DRD2
D(2) dopamine receptor (Dopamine D2 receptor)
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Dopamine (DA) signaling is critical for optimal cognitive performance. Aging is accompanied by a change in the strength of this signaling, with a loss of striatal and extrastriatal D2 binding potential. The reduction in dopamine modulation with age negatively influences various aspects of cognition. DRD2 C957T (rs6277) impacts DA D2 receptor density and availability, with C homozygotes linked to lower striatal DA availability and reduced executive functioning (EF), but also high extrastriatal binding potential. Here, we investigated in 176 participants aged 20-94 years whether: (1) DRD2 C carriers differ from T carriers in cortical thickness or subcortical volume in areas of high concentrations of D2 receptors that receive projections from mesocortical or nigrostriatal dopaminergic pathways; (2) whether the DRD2*COMT relationship has any synergistic effects on cortical thickness; (3) whether the effect of DRD2 on brain structure depends upon age; and (4) whether DRD2-related regional thinning affects executive function performance. We show that DRD2 impacts cortical thickness in the superior parietal lobule, precuneus, and anterior cingulate (marginal after FDR correction), while statistically controlling sex, age, and COMT genotype. Specifically, C homozygotes demonstrated thinner cortices than both heterozygotes and/or T homozygotes in an age-invariant manner. Additionally, DRD2 predicted executive function performance via cortical thickness. The results highlight that genetic influences on dopamine availability impact cognitive performance via the contribution of brain structure in cortical regions influenced by DRD2.
Keywords
- Aging
- Cortical thickness
- DRD2
- Dopamine
- Executive function
The beneficial effects of a physically active lifestyle in aging are well documented. Understanding the factors of importance for physical activity in older adults are therefore essential. Informed by animal and human data linking the dopamine system to motivation and reward processes, we investigated the associations between variations in dopamine genes and objectively measured physical activity and sedentary behaviour. Further, we aimed to verify whether higher age may exacerbate the impact of dopamine genes on physical activity. We analyzed data from 504 older adults, 66-87 years, from the population-based Swedish National study on Aging and Care in Kungsholmen (SNAC-K). Physical activity was measured with activPAL accelerometers and DNA was extracted from blood samples for genotyping. We assessed the effects of three dopamine relevant genetic variations (DRD1, DRD2, and DRD3) on daily time in sedentary behavior, light-intensity physical activity and moderate-to-vigorous physical activity using analyses of covariance, adjusting for sex, age and physical function. Higher dopamine receptor efficacy was related to moderate-to-vigorous physical activity, but not to light-intensity physical activity or sedentary time. DRD1 explained 2.7% of variance in moderate-to-vigorous physical activity, with more pronounced effect in people aged ≥80 years, about 10% of explained variance. Stronger genetic effects in older adults are in line with the well-established nonlinear effects of dopamine signaling on performance, expected to be exacerbated with aging. Individuals over 80 years, genetically predisposed to lower dopamine receptor efficacy, engaged on average 100 min/week in moderate-to-high physical activity, below the recommended levels beneficial for healthy aging. Our findings highlight that some individuals might need extra support to maintain a physically active lifestyle.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Cohort Studies
- Exercise
- Humans
- Receptors, Dopamine
- Sedentary Behavior
- Sweden
Keywords
- Accelerometery
- Aging
- Dopamine
- Genes
- Physical activity
- Sedentary behaviour
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.
