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Previous work has associated polymorphisms in the dopamine transporter gene (rs6347 in DAT1/SLC6A3) and brain derived neurotrophic factor gene (Val66Met in BDNF) with atrophy and memory decline. However, it is unclear whether these polymorphisms relate to atrophy and cognition through associations with Alzheimer's disease pathology. We tested for effects of DAT1 and BDNF polymorphisms on cross-sectional and longitudinal ß-amyloid (Aß) and tau pathology (measured with positron emission tomography (PET)), hippocampal volume, and cognition. We analyzed a sample of cognitively normal older adults (cross-sectional n = 321) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). DAT1 and BDNF interacted to predict Aß-PET, tau-PET, and hippocampal atrophy. Carriers of both "non-boptimal" DAT1 C and BDNF Met alleles demonstrated greater pathology and atrophy. Our findings provide novel links between dopamine and neurotrophic factor genes and AD pathology, consistent with previous research implicating these variants in greater risk for developing AD.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Anciano , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Factor Neurotrófico Derivado del Encéfalo/genética , Estudios Transversales , Péptidos beta-Amiloides , Tomografía de Emisión de Positrones , Atrofia , Proteínas tau/genética , Disfunción Cognitiva/genética , BiomarcadoresRESUMEN
The dopamine transporter gene (DAT1), a recognized genetic risk factor for attention deficit hyperactivity disorder (ADHD) is principally responsible for the regulation of dopamine synaptic levels and serves as a key target in many psychostimulants drugs. DAT1 gene methylation has been considered an epigenetic marker in ADHD. The identification of G-rich sequence motifs potential to form G-quadruplexes is correlated with functionally important genomic regions. Herein, biophysical and biochemical techniques are employed to investigate the structural polymorphism along with the effect of cytosine methylation on a 26-nt G-rich sequence present in the promoter region of the DAT1 gene. The gel electrophoresis, circular dichroism spectroscopy, and UV-thermal melting data are well correlated and conclude the formation of a parallel (bimolecular), as well as antiparallel (tetramolecular) G-quadruplex in Na+ solution. Interestingly, the existence of uni-, bi-, tri-, and tetramolecular quadruplex structures in K+ solution exhibited only the parallel type G-quadruplex. The results demonstrate that in presence of either cation (Na+ or K+) the cytosine methylation reserved the structural topologies unaltered. However, methylation lowers the thermal stability of G-quadruplexes and the duplex structures, as well. These findings provide insights to understand the regulatory mechanisms underlying the formation of the G-quadruplex structure induced by DNA methylation.
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Scientific studies have provided evidence that there is a relationship between violent and aggressive behaviors and addictions. Genes involved with the reward system, specifically the brain reward cascade (BRC), appear to be associated with various addictions and impulsive, aggressive, and violent behaviors. In our previous research, we examined the Taq A1 allele (variant D2 dopamine receptor gene) and the DAT-40 base repeat (a variant of the dopamine transporter gene) in 11 Caucasian boys at the Brown School in San Marcus, Texas, diagnosed with intermittent explosive disorder. Thirty supernormal controls were screened to exclude several reward-deficit behaviors, including pathological violence, and genotyped for the DRD2 gene. Additionally, 91 controls were screened to exclude ADHD, pathological violence, alcoholism, drug dependence, and tobacco abuse, and their results were compared with DAT1 genotype results. In the schoolboys vs. supercontrols, there was a significant association with the D2 variant and a trend with the dopamine transporter variant. Results support our hypothesis and the involvement of at least two gene risk alleles with adolescent violent/aggressive behaviors. This study and the research presented in this paper suggest that violent/aggressive behaviors are associated with a greater risk of addiction, mediated via various genes linked to the BRC. This review provides a contributory analysis of how gene polymorphisms, especially those related to the brain reward circuitry, are associated with violent behaviors.
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To describe animals that express abnormal behaviors as a model of Attention-Deficit Hyperactivity Disorder (ADHD) implies that the abnormalities are analogous to those expressed by ADHD patients. The diagnostic features of ADHD comprise inattentiveness, impulsivity, and hyperactivity and so these behaviors are fundamental for validation of any animal model of this disorder. Several experimental interventions such as neurotoxic lesion of neonatal rats with 6-hydroxydopamine (6-OHDA), genetic alterations, or selective inbreeding of rodents have produced animals that express each of these impairments to some extent. This article appraises the validity of claims that these procedures have produced a model of ADHD, which is essential if they are to be used to investigate the underlying cause(s) of ADHD and its abnormal neurobiology.
