The dopamine transporter: relevance to attention deficit hyperactivity disorder (ADHD)

The dopamine transporter is elevated in adults with attention deficit hyperactivity disorder (ADHD) compared with healthy controls [Lancet 354 (1999) 2132]. The findings have been confirmed by others in a different population using a different probe for the dopamine transporter. Notwithstanding the need to confirm these findings in a multi-center trial, several hypotheses are presented to account for these observations. A premise that elevated transporter levels result from medication is not supported by current data. Other possibilities, including hypertrophy of dopamine neuronal terminals in the striatum, dysfunctional regulation of dopamine or dopamine receptors, or anomalies in the dopamine transporter gene are presented as hypotheses. The feasibility of exploring these mechanisms in animal models or in human subjects is explored.     

The dopamine transporter gene and the impulsivity phenotype in attention deficit hyperactivity disorder: a case-control association study in a Korean sample

The dopamine transporter gene (DAT1) has been extensively studied as one of the candidate genes in attention-deficit/hyperactivity disorder (ADHD). Several studies have reported on the association between the DAT1 10-repeat allele and cognitive variables in ADHD. However, few studies have been designed to ascertain the association between DAT1 genotypes other than the 10-repeat allele and cognitive endophenotypes in ADHD. The aim of this study was to examine the relationship between the DAT1 genotypes and the candidate endophenotypes, inattention and impulsivity symptoms, as measured by the continuous performance test (CPT), in a Korean sample of 85 children diagnosed with DSM-IV ADHD. Compared to the normal control group, the frequencies of the 9/10 genotype were significantly higher in the ADHD probands (χ² = 13.45, p = 0.02, OR = 4.12, 95% CI: 2.21–12.34) and parents of probands (χ² = 11.60, p = 0.03). The 9-repeat allele frequencies were significantly higher in the ADHD probands (χ² = 11.55, p = 0.03, OR = 4.43, 95% CI: 1.55–11.78) and parents of probands (χ² = 12.70, p = 0.03) than the normal control group. Compared to the ADHD probands without the 9-repeat allele (n = 74), the mean T-score, with regard to the commission errors of the CPT, was significantly higher (p < 0.05) in the ADHD probands with the 9-repeat allele (n = 11). Compared to the ADHD probands with other DAT1 genotypes, the mean T-score, with respect to the commission errors of the CPT, was significantly higher in the ADHD probands with the 9/10 genotype (p < 0.05). The results of this study suggest the possibility of an association between the DAT1 9-repeat allele and the impulsivity phenotype of ADHD.     

多巴胺转运体基因与注意缺损多动障碍

目的　探讨注意缺损多动障碍（ＡＤＨＤ） 与多巴胺转运体（ＤＡＴ１） 基因间的关系。方法　分别采用基于单体型和基于基因型的单体型相对风险分析方法,在上海地区汉族人群中对ＡＤＨＤ 与ＤＡＴ１ 基因微卫星多态性进行遗传关联分析。结果　①上海地区汉族人中,ＤＡＴ１ 基因多态以４８０ ｂｐ 重复片段为主,其基因频率为９２％ 。②以父母双亲为对照,经ＧＨＲＲ 和ＨＨＲＲ 分析,ＤＡＴ１ 基因与ＡＤＨＤ 均无关联。结论　上海地区汉族人群中ＤＡＴ１ 基因多态与ＡＤＨＤ 无关。     

The cognitive genetics of attention deficit hyperactivity disorder (ADHD): sustained attention as a candidate phenotype

Here we describe the application of cognitive genetics to the study of attention deficit hyperactivity disorder (ADHD). Cognitive genetics owes much to the pioneering work of cognitive neuropsychologists such as John Marshall, whose careful observations of cognitive dissociations between brain-lesioned patients greatly advanced the theoretical understanding of normal cognitive function. These theories have in turn helped to constrain linkages between candidate genes and cognitive processes and thus help to drive the relatively new field of cognitive genetics in a hypothesis-driven fashion. We examined the relationship between sustained attention deficits in ADHD and genetic variation in a catecholamine-related gene, dopamine beta hydroxylase (DbetaH). DBH encodes the enzyme that converts dopamine to noradrenaline and is crucial to catecholamine regulation. A polymorphism with the DBH gene has been associated with ADHD. In fifty-two children with ADHD, we examined whether variation in the Taq I DBH gene polymorphism was related to sustained attention performance. Participants performed the Sustained Attention to Response Test (SART). Performance on the SART discriminates ADHD from control children, and in imaging work, is associated with right frontoparietal activation. A significant effect of DBH genotype was found on SART performance measures. Children possessing two copies of the ADHD-associated risk allele (A2) had significantly poorer sustained attention than those ADHD children who did not possess this allele or a non-genotyped control group. The DBH gene may contribute to the susceptibility for ADHD, in part because of its varying effects on the development of brain mechanisms mediating sustained attention.     

