Catechol-O-Methyltransferase (COMT) Val 108/158 Metpolymorphism does not modulate executive function in children with ADHD
© Taerk et al; licensee BioMed Central Ltd. 2004
Received: 12 August 2004
Accepted: 21 December 2004
Published: 21 December 2004
An association has been observed between the catechol-O-methyltransferase (COMT) gene, the predominant means of catecholamine catabolism within the prefrontal cortex (PFC), and neuropsychological task performance in healthy and schizophrenic adults. Since several of the cognitive functions typically deficient in children with Attention Deficit Hyperactivity Disorder (ADHD) are mediated by prefrontal dopamine (DA) mechanisms, we investigated the relationship between a functional polymorphism of the COMT gene and neuropsychological task performance in these children.
The Val 108/158 Met polymorphism of the COMT gene was genotyped in 118 children with ADHD (DSM-IV). The Wisconsin Card Sorting Test (WCST), Tower of London (TOL), and Self-Ordered Pointing Task (SOPT) were employed to evaluate executive functions. Neuropsychological task performance was compared across genotype groups using analysis of variance.
ADHD children with the Val/Val, Val/Met and Met/Met genotypes were similar with regard to demographic and clinical characteristics. No genotype effects were observed for WCST standardized perseverative error scores [F2,97 = 0.67; p > 0.05], TOL standardized scores [F2,99 = 0.97; p > 0.05], and SOPT error scores [F2,108 = 0.62; p > 0.05].
Contrary to the observed association between WCST performance and the Val 108/158 Met polymorphism of the COMT gene in both healthy and schizophrenic adults, this polymorphism does not appear to modulate executive functions in children with ADHD.
Attention Deficit Hyperactivity Disorder (ADHD) is a childhood psychiatric disorder characterized by symptoms of inattention, impulsivity and motor hyperactivity afflicting 6–8% of school-aged children in North America [1, 2]. Although ADHD is a disorder with complex and heterogeneous etiology, genetic factors appear to play a significant role in predisposing and perpetuating the development of the disorder as evidenced by twin [3, 4], family [5–7], and adoption studies . Association studies have implicated several susceptibility loci including a 40-base pair (bp) allele of the Variable Number of Tandem Repeats (VNTR) polymorphism of the SLC6A3 gene  and a 48-bp repeat polymorphism of the DRD4 gene . Attempts to replicate these findings have met with modest success possibly owing to the clinical heterogeneity characteristic of the disorder . One method that may act to augment the strength of these associations would be to identify endophenotypic intermediates conferring risk for the development of ADHD rather than attempting to identify direct linkages between genetic variations and the behavioural manifestation of the disorder.
Theories of dysregulated dopamine (DA) pathways in ADHD have been supported by the efficacy of dopamine agonists in reducing the core symptoms of the disorder . The mesocortical DA pathway appears to be integral to prefrontal cortex (PFC)-mediated cognitive functioning, specifically working memory , through the enhancement of task-related neural activity via D1 receptor activation . Both PET  and SPECT  imaging studies support a neuromodulatory role for DA in the PFC during tasks of executive function. In addition, administration of DA agonists to the rat PFC acts to enhance working memory in these animals . Consistent with this line of thinking, children with ADHD show deficits in performance of tasks of executive function [summarized in a meta-analysis by Sergeant et al. (2002)]  and significant improvement of performance under methylphenidate [19, 20]. These findings have prompted the hypothesis that the overt symptoms of ADHD are the manifestation of an underlying deficiency in a range of PFC-mediated cognitive domains, including working memory, planning, and set shifting, collectively regarded as executive function [21–23].
The hypothesized role of a dysfunctional mesocortical dopaminergic pathway in the development of symptoms of ADHD has encouraged the investigation of candidate genes involved in this pathway including SLC6A3 , DRD4  and, more recently, the catechol-O-methyltransferase (COMT) gene . The COMT, encoded by a gene located on chromosome 22q11, catalyzes the degradation of catecholamines, most importantly DA . A functional polymorphism of this gene, involving a substitution of Valine (Val) for Methionine (Met) at codon 108/158 (Val 108/158 Met), results in a 4-fold variation in enzyme activity, with individuals homozygous for either the Val or Met allele exhibiting either reduced or preserved levels of DA respectively . Although the dopamine transporter (DAT) is the predominant means of DA termination in most dopaminergic neurons , considerable evidence exists to suggest that the DAT may play a reduced role within the PFC [28–32], where other clearance mechanisms may be implicated. Comparison of DA metabolite levels within discrete brain loci in both rats  and monkeys , as well as the measurement of DA levels in COMT knock-out mice , suggest an important functional role for COMT in the PFC. If COMT is indeed inextricably linked to DA metabolism within the PFC, it is reasonable to assume that variations in enzyme activity, as dictated by the Val 108/158 Met polymorphism, may modulate the performance of tasks of executive functioning in healthy individuals, as well as individuals with reduced PFC basal dopamine levels. In support of this assumption, associations have been reported between the Val 108/158 Met polymorphism and performance on the Wisconsin Card Sorting Test (WCST) in healthy adults [36, 37]. In adults with Schizophrenia, a disorder characterized by dopaminergic hypofrontality , associations have also been observed between the COMT polymorphism and WCST performance [39–41]. Although one study reported an association between the COMT polymorphism and ADHD using a haplotype relative risk design , this study failed to investigate any indices of executive function and several other studies failed to replicate this finding [3, 42–44].