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Trastorno por Déficit de Atención con Hiperactividad , Animales , Conducta Animal , Modelos Animales de Enfermedad , Conducta Impulsiva , Oxidopamina/toxicidad , RatasRESUMEN
Accumulating research addressed epigenetic modifications and their role on behavioral phenotypes. We recently proposed to study methylation dynamics of two CpG motifs within the 5'-UTR of dopamine transporter (DAT) gene. Starting from a normative population sample of young adults, we selected three sub-groups based on their prevalent symptoms: subjects were assigned to Internalizing, Externalizing and Low-risk sub-groups according to elevated scores in specific phenotypic scales. Using a new approach, we calculated three independent matrixes of cross-correlation between CpG methylation levels, one within each phenotypic sub-group, to determine in which dynamics did the sub-groups differ. We found specific cross-correlation patterns in Externalizing (CpG1, 2 and 3, opposite to the methylation at CpG6) and Internalizing individuals (CpG1 methylation opposite to CpG2, 3 and 6), while Low-risk individuals could follow both trends. The aim of our study was to look for a specific DAT methylation pattern, providing a biomarker that allows early identification of the risk for psycho-pathological deviance.
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Síntomas Conductuales/genética , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Epigénesis Genética/genética , Adulto , Islas de CpG , Metilación de ADN/genética , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Regiones Promotoras Genéticas/genética , Riesgo , Adulto JovenRESUMEN
BACKGROUND: The dopamine transporter gene (DAT1), striatal network dysfunction, and visual memory deficits have been consistently reported to be associated with attention-deficit/hyperactivity disorder (ADHD). This study aimed to examine the effects of the DAT1 rs27048 (C)/rs429699 (T) haplotype on striatal functional connectivity and visual memory performance in youths with ADHD. METHOD: After excluding those who had excessive head motion, a total of 96 drug-naïve youths with ADHD and 114 typically developing (TD) youths were assessed with the resting-state functional magnetic resonance imaging and the delayed matching to sample (DMS) task for visual memory. We examined the effects of ADHD, DAT1 CT haplotype, and the ADHD × CT haplotype interaction on the functional connectivity of five striatal seeds. We also correlated visual memory performance with the functional connectivity of striatal subregions, which showed significant diagnosis × genotype interactions. RESULTS: Compared with TD youths, ADHD youths showed significant hypoconnectivity of the left dorsal caudate (DC) with bilateral sensorimotor clusters. Significant diagnosis × genotype interactions were found in the connectivity between the left DC and the right sensorimotor cluster, and between the right DC and the left dorsolateral prefrontal/bilateral anterior cingulate clusters. Furthermore, the connectivity of the left DC showing significant diagnosis × genotype interactions was associated with DMS performance in youths with ADHD who carried the DAT1 CT haplotype. CONCLUSIONS: A novel gene-brain-behavior association between the left DC functional connectivity and visual memory performance in ADHD youths with the DAT1 rs27048 (C)/rs429699 (T) haplotype suggests a differential effect of DAT1 genotype altering specific brain function causing neuropsychological dysfunction in ADHD.
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Trastorno por Déficit de Atención con Hiperactividad/genética , Trastorno por Déficit de Atención con Hiperactividad/fisiopatología , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Adolescente , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Niño , China , Femenino , Haplotipos , Humanos , Masculino , MemoriaRESUMEN
Objective: Studies to reduce the heterogeneity of attention-deficit/hyperactivity disorder (ADHD) have increased interest in the concept of sluggish cognitive tempo (SCT). The aim of this study was to investigate if the prevalence of two variable-number tandem repeats (VNTRs) located within the 3′-untranslated region of the DAT1 gene and in exon 3 of the dopamine D4 receptor (DRD4) gene differ among four groups (31 subjects with SCT but no ADHD, 146 individuals with ADHD but no SCT, 67 subjects with SCT + ADHD, and 92 healthy controls). Methods: We compared the sociodemographic profiles, neurocognitive domains, and prevalence of two VNTRs in SCT and ADHD subjects versus typically developing (TD) controls. Results: The SCT without ADHD group had a higher proportion of females and lower parental educational attainment. Subjects in this group performed worse on neuropsychological tests, except for psychomotor speed and commission errors, compared to controls. However, the ADHD without SCT group performed significantly worse on all neuropsychological domains than controls. We found that 4R homozygosity for the DRD4 gene was most prevalent in the ADHD without SCT group. The SCT without ADHD group had the highest 7R allele frequency, differing significantly from the ADHD without SCT group. Conclusion: The 7R allele of DRD4 gene was found to be significantly more prevalent in SCT cases than in ADHD cases. No substantial neuropsychological differences were found between SCT and ADHD subjects.