Attention-deficit/hyperactivity disorder (ADHD) association with the DAT1 core promoter -67 T allele

Association between attention deficit hyperactivity disorder (ADHD) and the 10-repeat allele of a polymorphism (a 40 bp variable number of tandem repeats) in the dopamine transporter gene (DAT1) has been reported by several groups. In this study, we examined whether either allele of the DAT1 core promoter -67 functional polymorphism is associated with ADHD in a case/control study. The allele and genotype frequencies of the polymorphism were studied in 110 patients and 120 controls, which were matched on the basis of sex, age and ethnicity. The genotype frequencies in the patients group were as follows: AA 19.2%; AT 65.2%; TT 15.4% vs. the genotype frequencies in the control group: AA 47.5%; AT 43.3%; TT 9.2% [chi2=20.73, df=2, P相似文献   

Association between the dopamine transporter gene and the inattentive subtype of attention deficit hyperactivity disorder in Taiwan

Attention deficit hyperactivity disorder (ADHD) is a common heritable childhood psychiatric disorder. Since methylphenidate, one of the main drugs used to treat ADHD, targets the dopamine transporter, this study examined the linkage disequilibrium (LD) structure of the dopamine transporter gene (DAT1) and investigated whether the DAT1 gene was associated with ADHD. This Chinese family-based association sample consisted of 273 DSM-IV diagnosed ADHD probands and their family members (n = 906). We screened 15 polymorphisms across the DAT1 gene, including 14 single nucleotide polymorphism (SNP) markers and the variable number of tandem repeat (VNTR) polymorphism in 3′-untranslated region (3′UTR). Calculations of pairwise LD revealed three main haplotype blocks (HBs): HB1 (intron 2 through intron 6), HB2 (intron 8 through intron 11), and HB3 (3′UTR). Family-Based Association Tests showed that no allele was significantly more transmitted than expected to the ADHD children for these 15 markers. Haplotype-Based Association Tests showed that a haplotype rs27048 (C)/rs429699 (T) was significantly associated with the inattentive subtype (P = 0.008). In quantitative analyses, this haplotype also demonstrated significant association with the inattention severity (P = 0.012). Our finding of the haplotype rs27048 (C)/rs429699 (T) as a novel genetic marker in the inattentive ADHD subtype suggests that variation in the DAT1 gene may primarily affect the inattentive subtype of ADHD.     

Investigation of attention deficit hyperactivity disorder (ADHD) sub-types in children via EEG frequency domain analysis

Aim of the study: To investigate the frequency domain effects and changes in electroencephalography (EEG) signals in children diagnosed with attention deficit hyperactivity disorder (ADHD).

Patients and methods: The study contains 40 children. All children were between the ages of 7 and 12 years. Participants were classified into four groups which were ADHD (n=20), ADHD-I (ADHD-Inattentive type) (n=10), ADHD-C (ADHD-Combined type) (n=10), and control (n=20) groups. In this study, the frequency domain of EEG signals for ADHD, subtypes and control groups were analyzed and compared using Matlab software. The mean age of the ADHD children's group was 8.7 years and the control group 9.1 years.

Results: Spectral analysis of mean power (μV²) and relative-mean power (%) was carried out for four different frequency bands: delta (0--4 Hz), theta (4--8 Hz), alpha (8--13 Hz) and beta (13--32 Hz). The ADHD and subtypes of ADHD-I, and ADHD-C groups had higher average power value of delta and theta band than that of control group. However, this is not the case for alpha and beta bands. Increases in delta/beta ratio and statistical significance were found only between ADHD-I and control group, and in delta/beta, theta/delta ratio statistical significance values were found to exist between ADHD-C and control group.

Conclusion: EEG analyzes can be used as an alternative method when ADHD subgroups are identified.     