Given the putative role of COMT in DA metabolism within the PFC [33–35], we hypothesized that the Val 108/158 Met polymorphism of the COMT gene will be associated with alterations in performance on tasks of executive function, a behavioural index of PFC integrity and function . Since dysfunctional DA neurotransmission  and deficient neuropsychological task performance  are both characteristic of children with ADHD, we further hypothesized that this association would be evident within this particular clinical population. Specifically, ADHD children expressing the high enzymatic activity Val allele (H), resulting in reduced PFC DA neurotransmission , will show more pronounced deficits in neuropsychological task performance than their low enzymatic activity Met allele (L) counterparts. In order to test this hypothesis, we used three measures of executive function: the WCST , a measure of set-shifting ability capable of differentiating between ADHD children and controls  and associated with the COMT polymorphism in normal [36, 37] and schizophrenic adults [39–41]; the Tower of London (TOL) , a measure of planning ability, which consistently differentiates ADHD children from controls , and the Self-Ordered Pointing Task (SOPT) , a measure of working memory also capable of differentiating between ADHD children and controls .
118 children were recruited from the Disruptive Behaviour Disorders Program and the children outpatient clinic at the Douglas Hospital. They were referred to these specialized care facilities by school principals, community social workers, and paediatricians.
Inclusion criteria required children to be between the ages of 6 and 12 years of age, meeting DSM-IV diagnosis criteria for ADHD . Diagnosis of ADHD was based on a structured clinical interview of parents using the DISC-IV (parental report) , school reports, teacher interviews, and clinical observation of the child. In the majority of cases, mothers were the primary informants for the collection of clinical information. Written reports from the child's school were also available in the majority of cases. Parents completed the Child Behavioural Checklist (CBCL) , a scale that assesses a variety of behavioural domains, and the Conners' Global Index for parents (CGI-P) . Teachers also completed the Conners' Global Index (CGI-T) . Assessments were made while children were free of medication. Exclusion criteria included a history of mental retardation, with an IQ less than or equal to 70 as measured by the WISC-III , and history of Tourette Syndrome, pervasive developmental disorder, psychosis or any medical condition or impairment that may interfere with the child's ability to complete the study.
A comprehensive neuropsychological test battery assessing different aspects of the central executive functions was administered to all children by trained research personnel. All children were assessed subsequent to a one-week medication "wash-out" period. Children were permitted to take breaks upon request and, in some cases, testing was carried out over two sessions. On average, the testing procedure lasted 1.5 hours. The research protocol was approved by the Research Ethics Board of the Douglas Hospital. Parents were explained the study and provided written consent. Children were also explained the study and gave their assent to participate as well.
Tests were selected according to their ability to tap into various performance domains of executive function. We restricted the number of tests in each domain in order to balance comprehensiveness with the co-operation of patients. Abstraction and concept formation were evaluated by means of the WCST (perseverative errors) . In this task, children are required to sort cards according to three different criteria (colour, number, or shape of signs presented on cards). Feedback on whether the child achieved a correct or incorrect match is given after each trial. The matching criterion changes after ten consecutive correct matches and the child has to identify the new matching criterion using the feedback (correct/incorrect) provided to them. Evidence of the reliability and validity of the WCST with various normal and clinical populations has been reported in several studies . Planning capacity was evaluated using the TOL . This test is used to assess planning and problem solving aspects of executive functioning. The validity and reliability of the TOL has been reported in numerous studies . Standardized administration and scoring procedures as well as normative data have been developed for paediatric populations . Visual Working Memory was evaluated using the abstract version of the SOPT . In this task, series of matrices of 6, 8, 10, and 12 images are presented to the child. The child is asked to select, by pointing, one different image on each page. Errors occur when the child points to images previously selected on the preceding pages. Each set is presented to the child three times. Successful performance on this task involves working memory as well as planning and monitoring skills. Shue & Douglas (1992) have reported significant differences in performance between ADHD children and normal controls on the SOPT .
The Val 108/158 Met polymorphism of the COMT gene was genotyped using a PCR based method as previously described . The PCR was performed in a 25 μl total reaction volume containing 1X PCR buffer, 200 uM dNTPs, 200 ng of primers (5'-GCGATGGTGGCACTCCAAGC; 5'-TTGGAGAGGCTGAGGCTGAC), 1 unit of Taq DNA polymerase, and 100 ng of genomic DNA. PCR products were electrophoresed on agarose-TAE gel along with 1 kb ad 100 bp DNA ladders, visualized under UV-light and coded according to the length of the PCR product. Genotypes were called by two independent and experienced technicians who were blind to all clinical data. No disconcordance in any of the readings was noted. Children were stratified according to genotype only after all neuropsychological task data was collected.