MeSH Terms
- Aging
- Brain
- Humans
- Memory, Short-Term
- Polymorphism, Genetic
- Receptors, Dopamine D2
Keywords
- Aging
- C957T
- DRD2
- Dopamine
- Working memory
- fMRI
To determine whether intervention-induced physical activity (PA) changes in sedentary older adults differed according to dopamine-related genotype. Randomized clinical trial (Lifestyle Interventions and Independence for Elders Trial (2010-13)). Multicenter study, 8 U.S. Volunteer sample of sedentary adults aged 70 to 89 at risk of disability (N=1635). Structured PA versus health education (HE) for an average of 2.6 years. Single-nucleotide polymorphisms of dopamine-related genes (dopamine receptor (DR) D1, DRD2, DRD3, and catechol-O-methyltransferase (COMT)) were assessed. Average moderate to vigorous PA (MVPA) was calculated using accelerometry (min/d) at baseline and 6, 12, and 24 months. Between-arm MVPA differences according to genotype and genotype with square root-transformed MVPA separately according to arm were tested, stratified according to race, and adjusted for multiple comparisons. White participants in the PA arm (n=513) had higher average square root transformed MVPA (4.91±1.91)than those in the HE arm (n=538) (4.51±1.82) (p=.001). Between-arm differences were greater for DRD2 Met/Met (high dopamine; HE: 4.76±1.80, PA: 5.53±1.60, p=.03) than Val/Val (low dopamine; HE: 4.58±1.92, PA: 4.81±1.83, p=.16); results were similar for COMT. In the PA arm, DRD2 Met/Met was associated with higher average MVPA (5.39±2.00) than Met/Val (4.46±2.51) (p=.01) and Val/Val (4.65±2.71) (p=.01). There were no associations for other genes. Associations were not significant in blacks but followed similar trends. Higher dopamine signaling may support changes in PA during an intervention. The role of dopamine-related pathways in promoting PA participation and enhancing response to interventions in sedentary older adults should be studied. clinicaltrials.gov Identifier: NCT01072500.
MeSH Terms
- Accelerometry
- Aged
- Catechol O-Methyltransferase
- Dopamine
- Exercise
- Exercise Therapy
- Female
- Humans
- Life Style
- Male
- Middle Aged
- Mobility Limitation
- Polymorphism, Single Nucleotide
- Receptors, Dopamine D2
- Risk Reduction Behavior
- Sedentary Behavior
- Signal Transduction
- Walking Speed
Keywords
- aging
- dopamine
- physical activity
- randomized controlled trial
Dopaminergic neuromodulation is critically important for brain and cognitive integrity. The DRD2/ANKK1 Taq1A polymorphism is associated with striatal dopamine (DA) D2 receptor availability. Some previous studies have found that the A allele of the Taq1A polymorphism influences brain structure, but the results are inconsistent, likely due to population heterogeneity and small sample sizes. We investigated the genetic effect on caudate volume in a large sample of older adults without dementia. Results show that A-allele carriers have smaller caudate volume compared to non-carriers in relatively older adults (n = 167; Mage = 77.8 years), whereas the genotype did not influence caudate volume in a younger age group (n = 220; Mage = 62.8 years). Cognitive performance was not significantly affected by the DRD2 gene. Our findings extend previous observations by showing magnified genetic effects on brain volume in old age, and provide evidence for a link between a DA-related genetic polymorphism and grey matter volume in a brain region within the nigrostriatal dopaminergic pathway.