Dopamine transporter gene,response to methylphenidate and cerebral blood flow in attention-deficit/hyperactivity disorder: a pilot study

The homozygosity of the 10-repeat allele at dopamine transporter gene (DAT1) seems to be associated with a poor response to methylphenidate (MPH) in children with attention-deficit/hyperactivity disorder (ADHD). This pilot study aimed to simultaneously assess polymorphisms at DAT1, response to MPH, and neuroimaging. Only ADHD children with at least a moderate response to MPH were included. Significantly higher regional cerebral blood flows assessed by single photon emission computerized tomography (SPECT) were detected in medial frontal and left basal ganglia areas in children with homozygosity for the 10-repeat allele at DAT1 gene (n = 4) than in children without this genotype (n = 4) (P < 0.05). These findings provide a preliminary connection between pharmacogenetics and neurobiological investigations on stimulant treatment of ADHD.     

EEG characteristics and visual cognitive function of children with attention deficit hyperactivity disorder (ADHD)

Using visual and auditory continuous performance tests (CPT) and EEG, cognitive function and EEG power were investigated in patients with attention deficit hyperactivity disorder (ADHD). CPT and EEG were conducted for 44 ADHD children and 44 healthy controls of comparable age and sex. The EEG power tests include relative power of theta, alpha, and beta, and theta/beta and theta/alpha ratios. ADHD patients showed significantly higher theta relative power, lower beta relative power, and higher theta/beta ratio (p < 0.05). ADHD patients showed a significantly lower score of auditory CPT (p < 0.05). The EEG power characteristics were correlated significantly with the visual attention function in ADHD children (p < 0.01). Higher-order level cognitive dysfunction affects ADHD pathogenesis. Cortical hypoarousal effects on several mechanisms including the fronto-striatal circuitry may be implicated in the inhibition of prepotent and premature responses.     

No association between catechol-O-methyltransferase (COMT) genotype and attention deficit hyperactivity disorder (ADHD) in Japanese children

Objective: This study ascertained the association between attention deficit/hyperactivity disorder (ADHD) in Japanese children and a polymorphism of catechol-O-methyltransferase (COMT), a dopamine-control gene. The secondary aim of the study was the evaluation of a putative association between methylphenidate (MPH) effect/adverse effects and the COMT genotype. Methods: To ascertain the distribution of the Val158Met variant of COMT, 50 children meeting ADHD inclusion criteria were compared with 32 healthy children. Clinical improvement and the occurrence of adverse effects were measured before and 3 months after MPH administration in children with ADHD, and analyzed for genotype association. Wechsler Intelligence Scale for Children-Third Edition (WISC-III), age, MPH dose were included as co-variables. Results: The occurrence of the COMT Val/Val genotype was significantly higher in children with ADHD (χ²(1) = 7.13, p < 0.01). However, there was no significant difference in the Val/Val genotype according to disorder, and WISC and ADHD rating scale scores, after correcting for the interaction between disorder and COMT genotype. Furthermore, no significant difference in MPH effect/adverse effects was observed in association with the COMT genotype in the ADHD group. Conclusions: These results showed a lack of association between the COMT Val/Val genotype and ADHD in Japan.     

Sleep quality in adult patients with attention deficit hyperactivity disorder (ADHD)

Sleep disorders are common in adults with attention deficit/hyperactivity disorder (ADHD). Two sleep questionnaires; the Brown ADD Scale, the Symptom-Checklist-90-R, and a self-developed symptom questionnaire were administered in this study. In a sample of 61 patients without comorbidity, current substance abuse and medication intake, sleep problems were reported more often than in healthy controls. A lack of being refreshed in the morning was very closely associated with ADHD symptomatology whereas insomnia was related to the presence of comorbidity and depressive symptoms. In the total sample (N = 120), medication intake (mainly stimulants) was not related to any of the sleep parameters. It seems important to screen adult patients with ADHD for the presence of sleep disorders, especially insomnia, restless legs syndrome, and sleep-related breathing disorders (the last in conjunction with the body mass index). Since primary sleep disorders are associated with cognitive impairment, one might expect that ADHD symptomatology may improve if comorbid sleep disorders are adequately treated in addition to the specific ADHD treatment.     

Neural correlates of performance monitoring in adult patients with attention deficit hyperactivity disorder (ADHD)

Introduction. In this study, the neural correlates of error processing in adult patients with attention deficit hyperactivity disorder (ADHD) are to be investigated for the first time. Recent studies in children with ADHD suggested, with some inconsistencies, deficits in error processing. Based on an analogue study with students, we hypothesized that ADHD patients show reduced amplitudes in the event-related potential (ERP) of the Pe (error positivity) but normal amplitudes of the ERN (error-related negativity) after incorrect responses. Method. In this study we investigated 34 adult ADHD patients and 34 healthy controls with a modified version of the Eriksen flanker task while recording the neural activity with 26 scalp EEG electrodes. Patients discontinued all medication at least 3 days prior to investigation. Age was included as a control variable for the statistical analyses. Results and conclusion. As hypothesized, we found reduced Pe amplitudes, but also reduced ERN values, in ADHD patients. Importantly, theses differences as well as the deficits in behavioural performance were mainly detectable in the younger subsample, but not in the elderly subsample. Our results indicate that adult ADHD patients are characterized by deficits in error processing, which vanish with age.     