The Val 108/158 Met polymorphism consists of both the low-activity Met (L) and high-activity Val (H) alleles. Subjects were stratified into three groups: two homozygous genotype groups (LL, HH) and one heterozygous genotype group (HL).
A one-way analysis of variance (ANOVA) where genotype (LL, HL, HH) was the independent variable and neuropsychological task performance (standardized WCST perseverative error score, standardized TOL total item score) was the dependent variable was performed. For the SOPT, no normalized scores are available and testing procedures involve several levels of difficulty (4). We therefore used a two-way, repeated measure, mixed design analysis of covariance (ANCOVA), where genotype and level of task difficulty were the between and within subjects independent variables, respectively, neuropsychological task performance (SOPT raw error score) was the dependent variable, and age was the covariate. As the TOL also involves multiple levels of task difficulty (12), we repeated the analysis for this test using the same statistical approach as that applied to the SOPT. A one-way ANCOVA, where genotype was the independent variable and age was the covariate, was performed on all other non-standardized measures of neuropsychological task performance (WCST number of categories completed, WCST number of trials to first category, TOL number of problems solved).
An investigation of linkage and within-family association between quantitative phenotypes (standardized WCST perseverative error score, standardized TOL error score, and SOPT error score) was conducted utilizing the Quantitative Trait Disequilibrium Test (QTDT) statistical software package .
Demographic and clinical characteristics of children with ADHD separated according to COMT genotype
χ2 = 7.39, df = 2 p = 0.02
F2,115 = 0.21, p = 0.81
F2,98 = 0.17, p = 0.84
CBCL (total score)
F2,112 = 0.87, p = 0.42
Income (% less than 20 K)
χ2 = 1.39, df = 2 p = 0.50
DISC-IV Inattention Items
F2,113 = 0.46, p = 0.63
DISC-IV Hyperactivity Items
F2,113 = 0.33, p = 0.72
DISC-IV ADHD Subtype (I/H/C)
χ2 = 5.68, df = 2 p = 0.22
χ2 = 3.21, df = 2 p = 0.20
χ2 = 3.57, df = 2 p = 0.17
χ2 = 1.17, df = 2 p = 0.56
The genotype distribution conformed to a Hardy-Weinberg equilibrium (χ2 = 0.42; df = 2, p = 0.81). 156 parents participated in the study and gave blood samples. Among these parents, 76 were heterozygous (M = 43 and F = 33) and transmitted the Val allele to their affected children in 28 occurrences, whereas this same allele was not transmitted in 29 occurrences [χ2 = 0.02; df = 1, p > 0.05 (transmission disequilibrium)]. Conversely, parents transmitted the Met allele to their affected children in 29 occurrences, whereas this same allele was not transmitted in 28 occurrences [χ2 = 0.02; df = 1, p > 0.05 (transmission disequilibrium)]. In addition, results from the QTDT revealed no evidence of linkage or within-family association between the three quantitative phenotypes and the COMT gene.
Neuropsychological task performance in children with ADHD
F2,97 = 0.67, p = 0.52
F2,99 = 0.97, p = 0.38
F2,108 = 0.62, p = 0.54
Previous studies have identified an association between the COMT polymorphism and a variety of indices reflecting executive control both in healthy [36, 37] and schizophrenic adults [39–41]. The COMT appears to be important to the regulation of dopamine metabolism within the PFC [33–35]. Since the PFC and dopamine pathways have been hypothesized to play an important role in the pathogenesis of ADHD [9–11, 60, 61]), we conducted this study in an attempt to test whether the COMT Val 108/158 Met polymorphism, which is known to be associated with a significant change in the catabolic capacity of this enzyme, modulates the risk for ADHD or various indices of executive control. Contrary to our expectations and findings in both healthy [36, 37] and schizophrenic adults [39–41], an association between the Val 108/158 Met functional polymorphism of the COMT gene and neuropsychological task performance reflecting executive control was not observed in children with ADHD. This result is consistent with the findings of a recent case-control study conducted by Mills et al. (2004), which, to our knowledge, is the only other study to investigate the relationship between the COMT Val 108/158 Met polymorphism and neuropsychological task performance in children with ADHD . However, this study did not include the WCST, the measure responsible for producing the most consistent results in the previous literature. In addition, we did not identify a biased transmission of either of the two alleles from parents to affected offspring.