MeSH Terms
- Age Factors
- Aged
- Aged, 80 and over
- Aging
- Caudate Nucleus
- Cognition
- Female
- Genotype
- Gray Matter
- Humans
- Image Processing, Computer-Assisted
- Magnetic Resonance Imaging
- Male
- Middle Aged
- Neuropsychological Tests
- Polymorphism, Single Nucleotide
- Protein-Serine-Threonine Kinases
- Receptors, Dopamine D2
Keywords
- ANKK1
- Aging
- Caudate
- D2 receptors
- Dopamine
- Taq1A
The fat mass and obesity associated gene (FTO) was the first gene identified by genome-wide association studies to correlate with higher body mass index (BMI) and increased odds of obesity. FTO remains the locus with the largest and most replicated effect on body weight, but the mechanism whereby FTO affects body weight and the development of obesity is not fully understood. Here we tested whether FTO is associated with differences in food cravings and a key aspect of dopamine function that has been hypothesized to influence food reward mechanisms. Moreover, as food cravings and dopamine function are known to decline with age, we explored effects of age on relations between FTO and food cravings and dopamine function. Seven-eight healthy subjects between 22 and 83years old completed the Food Cravings Questionnaire and underwent genotyping for FTO rs9939609, the first FTO single nucleotide polymorphism associated with obesity. Compared to TT homozygotes, individuals carrying the obesity-susceptible A allele had higher total food cravings, which correlated with higher BMI. Additionally, food cravings declined with age, but this age effect differed across variants of FTO rs9939609: while TT homozygotes showed the typical age-related decline in food cravings, there was no such decline among A carriers. All subjects were scanned with [18F]fallypride PET to assess a recent proposal that at the neurochemical level FTO alters dopamine D2-like receptor (DRD2) function to influence food reward related mechanisms. However, we observed no evidence of FTO effects on DRD2 availability.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Alpha-Ketoglutarate-Dependent Dioxygenase FTO
- Benzamides
- Body Mass Index
- Brain
- Craving
- Feeding Behavior
- Female
- Food
- Genetic Association Studies
- Humans
- Male
- Middle Aged
- Polymorphism, Single Nucleotide
- Positron-Emission Tomography
- Pyrrolidines
- Radiopharmaceuticals
- Receptors, Dopamine D2
- Young Adult
Keywords
- Aging
- Dopamine receptor availability
- FTO
- Food cravings
Alzheimer's disease is an irreversible, progressive brain disorder that slowly destroys cognitive skills and the ability to perform the simplest tasks. More than 5 million Americans are afflicted with Alzheimer's; a disorder which ranks third, just behind heart disease and cancer, as a cause of death for older people. With no real cure and in spite of enormous efforts worldwide, the disease remains a mystery in terms of treatment. Importantly, African-Americans are two times as likely as Whites to develop late-onset Alzheimer's disease and less likely to receive timely diagnosis and treatment. Dopamine function is linked to normal cognition and memory and carriers of the DRD2 Taq1A A1 allele have significant loss of D2 receptor density in the brain. Recent research has shown that A1 carriers have worse memory performance during long-term memory (LTM) updating, compared to non-carriers or A2-carriers. A1carriers also show less blood oxygen level-dependent (BOLD) activation in the left caudate nucleus which is important for LTM updating. This latter effect was only seen in older adults, suggesting magnification of genetic effects on brain functioning in the elderly. Moreover, the frequency of the A1 allele is 0.40 in African-Americans, with an approximate prevalence of the DRD2 A1 allele in 50% of an African-American subset of individuals. This is higher than what is found in a non-screened American population (≤ 28%) for reward deficiency syndrome (RDS) behaviors. Based on DRD2 known genetic polymorphisms, we hypothesize that the DRD2 Taq1A A1 allele magnifies the risk of Alzheimer's in aging African-Americans. Research linking this high risk for Alzheimer's in the African-American population, with DRD2/ANKK1-TaqIA polymorphism and neurocognitive deficits related to LTM, could pave the way for novel, targeted pro-dopamine homeostatic treatment.