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Humanos , Femenino , Trastorno por Déficit de Atención con Hiperactividad/diagnóstico , Trastorno por Déficit de Atención con Hiperactividad/genética , Cognición , Repeticiones de Minisatélite/genética , Receptores de Dopamina D4/genética , GenotipoRESUMEN
This narrative review describes an overview of the multiple effects of methylphenidate (MPH) in attention-deficit/hyperactivity disorder (ADHD) and its potential neurobiological targets. It addressed the following aspects: 1) MPH effects on attention and executive functions in ADHD; 2) the relation between MPH efficacy and dopamine transporter gene (DAT) polymorphism; and 3) the role of MPH as an epigenetic modulator in ADHD. Literature analysis showed that MPH, the most commonly used psychostimulant in the therapy of ADHD, acts on multiple components of the disorder. Marked improvements in attentional and executive dysfunction have been observed in children with ADHD during treatment with MPH, as well as reductions in neurological soft signs. MPH efficacy may be influenced by polymorphisms in the DAT, and better responses to treatment were associated with the 10/10 genotype. Innovative lines of research have suggested that ADHD etiopathogenesis and its neuropsychological phenotypes also depend on the expression levels of human endogenous retrovirus (HERV). In particular, several studies have revealed that ADHD is associated with HERV-H over-expression and that MPH administration results in decreased expression levels of this retroviral family and a reduction in the main symptoms of the disorder. In conclusion, there is a confirmed role for MPH as an elective drug in the therapy of ADHD alone or in association with behavioral therapy. Its effectiveness can vary based on DAT polymorphisms and can act as a modulator of HERV-H gene expression, pointing to targets for a precision medicine approach.
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The susceptibility to cannabis dependency results from the influence of numerous factors such as social, genetic, as well as epigenetic factors. Many studies have attempted to discover a molecular basis for this disease. However, our study aimed at evaluating the connection between altered methylation of the dopamine transporter gene (DAT1) promoter CpG sites and cannabis dependency. In the cases of some DNA sequences, including the DAT1 gene region, their methylation status in blood cells may reflect a systemic modulation in the whole organism. Consequently, we isolated the DNA from the peripheral blood cells from a group of 201 cannabis-dependent patients and 285 controls who were healthy volunteers and who were matched for age and sex. The DNA was subjected to bisulfite conversion and sequencing. Our analysis revealed no statistical differences in the general methylation status of the DAT1 gene promoter CpG island between the patients and controls. Yet, the analysis of individual CpG sites where methylation occurred indicated significant differences. These sites are known to be bound by transcription factors (e.g., SP1, p53, PAX5, or GR), which, apart from other functions, were shown to play a role in the development of the nervous system. Therefore, DAT1 gene promoter methylation studies may provide important insight into the mechanism of cannabis dependency.
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OBJECTIVES: The involvement of epigenetics mechanisms in the transcriptional regulation of key genes has been investigated in the initiation and progression of neurodegenerative disorders, including Parkinson's disease (PD). Among others, we, here, focused the attention on the dopamine transporter (DAT) gene playing a critical role in maintaining the integrity of dopaminergic neurons. MATERIALS AND METHODS: We performed bisulfite pyrosequencing to examine DNA methylation levels of six CpG sites in the 5'-UTR of DAT1 gene in human peripheral blood mononuclear cells (PBMCs) obtained from 101 sporadic PD patients and 59 healthy controls. RESULTS: We selectively report for CpG5 an increase in DNA methylation levels in PD subjects respect to controls, that almost reaches statistical significance (30.06 ± 12.4 vs 26.58 ± 7.6, P = .052). Of interest, a significantly higher methylation at specific CpG sites (ANOVA: P = .029) was observed in PD subjects with advanced stage of illness. Namely, a multivariate regression analysis showed that a higher methylation level at specific CpG sites in the group of PD patients was associated with increased methylation at CpG2, CpG3, and with H&Y stage but not with age and gender. This regression model explains the 38% of the variance of methylation at CpG5. CONCLUSION: Our results do seem to suggest that the methylation level of CpG5 is different between PD patients and controls. Moreover, this methylation level for CpG5 may be associated also with the stage of disease.