The absence of an association between the COMT Val 108/158 Met polymorphism and behavioral indices of executive function in children with ADHD may be explained by the young age of the population of patients included in the present study. Indeed it is possible that, due to age-related changes in the functional importance of the COMT within the prefrontal cortex, this association is observable only in adults. This possibility is supported by data in both rats [63–65] and humans [66, 67] suggesting that monoamine content and metabolism decrease with age. This age-related decrease may render functions dependent on monoamine content more prone to be dysfunctional at an older age. In addition, evidence from rat studies has indicated a positive correlation between aging and COMT activity [68–70]. This observation may suggest that the implication of the COMT in the catabolism of dopamine is developmentally regulated, with children relying less on this catabolic pathway than adults. Conversely, it has been reported that DAT density is inversely correlated with age . Taken together, the presence of an inverse and direct correlation between age and DAT density on the one hand and COMT activity on the other hand, may suggest that dopamine metabolism relies more on the DAT than on COMT activity in children compared to adults. This hypothesis is compatible with the fact that several studies have identified an association between the DAT [9, 60, 72–74], but not the COMT, gene and ADHD.
It is also possible that the negative result observed in the present study is due to a type II error (false negative) secondary to the lack of power of our sample to detect an association. However, using results from the WCST, the variable for which relevant genetic data already exists, we conducted a power analysis and determined that our sample size has sufficient power (80% at α = .05) to detect a mean difference of 11.2 on this measure. Furthermore, it is possible that some of the tests used in our assessment are mediated by the PFC but insensitive to PFC DA levels .
An additional limitation of the present study is that some genotype groups included few subjects. Increasing the sample size to achieve larger genotype groups would be necessary to reach firmer conclusions. This is particularly true for female subjects who were significantly underrepresented in the study (as is common to most clinical studies of ADHD). In order to generalize these negative results to females, a more comparable gender representation is required, particularly in view of some previous research indicating that the allelic distribution of the COMT may be gender dependent .
This study does not support the involvement of the Val 108/158 Met polymorphism of the COMT gene in increasing the risk for ADHD or in modulating several indices of executive functions in children with ADHD. This result is contrary to previous findings in both healthy and schizophrenic adults and may be related to developmental specificities.
This work was supported in part by grants from the Fonds de la Recherche en Santé du Québec, Réseau de Santé Mentale du Québec, and the Canadian Institutes of Health Research to RJ and ET. We thank Johanne Bellingham, Anna Polotskaia and Nicole Pawliuk for technical assistance.
- Szatmari P, Offord DR, Boyle MH: Ontario Child Health Study: prevalence of attention deficit disorder with hyperactivity. J Child Psychol Psychiatry. 1989, 30: 219-230.View ArticlePubMedGoogle Scholar
- Barkley RA: Attention-deficit hyperactivity disorder: A handbook for diagnosis and treatment. 1990, New York: GuilfordGoogle Scholar
- Barr CL, Wigg K, Malone M, Schachar R, Tannock R, Roberts W, Kennedy JL: Linkage study of catechol-O-methyltransferase and attention-deficit hyperactivity disorder. Am J Med Genet. 1999, 88: 710-713. 10.1002/(SICI)1096-8628(19991215)88:6<710::AID-AJMG23>3.0.CO;2-Q.View ArticlePubMedGoogle Scholar
- Levy F, Hay DA, McStephen M, Wood C, Waldman I: Attention-deficit hyperactivity disorder: a category or a continuum? Genetic analysis of a large-scale twin study. J Am Acad Child Adolesc Psychiatry. 1997, 36: 737-744. 10.1097/00004583-199706000-00009.View ArticlePubMedGoogle Scholar