MeSH Terms
- African Americans
- Aging
- Alleles
- Alzheimer Disease
- Dopamine
- Genetic Association Studies
- Humans
- Polymorphism, Genetic
- Receptors, Dopamine D2
- Risk Factors
Keywords
- African Americans
- Alzheimer’s disease
- DRD2 gene
- Dopamine
- Early life stress
- Long-term memory (LTM)
- Reward deficiency syndrome
Little is known about the effects of risk factors on attention-deficit/hyperactivity disorder (ADHD) symptom over time. Here, we longitudinally studied the role of candidate genes, pre- and perinatal factors, and their interactions on ADHD symptoms between ages 10 and 18 years. Subjects were part of the general population or clinic-referred cohort of the TRacking Adolescents' Individual Lives Survey (n = 1667). At mean ages of 11.1 (T1), 13.4 (T2), and 16.2 years (T3), ADHD symptoms were assessed with the Child Behavior Checklist. Linear Mixed Models were used to examine the association of candidate genes (i.e., DRD4, DRD2, 5-HTTLPR, COMT, and MAOA), pre- and perinatal factors (i.e., index measure of various pregnancy and delivery complications, maternal smoking, maternal drinking, and low birth weight), and their interactions with ADHD symptoms across adolescence. Pregnancy and delivery complications were associated with a higher level of ADHD symptoms across all time points, but with a significantly declining influence over time (p = 0.006). We found no main effects of the candidate genes on ADHD symptoms throughout adolescence. The simultaneous presence of the low activity MAOA genotype and low birth weight (p < 0.001) and of the 5-HTTLPR LL-allele and respectively pregnancy and delivery complications (p = 0.04) and maternal smoking (p = 0.04) were associated with more ADHD symptoms particularly during early adolescence, and these influences significantly decreased over time. Findings suggest an age-dependent role of gene-environment interactions on ADHD symptoms across adolescence.
MeSH Terms
- Adolescent
- Aging
- Attention Deficit Disorder with Hyperactivity
- Child
- Female
- Gene-Environment Interaction
- Genotype
- Humans
- Male
- Monoamine Oxidase
- Polymorphism, Single Nucleotide
- Pregnancy
- Pregnancy Complications
- Prenatal Exposure Delayed Effects
- Psychiatric Status Rating Scales
- Serotonin Plasma Membrane Transport Proteins
Previous research shows that associative memory declines more than item memory in aging. Although the underlying mechanisms of this selective impairment remain poorly understood, animal and human data suggest that dopaminergic modulation may be particularly relevant for associative binding. We investigated the influence of dopamine (DA) receptor genes on item and associative memory in a population-based sample of older adults (n = 525, aged 60 years), assessed with a face-scene item associative memory task. The effects of single-nucleotide polymorphisms of DA D1 (DRD1; rs4532), D2 (DRD2/ANKK1/Taq1A; rs1800497), and D3 (DRD3/Ser9Gly; rs6280) receptor genes were examined and combined into a single genetic score. Individuals carrying more beneficial alleles, presumably associated with higher DA receptor efficacy (DRD1 C allele; DRD2 A2 allele; DRD3 T allele), performed better on associative memory than persons with less beneficial genotypes. There were no effects of these genes on item memory or other cognitive measures, such as working memory, executive functioning, fluency, and perceptual speed, indicating a selective association between DA genes and associative memory. By contrast, genetic risk for Alzheimer disease (AD) was associated with worse item and associative memory, indicating adverse effects of APOE ε4 and a genetic risk score for AD (PICALM, BIN1, CLU) on episodic memory in general. Taken together, our results suggest that DA may be particularly important for associative memory, whereas AD-related genetic variations may influence overall episodic memory in older adults without dementia.
MeSH Terms
- Aging
- Alzheimer Disease
- Apolipoproteins E
- Association
- Cohort Studies
- Female
- Genotyping Techniques
- Humans
- Male
- Memory
- Middle Aged
- Neuropsychological Tests
- Polymorphism, Single Nucleotide
- Receptors, Dopamine
Many studies have suggested that individual differences in aging phenotypes may be associated to polymorphisms affecting gene regulation. As single-nucleotide polymorphisms (SNPs) in the 3'-untranslated regions (3'UTR) targeted by microRNAs (miRNAs) can alter the strength of miRNA binding (and, consequently, the regulation of target genes), we wondered whether these SNPs (known as miRSNPs) affect the individual chance to become long-lived. Thus, we estimated the effect of miRSNPs falling in the 3'-untranslated regions of 140 aging-related genes on the DNA/miRNA bond. The 24 miRSNPs with the highest difference of binding energy between the two alleles were then investigated for their association with longevity by case-control analysis. Two SNPs,SIRT2-rs45592833 G/T and DRD2-rs6276 A/G, provided a significant association with human longevity, also after correcting for multiple comparisons. For both SNPs, the minor allele was associated with a significantly decreased chance to became long-lived in an allele dose-dependent manner (p= 1.090 × 10(-6)and 1.964 × 10(-4)forSIRT2 and DRD2, respectively). The results indicate that the individual aging phenotype may be affected by the variability of specific miRNA targeted regions, as shown for SIRT2 and DRD2, and may suggest further studies to analyze the variability of gene expression regulation as a modulator of aging phenotypes.