Sensitivity to delay of reinforcement in two animal models of attention deficit hyperactivity disorder (ADHD)

An altered response to reinforcement has been proposed as a mechanism underlying many of the symptoms of attention deficit hyperactivity disorder (ADHD). We measured sensitivity to delay of reinforcement in two animal models of ADHD, the spontaneously hypertensive rat (SHR) and a newly proposed model, the genetically hypertensive (GH) rat. A task previously used to measure effects of delay of reinforcement in children with ADHD was adapted for use in the present experiment. The SHR and GH rats were compared to their respective genetic control strains, Wistar-Kyoto (WKY), and Wistar (WI). The experimental task required pressing one of two available levers each trial. One lever delivered an immediate reinforcement, and the other lever a delayed reinforcement. Both the SHR and GH strains allocated significantly more responses to the immediately reinforced lever than their genetic control strains. Individual instances of reinforcement differentially affected response allocation in the GH but not the SHR. These findings support the use of the SHR and GH rat to model altered response to reinforcement, and demonstrate the additional value of the GH strain to model the effects of individual instances of reinforcement in children with ADHD.     

A drosophila model for attention deficit hyperactivity disorder (ADHD): No evidence of association with PRKG1 gene

Attention deficit hyperactivity disorder (ADHD) is a prevalent psychiatric condition in children and follow up studies have indicated that 22–33% of patients continue to suffer from ADHD during late adolescence and adulthood. The action of psychostimulant drugs may be determined by additional mechanisms beyond the dopamine transporter and receptors. We are exploring new methodology for discovering these mechanisms. For example, in Drosophila, such an additional determinant of psychostimulant action could be protein kinase G (PKG) that affects food-search behavior. Here we initiated studies with the human homologue of PKG, the PRKG1 gene. The aim of this study was to investigate for the presence of linkage disequilibrium between the protein kinase G gene (PRKG1) and adult ADHD in a sample of nuclear families. Genotyping data for the C2276T polymorphism were analyzed using the Transmission Disequilibrium Test (TDT). Sixty three nuclear families were informative for the TDT on C2276T polymorphism, which showed no preferential transmission of either allele (chi-square=0.778, df=1, p=0.316). These findings exclude a direct involvement of this genetic marker of the Protein kinase G gene in the pathogenesis of ADHD.     

Excessive daytime sleepiness in adults with possible attention deficit/hyperactivity disorder (ADHD): a web-based cross-sectional study

ObjectivesArousal dysregulation has been speculated to be involved in the pathological mechanism of attention deficit/hyperactivity disorder (ADHD). However, there has been no epidemiological study assessing the real condition of excessive daytime sleepiness (EDS) in adults with ADHD. This study investigated the prevalence of EDS and the relationship between sleepiness and ADHD symptoms in adults with possible ADHD.MethodsAn observational, cross-sectional, web-based study was performed. Participants were 9822 Japanese adults aged 20–69 years who completed an Internet-based questionnaire that assessed ADHD symptoms, autistic traits, depressive symptoms, chronotype, sleepiness, and sleep disturbances.ResultsParticipants with possible ADHD were more likely than non-ADHD participants to have an evening chronotype and experience depressive symptoms, sleepiness, and sleep disturbances. The rates of having moderate and severe sleepiness in the possible ADHD group were higher than those in the non-ADHD group. Hierarchical logistic regression analyses revealed that the presence of ADHD symptoms was independently associated with EDS even after adjusting for factors related to the presence of sleepiness. When examining inattention and hyperactivity scores among participants with possible ADHD, the inattention score was significantly higher in the severe EDS group compared with the moderate and non-EDS groups.ConclusionsEDS was relatively common in adults with possible ADHD. ADHD symptoms, especially inattentiveness, were associated with the formation of EDS in this population.     