- Biederman J, Faraone SV, Keenan K, Benjamin J, Krifcher B, Moore C, Sprich-Buckminster S, Ugaglia K, Jellinek MS, Steingard R: Further evidence for family-genetic risk factors in attention deficit hyperactivity disorder. Patterns of comorbidity in probands and relatives psychiatrically and pediatrically referred samples. Arch Gen Psychiatry. 1992, 49: 728-738.View ArticlePubMedGoogle Scholar
- Faraone SV, Biederman J, Milberger S: An exploratory study of ADHD among second-degree relatives of ADHD children. Biol Psychiatry. 1994, 35: 398-402. 10.1016/0006-3223(94)90006-X.View ArticlePubMedGoogle Scholar
- Hechtman L: Families of children with attention deficit hyperactivity disorder: a review. Can J Psychiatry. 1996, 41: 350-360.PubMedGoogle Scholar
- Cadoret RJ, Stewart MA: An adoption study of attention deficit/hyperactivity/aggression and their relationship to adult antisocial personality. Compr Psychiatry. 1991, 32: 73-82. 10.1016/0010-440X(91)90072-K.View ArticlePubMedGoogle Scholar
- Cook EH, Stein MA, Krasowski MD, Cox NJ, Olkon DM, Kieffer JE, Leventhal BL: Association of attention-deficit disorder and the dopamine transporter gene. Am J Hum Genet. 1995, 56: 993-998.PubMedPubMed CentralGoogle Scholar
- LaHoste GJ, Swanson JM, Wigal SB, Glabe C, Wigal T, King N, Kennedy JL: Dopamine D4 receptor gene polymorphism is associated with attention deficit hyperactivity disorder. Mol Psychiatry. 1996, 1: 121-124.PubMedGoogle Scholar
- Faraone SV, Biederman J, Chen WJ, Milberger S, Warburton R, Tsuang MT: Genetic heterogeneity in attention-deficit hyperactivity disorder (ADHD): gender, psychiatric comorbidity, and maternal ADHD. J Abnorm Psychol. 1995, 104: 334-345. 10.1037//0021-843X.104.2.334.View ArticlePubMedGoogle Scholar
- Arnold LE, Abikoff HB, Cantwell DP, Conners CK, Elliott G, Greenhill LL, Hechtman L, Hinshaw SP, Hoza B, Jensen PS, Kraemer HC, March JS, Newcorn JH, Pelham WE, Richters JE, Schiller E, Severe JB, Swanson JM, Vereen D, Wells KC: National Institute of Mental Health Collaborative Multimodal Treatment Study of Children with ADHD (the MTA). Design challenges and choices. Arch Gen Psychiatry. 1997, 54: 865-870.View ArticlePubMedGoogle Scholar
- Goldman-Rakic PS: The cortical dopamine system: role in memory and cognition. Adv Pharmacol. 1998, 42: 707-711.View ArticlePubMedGoogle Scholar
- Williams GV, Goldman-Rakic PS: Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature. 1995, 376: 572-575. 10.1038/376572a0.View ArticlePubMedGoogle Scholar
- Mattay VS, Berman KF, Ostrem JL, Esposito G, Van Horn JD, Bigelow LB, Weinberger DR: Dextroamphetamine enhances "neural network-specific" physiological signals: a positron-emission tomography rCBF study. J Neurosci. 1996, 16: 4816-4822.PubMedGoogle Scholar
- Daniel DG, Weinberger DR, Jones DW, Zigun JR, Coppola R, Handel S, Bigelow LB, Goldberg TE, Berman KF, Kleinman JE: The effect of amphetamine on regional cerebral blood flow during cognitive activation in schizophrenia. J Neurosci. 1991, 11: 1907-1917.PubMedGoogle Scholar
- Floresco SB, Phillips AG: Delay-dependent modulation of memory retrieval by infusion of a dopamine D1 agonist into the rat medial prefrontal cortex. Behav Neurosci. 2001, 115: 934-939. 10.1037//0735-7044.115.4.934.View ArticlePubMedGoogle Scholar
- Sergeant JA, Geurts H, Oosterlaan J: How specific is a deficit of executive functioning for attention-deficit/hyperactivity disorder?. Behav Brain Res. 2002, 130: 3-28. 10.1016/S0166-4328(01)00430-2.View ArticlePubMedGoogle Scholar
- Douglas VI, Barr RG, O'Neill ME, Britton BG: Short term effects of methylphenidate on the cognitive, learning and academic performance of children with attention deficit disorder in the laboratory and the classroom. J Child Psychol Psychiatry. 1986, 27: 191-211.PubMedGoogle Scholar
- Berman T, Douglas VI, Barr RG: Effects of methylphenidate on complex cognitive processing in attention-deficit hyperactivity disorder. J Abnorm Psychol. 1999, 108: 90-105. 10.1037//0021-843X.108.1.90.View ArticlePubMedGoogle Scholar
- Barkley RA: Behavioral inhibition, sustained attention, and executive functions: constructing a unifying theory of ADHD. Psychol Bull. 1997, 121: 65-94. 10.1037//0033-2909.121.1.65.View ArticlePubMedGoogle Scholar
- Tannock R: Attention deficit hyperactivity disorder: advances in cognitive, neurobiological, and genetic research. J Child Psychol Psychiatry. 1998, 39: 65-99. 10.1017/S0021963097001777.View ArticlePubMedGoogle Scholar