MeSH Terms
- 3' Untranslated Regions
- Aged
- Aged, 80 and over
- Case-Control Studies
- Female
- Genotype
- Humans
- Logistic Models
- Longevity
- Male
- MicroRNAs
- Polymorphism, Single Nucleotide
- Receptors, Dopamine D2
- Sirtuin 2
Keywords
- DRD2
- Longevity
- SIRT2
- SNP
- miRNA
A number of genetic polymorphisms are related to individual differences in cognitive performance. Striatal dopamine (DA) functions, associated with cognitive performance, are linked to the TaqIA polymorphism of the DRD2/ANKK1 gene. In humans, presence of an A1 allele of the DRD2/ANKK1-TaqIA polymorphism is related to reduced density of striatal DA D2 receptors. The resource-modulation hypothesis assumes that aging-related losses of neurochemical and structural brain resources modulate the extent to which genetic variations affect cognitive functioning. Here, we tested this hypothesis using functional MRI during long-term memory (LTM) updating in younger and older carriers and noncarriers of the A1-allele of the TaqIa polymorphism. We demonstrate that older A1-carriers have worse memory performance, specifically during LTM updating, compared to noncarriers. Moreover, A1-carriers exhibited less blood oxygen level-dependent (BOLD) activation in left caudate nucleus, a region critical to updating. This effect was only seen in older adults, suggesting magnification of genetic effects on functional brain activity in aging. Further, a positive relationship between caudate BOLD activation and updating performance among non-A1 carriers indicated that caudate activation was behaviorally relevant. These results demonstrate a link between the DRD2/ANKK1-TaqIA polymorphism and neurocognitive deficits related to LTM updating, and provide novel evidence that this effect is magnified in aging.
MeSH Terms
- Adult
- Aged
- Aging
- Brain Mapping
- Caudate Nucleus
- Cerebrovascular Circulation
- Female
- Genotyping Techniques
- Heterozygote
- Humans
- Magnetic Resonance Imaging
- Male
- Memory, Long-Term
- Neuropsychological Tests
- Organ Size
- Oxygen
- Polymorphism, Single Nucleotide
- Protein-Serine-Threonine Kinases
- Receptors, Dopamine D2
- Young Adult
Keywords
- DRD2
- aging
- dopamine
- functional magnetic resonance imaging (fMRI)
- memory
- striatum
- updating
In this study, the effect of maternal deprivation (MD) and chronic unpredictable stress (CUS) in inducing depressive behaviors and associated molecular mechanism were investigated in rats. Maternal deprivation was established by separating pups from their mothers for 6 hours daily from postnatal day 1 to day 14. Chronic unpredictable stress was established by water deprivation, elevated open platform, food deprivation, restraint stress and electric foot shock. The depressive behaviors were determined by use of sucrose preference test and forced swim test. Rats in MD/CUS group exhibited lower sucrose preference rate, longer immobility time, and lighter body weights than rats in other groups (MD/control, non-MD/CUS and non-MD/control group). Meanwhile, higher miR-504 expression and lower dopamine receptor D1 (DRD1) and D2 (DRD2) expression were observed in the nucleus accumbens of rats in the MD/CUS group than in the other three groups. MiR-504 expression correlated negatively with DRD1 gene expression and sucrose preference rate in the sucrose preference test, but correlated positively with immobility time in forced swim test. Both DRD2 mRNA and protein expression correlated negatively with immobility time in forced swim test. These results suggest that MD enhances behavioral vulnerability to stress during adulthood, which is associated with the upregulation of miR-504 and downregulation of DRD2 expression in the nucleus accumbens.
