD susceptibility under other genetic models in the whole population. Moreover, subgroups based on ethnicity and genotyping methods showed this association in the Caucasian subgroup under recessive genetic model (OR: 0.85, 95% CI:0.76,0.95, P = .003) and additive genetic models (OR:0.87,95%CI:0.79,0.96, P = .004) were existed. Besides, no significant association was detected under 6 genetic models in the Asian populations and PCR-RFLP subgroup.Conclusions:The current meta-analysis suggested that a significant association between DRD2 TaqIA polymorphism and PD under the recessive genetic mode, and additive genetic models, especially in Caucasians.

The Genomic Landscape of Sporadic Prolactinomas.

Somatic GNAS and USP8 mutations have been implicated in sporadic somatotrophinomas and corticotrophinomas, respectively. However, no genes are known to be recurrently mutated in sporadic prolactinomas. The prevalence of copy number variants (CNV), which is emerging as a mechanism of tumorigenesis in sporadic pituitary adenomas in general, is also unclear in prolactinomas. To characterize the genetic events underpinning sporadic prolactinomas, we performed whole exome sequencing of paired tumor and germline DNA from 12 prolactinoma patients. We observed recurrent large-scale CNV, most commonly in the form of copy number gains. We also identified sequence variants of interest in 15 genes. This included the DRD2, PRL, TMEM67, and MLH3 genes with plausible links to prolactinoma formation. Of the 15 genes of interest, CNV was seen at the gene locus in the corresponding tumor in 10 cases, and pituitary expression of eight genes was in the top 10% of tissues. However, none of our shortlisted somatic variants appeared to be classical driver mutations as no variant was found in more than one tumor. Future directions of research include mechanistic studies to investigate how CNV may contribute to prolactinoma formation, larger studies of relevant prolactinoma subsets according to clinical characteristics, and additional genetic investigations for aberrations not captured by whole exome sequencing.

The relationship of age and DRD2 polymorphisms to frontostriatal brain activity and working memory performance

Dopamine (DA) in both prefrontal cortex (PFC) and caudate nucleus is critical for working memory (WM) function. The C957T and Taq1A polymorphisms of the DRD2 gene are related to DA D2 receptor densities in PFC and striatum. Using functional MRI, we investigated the relationship of age and these 2 DRD2 gene polymorphisms to WM function and examined possible age by gene interactions. Results demonstrated less caudate activity for older adults (70–80 years; n = 112) compared with the younger age group (25–65 years; n = 191), suggesting age-related functional differences in this region. Importantly, there was a gene-related difference regarding WM performance and frontostriatal brain activity. Specifically, better WM performance and greater activity in PFC were found among C957T C allele carriers. Combined genetic markers for increased DA D2 receptor density were associated with greater caudate activity and higher WM updating performance. The genetic effects on blood oxygen level–dependent activity were only observed in older participants, suggesting magnified genetic effects in aging. Our findings emphasize the importance of DA-related genes in regulating WM functioning in aging and demonstrate a positive link between DA and brain activation in the frontostriatal circuitry.