- Douglas VI: Cognitive deficits in children with attention-deficit disorder with hyperactivity. In Attention deficit disorder: criteria, cognition, intervention. Edited by: Bloomingdale LM, Sergeant JA. 1988, London: Pergamon, 65-82.Google Scholar
- Eisenberg J, Mei-Tal G, Steinberg A, Tartakovsky E, Zohar A, Gritsenko I, Nemanov L, Ebstein RP: Haplotype relative risk study of catechol-O-methyltransferase (COMT) and attention deficit hyperactivity disorder (ADHD): association of the high-enzyme activity Val allele with ADHD impulsive-hyperactive phenotype. Am J Med Genet. 1999, 88: 497-502.View ArticlePubMedGoogle Scholar
- Weinshilboum RM, Otterness DM, Szumlanski CL: Methylation pharmacogenetics: catechol O-methyltransferase, thiopurine methyltransferase, and histamine N-methyltransferase. Annu Rev Pharmacol Toxicol. 1999, 39: 19-52. 10.1146/annurev.pharmtox.39.1.19.View ArticlePubMedGoogle Scholar
- Lachman HM, Papolos DF, Saito T, Yu YM, Szumlanski CL, Weinshilboum RM: Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics. 1996, 6: 243-250.View ArticlePubMedGoogle Scholar
- Giros B, Jaber M, Jones SR, Wightman RM, Caron MG: Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature. 1996, 379: 606-612. 10.1038/379606a0.View ArticlePubMedGoogle Scholar
- Sesack SR, Hawrylak VA, Guido MA, Levey AI: Cellular and subcellular localization of the dopamine transporter in rat cortex. Adv Pharmacol. 1998, 42: 171-174.View ArticlePubMedGoogle Scholar
- Lewis DA, Melchitzky DS, Sesack SR, Whitehead RE, Auh S, Sampson A: Dopamine transporter immunoreactivity in monkey cerebral cortex: regional, laminar, and ultrastructural localization. J Comp Neurol. 2001, 432: 119-136. 10.1002/cne.1092.View ArticlePubMedGoogle Scholar
- Dougherty DD, Bonab AA, Spencer TJ, Rauch SL, Madras BK, Fischman AJ: Dopamine transporter density in patients with attention deficit hyperactivity disorder. Lancet. 1999, 354: 2132-2133. 10.1016/S0140-6736(99)04030-1.View ArticlePubMedGoogle Scholar
- Moron JA, Brockington A, Wise RA, Rocha BA, Hope BT: Dopamine uptake through the norepinephrine transporter in brain regions with low levels of the dopamine transporter: evidence from knock-out mouse lines. J Neurosci. 2002, 22: 389-395.PubMedGoogle Scholar
- Wayment HK, Schenk JO, Sorg BA: Characterization of extracellular dopamine clearance in the medial prefrontal cortex: role of monoamine uptake and monoamine oxidase inhibition. J Neurosci. 2001, 21: 35-44.PubMedGoogle Scholar
- Karoum F, Chrapusta SJ, Egan MF: 3-Methoxytyramine is the major metabolite of released dopamine in the rat frontal cortex: reassessment of the effects of antipsychotics on the dynamics of dopamine release and metabolism in the frontal cortex, nucleus accumbens, and striatum by a simple two pool model. J Neurochem. 1994, 63: 972-979.View ArticlePubMedGoogle Scholar
- Elsworth JD, Leahy DJ, Roth RH, Redmond DE: Homovanillic acid concentrations in brain, CSF and plasma as indicators of central dopamine function in primates. J Neural Transm. 1987, 68: 51-62.View ArticlePubMedGoogle Scholar
- Gogos JA, Morgan M, Luine V, Santha M, Ogawa S, Pfaff D, Karayiorgou M: Catechol-O-methyltransferase-deficient mice exhibit sexually dimorphic changes in catecholamine levels and behavior. Proc Natl Acad Sci U S A. 1998, 95: 9991-9996. 10.1073/pnas.95.17.9991.View ArticlePubMedPubMed CentralGoogle Scholar
- Malhotra AK, Kestler LJ, Mazzanti C, Bates JA, Goldberg T, Goldman D: A functional polymorphism in the COMT gene and performance on a test of prefrontal cognition. Am J Psychiatry. 2002, 159: 652-654. 10.1176/appi.ajp.159.4.652.View ArticlePubMedGoogle Scholar
- Mattay VS, Goldberg TE, Fera F, Hariri AR, Tessitore A, Egan MF, Kolachana B, Callicott JH, Weinberger DR: Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine. Proc Natl Acad Sci U S A. 2003, 100: 6186-6191. 10.1073/pnas.0931309100.View ArticlePubMedPubMed CentralGoogle Scholar
- Weinberger DR, Berman KF: Speculation on the meaning of cerebral metabolic hypofrontality in schizophrenia. Schizophr Bull. 1988, 14: 157-168.View ArticlePubMedGoogle Scholar
- Egan MF, Goldberg TE, Kolachana BS, Callicott JH, Mazzanti CM, Straub RE, Goldman D, Weinberger DR: Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci U S A. 2001, 98: 6917-6922. 10.1073/pnas.111134598.View ArticlePubMedPubMed CentralGoogle Scholar