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Regiones no Traducidas 5'/genética , Metilación de ADN , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Enfermedad de Parkinson/genética , Factores de Edad , Anciano , Islas de CpG/genética , Neuronas Dopaminérgicas/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Monocitos/química , Enfermedad de Parkinson/patología , Factores SexualesRESUMEN
BACKGROUND: Genetic polymorphisms of the dopamine transporter gene (DAT1) and perinatal complications associated with poor oxygenation are risk factors for attentional problems in childhood and may show interactive effects. METHODS: We created a novel expression-based polygenic risk score (ePRS) reflecting variations in the function of the DAT1 gene network (ePRS-DAT1) in the prefrontal cortex and explored the effects of its interaction with perinatal hypoxic-ischemic-associated conditions on cognitive flexibility and brain gray matter density in healthy children from two birth cohorts-MAVAN from Canada (n = 139 boys and girls) and GUSTO from Singapore (n = 312 boys and girls). RESULTS: A history of exposure to several perinatal hypoxic-ischemic-associated conditions was associated with impaired cognitive flexibility only in the high-ePRS group, suggesting that variation in the prefrontal cortex expression of genes involved in dopamine reuptake is associated with differences in this behavior. Interestingly, this result was observed in both ethnically distinct birth cohorts. Additionally, parallel independent component analysis (MAVAN cohort, n = 40 children) demonstrated relationships between single nucleotide polymorphism-based ePRS and gray matter density in areas involved in executive (cortical regions) and integrative (bilateral thalamus and putamen) functions, and these relationships differ in children from high and low exposure to hypoxic-ischemic-associated conditions. CONCLUSIONS: These findings reveal that the impact of conditions associated with hypoxia-ischemia on brain development and executive functions is moderated by genotypes associated with dopamine signaling in the prefrontal cortex. We discuss the potential impact of innovative genomic and environmental measures for the identification of children at high risk for impaired executive functions.
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Encéfalo/patología , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Función Ejecutiva/fisiología , Sustancia Gris/patología , Hipoxia-Isquemia Encefálica/genética , Hipoxia-Isquemia Encefálica/patología , Corteza Prefrontal/metabolismo , Niño , Preescolar , Estudios de Cohortes , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/fisiología , Femenino , Humanos , Masculino , Herencia Multifactorial , Polimorfismo de Nucleótido SimpleRESUMEN
L-dopa-induced dyskinesias (LID) is a common motor side effect of levodopa therapy of Parkinson's disease (PD). The identified predictors may only partially account for the risk of developing LID and genetic factors may contribute to this variability. The present study is aimed to investigate whether polymorphisms in the dopamine transporter gene (DAT) are associated with the risk of developing LID. Genotyping of the 40-bp VNTR (rs28363170) and rs393795 (A/C) polymorphisms of the DAT gene was performed in a well-characterized cohort of 181 Italian PD patients in treatment with L-DOPA for 3 years or more. The results of our study show that there is no difference in dyskinesias prevalence among carriers of the two DAT gene polymorphisms. However, the combination of the two genotypes 10R/10R (rs28363170) and A carrier (rs393795) of the DAT gene reduces the risk of LID occurrence during long-term therapy with l-DOPA with respect to the PD subjects who did not carry these alleles (OR = 0.31; 95% CI, 0.09-0.88). Also based on a logistic regression analysis, the 10R/10R and the A carrier allele of the rs393795 polymorphisms of the DAT gene, could reduce the susceptibility to develop LID during levodopa therapy adjusted by demographical and clinical variables (OR = 0.19; 95% CI, 0.05-0.69). Additional studies further investigating the rs28363170 and rs393795 polymorphisms with LID in PD are needed to clarify their role in different ethnicities.