Evaluation of sleep organization in patients with attention deficit hyperactivity disorder (ADHD) and ADHD as a comorbidity of epilepsy

Objective/backgroundEpilepsy or attention deficit hyperactivity disorder (ADHD) can influence sleep organization in different ways. The aim of this study was to evaluate sleep organization in children and adolescents with ADHD and epilepsy, and to analyze the influence of methylphenidate.MethodsThis was an observational, cross-sectional study of children and adolescents with epilepsy, who were seizure free for at least three months, and were also diagnosed with ADHD. They were selected from the epilepsy and child neurology outpatient clinic of a university hospital in Brazil. After sample size calculation, patients were consecutively included into four different groups, with 21 patients each: epilepsy + ADHD using methylphenidate, epilepsy + ADHD not using methylphenidate, only ADHD, and a healthy control group. All participants were evaluated with the Sleep Disturbance Scale for Children (SDSC) and monitored with actigraphy for five nights/days.ResultsActigraphic analysis showed a higher number of night awakenings in the epilepsy + ADHD groups; they were most prominent in the group without methylphenidate (p = 0.001). Parental reports demonstrated a higher risk for sleep disturbances in the epilepsy + ADHD without methylphenidate and the ADHD groups (p < 0.001).ConclusionPrimary ADHD as a comorbidity of epilepsy impairs sleep organization in children, and the use of short-acting methylphenidate seems to improve it. Both objective (actigraphic) and subjective (SDSC) measures showed significant sleep alterations between primary ADHD and ADHD as a comorbidity of epilepsy; this was most prominent in the group without methylphenidate.     

Changes in the second messenger cyclic AMP during development may underlie motoric symptoms in attention deficit/hyperactivity disorder (ADHD)

The transitions that occur in the ascending dopamine systems between childhood and adulthood parallel the emergence, course, and severity of attention-deficit hyperactivity disorder (ADHD) symptoms. Behaviorally, rats are more active in open field during periadolescence, and activity levels decline by 50% in males by adulthood. This peak in behavior parallels a transient overproduction in D1 and D2 dopamine receptors that occurs at puberty in rat striatum (STR) and prefrontal cortex (PFC), followed by a decline in receptor density into adulthood. While tempting to speculate that receptor density plays a role in the waning of ADHD symptoms, receptor overproduction does not occur in the nucleus accumbens (NA), which demonstrates only a modest rise in receptor density (10–20%). Given the importance of the accumbens in locomotor activity, an alternative explanation for increased activity was sought. The second messenger system cyclic adenosine monophosphate (cAMP) has classically been associated with dopamine receptors. The results of these studies demonstrate that cAMP accumulation in the accumbens and the STR parallel the observed rise and fall in activity levels in rats. At puberty, basal cAMP levels are 35% higher relative to adulthood in male accumbens, while a modest 7% change was observed in STR. Forskolin-stimulated cAMP was 240–300% higher in STR and accumbens at puberty before declining with maturation. These findings suggest that, the adolescent dopamine system has a much higher ‘tone’ relative to adults. However, pharmacological responsiveness of cAMP to D1 or D2 stimulation demonstrates an overall blunted response during puberty relative to adulthood. This finding is consistent with a hyposensitivity to stress and pharmacological agents at puberty in animals that are in a hyperdopaminergic state. These findings of combined elevated cAMP accumulation and reduced cAMP sensitivity during adolescence have clinical implications for hypothesized mechanism and course of ADHD and its treatment. The maturational decline in cAMP activity may explain why this disorder recedes, while, simultaneously cAMP becomes more responsive to D1 and D2 receptor stimulation in adulthood.     

A preliminary report of the dopamine receptor D4 and the dopamine transporter 1 gene polymorphism and its association with attention deficit hyperactivity disorder

Attention deficit hyperactivity disorder (ADHD) is one of the most prevalent childhood-onset psychiatric syndromes affecting 5%–10% of school-age children worldwide. Distortions in the catecholaminergic system seem to be responsible for this condition. Within this system there are several candidate genes, the dopamine receptor D₄ (DRD4) and the dopamine transporter 1 (DAT1), with common polymorphism which might be associated with ADHD. We performed a family based association study with 36 trios and 19 parent proband pairs. All diagnoses were confirmed by the “Hypescheme” diagnostic computer program. In this study we did not observe an association of ADHD with DRD4 and DAT1 polymorphism neither by the haplotype relative risk (HRR) method nor by the transmission disequilibrium test (TdT) method. The odds ratio for the DRD4 7-allele was 1.01 and 0.94 for both statistical tests, respectively, and the respective odds ratio for the DAT1 6-allele were 0.91 and 0.88.