- Joober R, Gauthier J, Lal S, Bloom D, Lalonde P, Rouleau G, Benkelfat C, Labelle A: Catechol-O-methyltransferase Val-108/158-Met gene variants associated with performance on the Wisconsin Card Sorting Test. Arch Gen Psychiatry. 2002, 59: 662-663. 10.1001/archpsyc.59.7.662.View ArticlePubMedGoogle Scholar
- Bilder RM, Volavka J, Czobor P, Malhotra AK, Kennedy JL, Ni X, Goldman RS, Hoptman MJ, Sheitman B, Lindenmayer JP, Citrome L, McEvoy JP, Kunz M, Chakos M, Cooper TB, Lieberman JA: Neurocognitive correlates of the COMT Val(158)Met polymorphism in chronic schizophrenia. Biol Psychiatry. 2002, 52: 701-707. 10.1016/S0006-3223(02)01416-6.View ArticlePubMedGoogle Scholar
- Payton A, Holmes J, Barrett JH, Hever T, Fitzpatrick H, Trumper AL, Harrington R, McGuffin P, O'Donovan M, Owen M, Ollier W, Worthington J, Thapar A: Examining for association between candidate gene polymorphisms in the dopamine pathway and attention-deficit hyperactivity disorder: a family-based study. Am J Med Genet. 2001, 105: 464-470. 10.1002/ajmg.1407.View ArticlePubMedGoogle Scholar
- Tahir E, Yazgan Y, Cirakoglu B, Ozbay F, Waldman I, Asherson PJ: Association and linkage of DRD4 and DRD5 with attention deficit hyperactivity disorder (ADHD) in a sample of Turkish children. Mol Psychiatry. 2000, 5: 396-404. 10.1038/sj.mp.4000744.View ArticlePubMedGoogle Scholar
- Kirley A, Hawi Z, Daly G, McCarron M, Mullins C, Millar N, Waldman I, Fitzgerald M, Gill M: Dopaminergic system genes in ADHD: toward a biological hypothesis. Neuropsychopharmacology. 2002, 27: 607-619.PubMedGoogle Scholar
- Weinberger DR: A connectionist approach to the prefrontal cortex. J Neuropsychiatry Clin Neurosci. 1993, 5: 241-253.View ArticlePubMedGoogle Scholar
- Elia J, Gulotta C, Rose SR, Marin G, Rapoport JL: Thyroid function and attention-deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 1994, 33: 169-172.View ArticlePubMedGoogle Scholar
- Grant DA, Berg EAA: A behavioral analysis of degree of reinforcement and ease of shifting to new responses in a Weigel-type card-sorting problem. Journal of Experimental Psychology. 1948, 38: 404-411.View ArticlePubMedGoogle Scholar
- Shallice T: Specific impairments of planning. Philos Trans R Soc Lond B Biol Sci. 1982, 298: 199-209.View ArticlePubMedGoogle Scholar
- Petrides M, Milner B: Deficits on subject-ordered tasks after frontal- and temporal-lobe lesions in man. Neuropsychologia. 1982, 20: 249-262. 10.1016/0028-3932(82)90100-2.View ArticlePubMedGoogle Scholar
- Lahey BB, Applegate B, McBurnett K, Biederman J, Greenhill L, Hynd GW, Barkley RA, Newcorn J, Jensen P, Richters J: DSM-IV field trials for attention deficit hyperactivity disorder in children and adolescents. Am J Psychiatry. 1994, 151: 1673-1685.View ArticlePubMedGoogle Scholar
- National Institute of Mental Health: NIMH DISC-IV. 1998, Joy and William Ruane Center to Identify and Treat Mood Disorders: Columbia UniversityGoogle Scholar
- Achenbach TM: The child behavior checklist/4–18 and 1991 profile. 1991, Burlington, Vermont, University of VermontGoogle Scholar
- Conners CK: Conners' Global Index-Parents. 2003. 1997, North Noranda, NY, Multihealth Systems IncGoogle Scholar
- Conners CK: Conners' Global Index-Teacher. 2003. 1997, North Noranda, NY, Multihealth Systems IncGoogle Scholar
- Wechsler D: Wechsler Intelligence Scale for Children-Third Edition: Manual. 1991, San Antonio, TX: Psychological CorporationGoogle Scholar
- Krikorian R, Bartok J, Gay N: Tower of London procedure: a standard method and developmental data. J Clin Exp Neuropsychol. 1994, 16: 840-850.View ArticlePubMedGoogle Scholar
- Shue KL, Douglas VI: Attention deficit hyperactivity disorder and the frontal lobe syndrome. Brain Cogn. 1992, 20: 104-124. 10.1016/0278-2626(92)90064-S.View ArticlePubMedGoogle Scholar
- Abecasis GR, Cardon LR, Cookson WO: A general test of association for quantitative traits in nuclear families. Am J Hum Genet. 2000, 66: 279-292. 10.1086/302698.View ArticlePubMedGoogle Scholar
- Qian Q, Wang Y, Zhou R, Li J, Wang B, Glatt S, Faraone SV: Family-based and case-control association studies of catechol-O-methyltransferase in attention deficit hyperactivity disorder suggest genetic sexual dimorphism. Am J Med Genet. 2003, 118B: 103-109. 10.1002/ajmg.b.10064.View ArticlePubMedGoogle Scholar