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Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Discinesia Inducida por Medicamentos/genética , Predisposición Genética a la Enfermedad/genética , Levodopa/efectos adversos , Enfermedad de Parkinson/genética , Polimorfismo Genético , Anciano , Alelos , Discinesia Inducida por Medicamentos/epidemiología , Femenino , Genotipo , Haplotipos , Humanos , Italia/epidemiología , Masculino , Repeticiones de Minisatélite/genética , PrevalenciaRESUMEN
Introduction: Hippocampal neuroanatomy is affected by genetic variations in dopaminergic candidate genes and environmental insults, such as early onset of chronic cannabis exposure. Here, we examine how hippocampal total and subregional volumes are affected by cannabis use and functional polymorphisms of dopamine-relevant genes, including the catechol-O-methyltransferase (COMT), dopamine transporter (DAT1), and the brain-derived neurotrophic factor (BDNF) genes. Material and Methods: We manually traced total hippocampal volumes and automatically segmented hippocampal subregions using high-resolution MRI images, and performed COMT, DAT1, and BDNF genotyping in 59 male Caucasian young adults aged 18-30 years. These included 30 chronic cannabis users with early-onset (regular use at <16 years) and 29 age-, education-, and intelligence-matched controls. Results: Cannabis use and dopaminergic gene polymorphism had both distinct and interactive effects on the hippocampus. We found emerging alterations of hippocampal total and specific subregional volumes in cannabis users relative to controls (i.e., CA1, CA2/3, and CA4), and associations between cannabis use levels and total and specific subregional volumes. Furthermore, total hippocampal volume and the fissure subregion were affected by cannabis×DAT1 polymorphism (i.e., 9/9R and in 10/10R alleles), reflecting high and low levels of dopamine availability. Conclusion: These findings suggest that cannabis exposure alters the normal relationship between DAT1 polymorphism and the anatomy of total and subregional hippocampal volumes, and that specific hippocampal subregions may be particularly affected.
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BACKGROUND: The dopamine transporter gene (DAT1) and visual memory deficits have been consistently reported to be associated with attention-deficit/hyperactivity disorder (ADHD). This study aimed to examine whether a DAT1 haplotype affected functional and structural brain alterations in children with ADHD and whether those alterations were associated with visual memory. METHOD: We recruited a total of 37 drug-naïve children with ADHD (17 with the DAT1 rs27048 (C)/rs429699 (T) haplotype and 20 without the CT haplotype) and 37 typically developing children (17 with the CT haplotype and 20 without the CT haplotype). Visual memory was assessed by the pattern recognition memory (PRM) and spatial recognition memory (SRM) tasks. We analyzed functional and structural brain architecture with regional homogeneity (ReHo) and gray matter volume (GMV). RESULTS: The CT haplotype was associated with decreased ReHo in the left superior occipital gyrus, cuneus, and precuneus; and decreased GMV in the left superior occipital gyrus, cuneus, and precuneus, and in the right angular gyrus. Significant interactions of ADHD and the CT haplotype were found in the right postcentral gyrus for ReHo and in the right supplementary motor area for GMV. For the ADHD-CT group, we found negative correlations of total correct responses in PRM and SRM and positive correlations of mean latency of correct responses in PRM with the GMV in the left superior occipital gyrus, cuneus, and precuneus. CONCLUSIONS: Our findings suggest that the DAT1-related GMV alterations in the posterior cortical regions may contribute to visual memory performance in children with ADHD.
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Trastorno por Déficit de Atención con Hiperactividad , Corteza Cerebral , Disfunción Cognitiva , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Sustancia Gris/patología , Reconocimiento Visual de Modelos/fisiología , Reconocimiento en Psicología/fisiología , Memoria Espacial/fisiología , Adolescente , Trastorno por Déficit de Atención con Hiperactividad/complicaciones , Trastorno por Déficit de Atención con Hiperactividad/genética , Trastorno por Déficit de Atención con Hiperactividad/patología , Trastorno por Déficit de Atención con Hiperactividad/fisiopatología , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/patología , Corteza Cerebral/fisiopatología , Niño , Disfunción Cognitiva/etiología , Disfunción Cognitiva/genética , Disfunción Cognitiva/patología , Disfunción Cognitiva/fisiopatología , Femenino , Neuroimagen Funcional , Sustancia Gris/diagnóstico por imagen , Haplotipos , Humanos , Imagen por Resonancia Magnética , MasculinoRESUMEN
In the present study, we investigated the possible gene-environment correlation between the dopamine transporter gene (DAT1) polymorphism and childhood experiences of abuse and neglect. Genetic information was obtained from 1,442 male and 2,178 female twins and their siblings drawn from a Finnish population-based sample. The Childhood Trauma Questionnaire was used to measure the childhood experiences of abuse and neglect. In men, the DAT1 polymorphism was associated with having experienced sexual abuse in childhood, such that men with the 9R9R genotype reported less sexual abuse experiences than men with the 9R10R or the 10R10R genotypes. In women, there was an association between the DAT1 polymorphism and childhood experiences of emotional abuse, such that women with the 9R9R genotype reported less emotional abuse experiences than women with the 9R10R or 10R10R genotypes. No other associations between the DAT1 polymorphism and childhood experiences of abuse and neglect were found. In sum, the results suggested that some genetic components might predispose children to experience childhood abuse and neglect. Possible reasons for this association were discussed.