MeSH Terms
- Aging
- Animals
- Behavior, Animal
- Choice Behavior
- Depression
- Female
- Gene Expression Regulation
- Male
- Maternal Deprivation
- MicroRNAs
- Nucleus Accumbens
- RNA, Messenger
- Rats
- Rats, Sprague-Dawley
- Receptors, Dopamine D1
- Receptors, Dopamine D2
- Stress, Psychological
- Sucrose
Human behavior is influenced by a number of brain neurotransmitters. Central dopamine, serotonin and melanocortin systems have special importance for male sexual function. We searched for associations between male aging symptoms and polymorphic sites of serotonin (5-HTR1B), melanocortin (MC4R) and dopamine (DRD2, DRD4) receptors. In a population-based sample, genotyping of 5-HTR1B (polymorphism: G861C), MC4R (polymorphisms: C-2745T, Val103Ile), DRD2 (polymorphism: C313T) and DRD4 (polymorphism: 48-bp VNTR) was performed in 387 healthy men. The Aging Males' Symptoms (AMS) scale was used to evaluate specific ailments of aging men. We analyzed answers to questions from the AMS scale. Five points of the questionnaire addressed sexual symptoms of the aging male: feeling of passing one's peak, decrease in beard growth, decrease in ability/frequency to perform sexually, decrease in the number of morning erections, and decrease in sexual desire/libido (lacking pleasure in sex, lacking desire for sexual intercourse). Relations between reported symptoms and variants of the polymorphic sites of the studied genes were assessed. After adjusting for confounding factors (education, arterial hypertension, physical activity, weight, waist circumference) an association between the sexual dimension of AMS and genetic variants of 5-HTR1B G861C (p = 0.04) was observed. Variability of neurotransmitter receptor genes may be associated with sexual symptoms of aging in men.
MeSH Terms
- Adult
- Aged
- Aging
- Genetic Variation
- Humans
- Male
- Middle Aged
- Poland
- Polymorphism, Genetic
- Receptor, Serotonin, 5-HT1B
- Receptors, Neurotransmitter
- Sexual Behavior
- Statistics as Topic
Healthy aging beyond the age of 65 is characterized by a general decrease in cognitive control over actions: old adults have more difficulty than young adults in stopping overt responses. Responsible for this cognitive decrement is the continuous decline of striatal and extrastriatal dopamine (DA). The resource-modulation hypothesis assumes that genetic variability is more likely to result in performance differences when brain resources move away from close-to-optimal levels, as in aging. To test this hypothesis we investigated, first, whether individual differences in the C957T polymorphism at DRD2 gene (rs6277) contribute to individual differences in the proficiency to inhibit behavioral responses in a stop-signal task. Second, we assessed whether this genetic effect is magnified in older adults, due to the considerable decline in dopamine function. Our findings show that individuals carrying genotype associated with higher density of extrastriatal D2 receptors (C957T CC) were more efficient in inhibiting unwanted action tendencies, but not in term of response execution. This effect was stronger in older than in younger adults. Our findings support the idea that aging-related decline in dopamine availability alters the balance between genotypes and cognitive functions.
MeSH Terms
- Age Factors
- Aged
- Aged, 80 and over
- Aging
- Analysis of Variance
- Cognition Disorders
- Decision Making
- Female
- Functional Laterality
- Genotype
- Humans
- Inhibition, Psychological
- Intelligence Tests
- Male
- Polymorphism, Single Nucleotide
- Reaction Time
- Receptors, Dopamine D2
- Young Adult