- Barr CL, Xu C, Kroft J, Feng Y, Wigg K, Zai G, Tannock R, Schachar R, Malone M, Roberts W, Nothen MM, Grunhage F, Vandenbergh DJ, Uhl G, Sunohara G, King N, Kennedy JL: Haplotype study of three polymorphisms at the dopamine transporter locus confirm linkage to attention-deficit/hyperactivity disorder. Biol Psychiatry. 2001, 49: 333-339. 10.1016/S0006-3223(00)01053-2.View ArticlePubMedGoogle Scholar
- Faraone SV, Biederman J: Pathophysiology of attention-deficit hyperactivity disorder. In ACNP's fifth generation of progress-version 2. Edited by: Davis K, Charney D, Coyle JT, Nemeroff C. 2002, New York: Lipponcott, Williams, WilkensGoogle Scholar
- Mills S, Langley K, Van den Bree M, Street E, Turic D, Owen MJ, O'Donovan MC, Thapar A: No evidence of association between Catechol-O-Methyltransferase (COMT) Val158Met genotype and performance on neuropsychological tasks in children with ADHD: a case-control study. BMC Psychiatry. 2004, 4: 15-10.1186/1471-244X-4-15.View ArticlePubMedPubMed CentralGoogle Scholar
- Demarest KT, Riegle GD, Moore KE: Characteristics of dopaminergic neurons in the aged male rat. Neuroendocrinology. 1980, 31: 222-227.View ArticlePubMedGoogle Scholar
- Estes KS, Simpkins JW: Age-related alterations in catecholamine concentrations in discrete preoptic area and hypothalamic regions in the male rat. Brain Res. 1980, 194: 556-560. 10.1016/0006-8993(80)91241-X.View ArticlePubMedGoogle Scholar
- Lee JJ, Chang CK, Liu IM, Chi TC, Yu HJ, Cheng JT: Changes in endogenous monoamines in aged rats. Clin Exp Pharmacol Physiol. 2001, 28: 285-289. 10.1046/j.1440-1681.2001.03439.x.View ArticlePubMedGoogle Scholar
- Carlsson A, Winblad B: Influence of age and time interval between death and autopsy on dopamine and 3-methoxytyramine levels in human basal ganglia. J Neural Transm. 1976, 38: 271-276.View ArticlePubMedGoogle Scholar
- Riederer P, Wuketich S: Time course of nigrostriatal degeneration in parkinson's disease. A detailed study of influential factors in human brain amine analysis. J Neural Transm. 1976, 38: 277-301.View ArticlePubMedGoogle Scholar
- Stramentinoli G, Gualano M, Algeri S, de Gaetano G, Rossi EC: Catechol-o-methyl transferase (COMT) in human and rat platelets. Thromb Haemost. 1978, 39: 238-239.PubMedGoogle Scholar
- Venero JL, Machado A, Cano J: Turnover of dopamine and serotonin and their metabolites in the striatum of aged rats. J Neurochem. 1991, 56: 1940-1948.View ArticlePubMedGoogle Scholar
- Galva MD, Bondiolotti GP, Olasmaa M, Picotti GB: Effect of aging on lazabemide binding, monoamine oxidase activity and monoamine metabolites in human frontal cortex. J Neural Transm Gen Sect. 1995, 101: 83-94.View ArticlePubMedGoogle Scholar
- Meng SZ, Ozawa Y, Itoh M, Takashima S: Developmental and age-related changes of dopamine transporter, and dopamine D1 and D2 receptors in human basal ganglia. Brain Res. 1999, 843: 136-144. 10.1016/S0006-8993(99)01933-2.View ArticlePubMedGoogle Scholar
- Gill M, Daly G, Heron S, Hawi Z, Fitzgerald M: Confirmation of association between attention deficit hyperactivity disorder and a dopamine transporter polymorphism. Mol Psychiatry. 1997, 2: 311-313. 10.1038/sj.mp.4000290.View ArticlePubMedGoogle Scholar
- Roman T, Schmitz M, Polanczyk G, Eizirik M, Rohde LA, Hutz MH: Attention-deficit hyperactivity disorder: a study of association with both the dopamine transporter gene and the dopamine D4 receptor gene. Am J Med Genet. 2001, 105: 471-478. 10.1002/ajmg.1408.View ArticlePubMedGoogle Scholar
- Rowe DC, Stever C, Chase D, Sherman S, Abramowitz A, Waldman ID: Two dopamine genes related to reports of childhood retrospective inattention and conduct disorder symptoms. Mol Psychiatry. 2001, 6: 429-433. 10.1038/sj.mp.4000874.View ArticlePubMedGoogle Scholar
- Collins P, Roberts AC, Dias R, Everitt BJ, Robbins TW: Perseveration and strategy in a novel spatial self-ordered sequencing task for nonhuman primates: effects of excitotoxic lesions and dopamine depletions of the prefrontal cortex. J Cogn Neurosci. 1998, 10: 332-354. 10.1162/089892998562771.View ArticlePubMedGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2350/5/30/prepub
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