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Maltrato a los Niños/psicología , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Interacción Gen-Ambiente , Genotipo , Polimorfismo Genético/genética , Adulto , Niño , Femenino , Frecuencia de los Genes/genética , Humanos , Masculino , Encuestas y CuestionariosRESUMEN
BACKGROUND: The current study examined independent and interactive effects of polymorphisms of the mu opioid receptor gene (OPRM1, A118G) and variable number tandem repeats of the dopamine transporter gene (DAT1, SLC6A3) on alcohol consumption and subjective responses to alcohol in 127 young, healthy, social drinkers. METHODS: Participants completed an in-person assessment, which included self-reported alcohol drinking patterns and blood sampling for DNA, and in a second visit, a cumulative alcohol dosing procedure with subjective ratings across multiple time points and breath alcohol contents (0.03 to 0.1%). DNA was analyzed for OPRM1 AA versus AG/GG (*G) genotypes, DAT1 10-repeat allele (A10) versus 9 or lesser alleles (A9), and ancestral informative markers. RESULTS: There were significant epistatic interactions between OPRM1 and DAT1 genotypes. Subjective High Assessment Scale scores after alcohol consumption were highest in *G and A9 carriers, and lowest in *G and A10 carriers. Negative subjective effects were also highest in *G and A9 carriers. Effects were similar in a sensitivity analysis limited to Caucasian subjects. There were independent and epistatic interactions on drinking. The OPRM1 *G allele was independently associated with fewer heavy drinking days. The A9 allele was associated with a greater number of drinking days, which was attenuated in carriers of the *G allele. CONCLUSIONS: These findings highlight the biological importance of interactions between these 2 genes and interactions between brain opioid and dopamine systems.
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Consumo de Bebidas Alcohólicas/genética , Consumo de Bebidas Alcohólicas/psicología , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Epistasis Genética/genética , Polimorfismo de Nucleótido Simple/genética , Receptores Opioides mu/genética , Adulto , Pruebas Respiratorias/métodos , Femenino , Humanos , Masculino , Método Simple Ciego , Adulto JovenRESUMEN
Genetic polymorphism in the 3'-untranslated region (3'-UTR) of the dopamine transporter (DAT) gene has been reported in both human and nonhuman primates, and the variable number of tandem repeats (VNTR) polymorphism has been related to several neurological and psychiatric disorders. As New World primates have been employed as models in biomedical research in these fields, in the present study we assessed genetic variation in the DAT gene in 25 robust capuchin monkeys (Sapajus spp.) and 39 common marmosets (Callithrix jacchus). Using enzymatic amplification followed by sequencing of amplified fragments, a VNTR polymorphism in the 3'-UTR region of the DAT gene was identified in both robust capuchins and common marmosets. The polymorphic tandem repeat of 40-bp basic units is similar to the human VNTR consensus sequence, with size variants composed of 9, 10, and 11 units in marmosets and 8, 9, 13, and 17 basic units in capuchins. We found behavioral evidence that carrying the 10-repeat DAT allele promotes flexible choice and maximization of foraging in marmosets tested in an operant choice paradigm. Moreover, in an intertemporal choice task, capuchins with longer repeat variants show less self-controlled choices than capuchins with at least one short repeat variant. Future research should focus on the relationship between these DAT polymorphisms, dopamine reuptake via the dopamine transporter, and behavioral and cognitive variation across New World monkey individuals.
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Regiones no Traducidas 3' , Callithrix/genética , Cebinae/genética , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Repeticiones de Minisatélite , Polimorfismo Genético , Animales , Secuencia de Bases , Callithrix/metabolismo , Cebinae/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Filogenia , Alineación de SecuenciaRESUMEN
OBJECTIVES: To examine the association of the DNA methylation of DAT1 and DRD4 gene with methylphenidate (MPH) response in attention deficit hyperactivity disorder (ADHD). METHODS: One hundred and eleven DSM-IV defined ADHD Chinese Han children were recruited. Inattention, hyperactivity-impulsivity and oppositional symptoms were evaluated by the Swanson, Nolan and Pelham-IV-parent rating scale (SNAP-IV-P) at baseline and 6 weeks after MPH treatment. DNA methylation of CpG sites in the promoter sequences of DAT1 and DRD4 was examined for association with treatment response. RESULTS: Greater improvement on the SNAP-IV-P total score and percentage change from baseline score were both significantly correlated with DAT1 methylation (rho =-0.222, P = .019 and rho = -0.203, P = .032, respectively). A secondary analysis demonstrated that the effect of DAT1 methylation on symptom response was primarily related to the percentage change in oppositional symptoms (rho = -0.242; P = .012), with a smaller significant effect on hyperactivity-impulsivity (rho = -0.192; P = .045). No significant correlation was found between the treatment effect on inattention and DAT1 methylation (rho = -0.101; P = .292). No significant correlation was observed between mean DRD4 methylation and measures of treatment outcome or baseline symptoms. CONCLUSIONS: Our findings provide initial evidence for the involvement of the epigenetic alterations of DAT1 in modulating the response to MPH treatment in ADHD, primarily on oppositional and hyperactive-impulsive symptoms.
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Déficit de la Atención y Trastornos de Conducta Disruptiva/tratamiento farmacológico , Déficit de la Atención y Trastornos de Conducta Disruptiva/genética , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Inhibidores de Captación de Dopamina/farmacología , Metilfenidato/farmacología , Evaluación de Resultado en la Atención de Salud , Niño , Metilación de ADN , Inhibidores de Captación de Dopamina/administración & dosificación , Femenino , Humanos , Masculino , Metilfenidato/administración & dosificación , Receptores de Dopamina D4/genéticaRESUMEN
Objective To investigate the correlation of methylation status in DA T1 and DRD4 genes and severity of clinical manifestations in ADHD patients.Methods One hundrd eleven DSM-Ⅳ defined ADHD patients were enrolled in this study and the demographic data were collected.Clinical symptoms were also assessed by Attention Deficit Hyperactivity Disorder Rating Scale-Ⅳ Home Version (ADHD-RS-Ⅳ) and self-developed Oppositional Defiant Disorder (ODD) rating scale.Bisulfite genomic sequencing (BGS) was used to detect the methylation status of every CpG site in DA T1 and DRD4 promoter CpG island in peripheral venous blood.Results The DNA methylation level in total CpG island for DA T1 was higher in individuals without depression,anxiety or ADHD family history compared to individuals with above family histories (P＜0.05).The differences on methylation levels for DA T1 and DRD4 were not significant between high and low ADHD-RS-Ⅳ total score (≤30 vs.＞30),ADHD-RS-Ⅳ inattention score (≤ 17 vs.＞17),and ADHD-RS-Ⅳ hyperactivity/impulsivity score (≤13 vs.＞13) subgroups (all P＜0.05).The methylation levels in total CpG island in DA T1 was higher in individuals whose ODD score were ＜9 compared to those whose ODD score were ≥9 (P＜0.05).Conclusions Methylation status of CpG island in DAT1 may influence the severity of oppositional defiant symptom in ADHD patients,which is correlated with depression,anxiety and ADHD family histories.
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The role of dopamine in controlling behavior remains poorly understood. In this study we examined licking behavior in an established hyperdopaminergic mouse model-dopamine transporter knockout (DAT KO) mice. DAT KO mice showed higher rates of licking, which is due to increased perseveration of licking in a bout. By contrast, they showed increased individual lick durations, and reduced inter-lick intervals. During extinction, both KO and control mice transiently increased variability in lick pattern generation while reducing licking rate, yet they showed very different behavioral patterns. Control mice gradually increased lick duration as well as variability. By contrast, DAT KO mice exhibited more immediate (within 10 licks) adjustments-an immediate increase in lick duration variability, as well as more rapid extinction. These results suggest that the level of dopamine can modulate the persistence and pattern generation of a highly stereotyped consummatory behavior like licking, as well as new learning in response to changes in environmental feedback. Increased dopamine in DAT KO mice not only increased perseveration of bouts and individual lick duration, but also increased the behavioral variability in response to the extinction contingency and the rate of extinction.