Mechanism of action of methylphenidate: Insights from PET imaging studies

Nd, Volkow; Js, Fowler; Wang, G; Ding, Yu‐Shin; Gatley, S.J.

doi:10.1177/070674370200601s05

Cited by 311 publications

(217 citation statements)

References 38 publications

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“…As mentioned above, DAT is primarily responsible for presynaptic reuptake of dopamine, and it has been shown that MPH blocks DAT and increases extracellular dopamine (Spencer et al, 2005;Swanson et al, 2007;Volkow et al, 2002Volkow et al, , 2005Volkow et al, , 2007. Although initial reports found large (up to 70%) increases in striatal DAT in ADHD (Dougherty et al, 1999; Krause ADHD and attention networks G Bush al, 2000), subsequent reports using different ligands and techniques have found lesser effect sizes, and in some cases, even lower DAT in ADHD .…”

Section: Functional Studies: Pet and Fmrimentioning

confidence: 99%

Attention-Deficit/Hyperactivity Disorder and Attention Networks

Bush

2009

Neuropsychopharmacol

297

253

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Research attempting to elucidate the neuropathophysiology of attention-deficit/hyperactivity disorder (ADHD) has not only shed light on the disorder itself, it has simultaneously provided new insights into the mechanisms of normal cognition and attention. This review will highlight and integrate this bidirectional flow of information. Following a brief overview of ADHD clinical phenomenology, ADHD studies will be placed into a wider historical perspective by providing illustrative examples of how major models of attention have influenced the development of neurocircuitry models of ADHD. The review will then identify major components of neural systems potentially relevant to ADHD, including attention networks, reward/feedbackbased processing systems, as well as a 'default mode' resting state network. Further, it will suggest ways in which these systems may interact and be influenced by neuromodulatory factors. Recent ADHD imaging data will be selectively provided to both illustrate the field's current level of knowledge and to show how such data can inform our understanding of normal brain functions. The review will conclude by suggesting possible avenues for future research.

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Section: Functional Studies: Pet and Fmrimentioning

confidence: 99%

Attention-Deficit/Hyperactivity Disorder and Attention Networks

Bush

2009

Neuropsychopharmacol

297

253

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“…Stimulant medications bind to the DAT, inhibiting reuptake and increasing synaptic dopamine (Volkow et al, 2002). The DAT gene (DAT1) was initially investigated as a primary candidate gene for ADHD susceptibility.…”

Section: Introductionmentioning

confidence: 99%

Dopamine Transporter Genotype and Methylphenidate Dose Response in Children with ADHD

Stein

Waldman

Sarampote

et al. 2005

Neuropsychopharmacol

130

117

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Stimulant medications, such as methylphenidate (MPH), are the most commonly used, effective treatment for ADHD. MPH acts primarily by inhibiting the dopamine transporter (DAT), a protein responsible for the reuptake of dopamine from the synapse into presynaptic terminals. We sought to evaluate the relationship between DAT1 3 0 -untranslated region (3 0 -UTR) variable number tandem repeats (VNTR) genotypes and dose response to MPH. Children with ADHD (n ¼ 47), ages 5-16 years (mean ¼ 9.02 years), underwent a 4-week, double-blinded, crossover trial with forced weekly dosage changes. Children were genotyped for the DAT1 VNTR and evaluated on placebo and three dosage levels of OROS s MPH. Parents and clinicians who were blind to genotype and medication status rated ADHD symptoms, impairment, and stimulant side effects each week. Children who were homozygous for the less common, 9-repeat DAT1 3 0 -UTR genotype displayed a distinct dose-response curve from that of the other genotype groups, with an absence of typical linear improvement when the dose was increased from 18 mg to 36 and 54 mg. Further research is needed to determine the mechanisms related to poor response in patients with the 9/9-repeat genotype, and to determine if this group responds differentially to alternative treatments.

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“…28 In addition, the DAT1 10R has been associated with poor response to methylphenidate (MPH) in ADHD. 29,30 MPH has been shown to block the dopamine transporter in vivo, 31,32 and may therefore be more effective in those individuals who have more in vivo availability of the transporter.…”

mentioning

confidence: 99%

Differential effects of DRD4 and DAT1 genotype on fronto-striatal gray matter volumes in a sample of subjects with attention deficit hyperactivity disorder, their unaffected siblings, and controls

et al. 2005

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Genetic influences on behavior are complex and, as such, the effect of any single gene is likely to be modest. Neuroimaging measures may serve as a biological intermediate phenotype to investigate the effect of genes on human behavior. In particular, it is possible to constrain investigations by prior knowledge of gene characteristics and by including samples of subjects where the distribution of phenotypic variance is both wide and under heritable influences. Here, we use this approach to show a dissociation between the effects of two dopamine genes that are differentially expressed in the brain. We show that the DAT1 gene, a gene expressed predominantly in the basal ganglia, preferentially influences caudate volume, whereas the DRD4 gene, a gene expressed predominantly in the prefrontal cortex, preferentially influences prefrontal gray matter volume in a sample of subjects including subjects with ADHD, their unaffected siblings, and healthy controls. This demonstrates that, by constraining our investigations by prior knowledge of gene expression, including samples in which the distribution of phenotypic variance is wide and under heritable influences, and by using intermediate phenotypes, such as neuroimaging, we may begin to map out the pathways by which genes influence behavior. Investigators interested in the effect of genes on behavior face a challenge in that behavior is complex, and is likely affected by multiple genes, as well as gene-gene and gene-environment interactions. As such, the effect of any single gene on behavior is probably only small. Indeed, studies investigating the effect of genotype on behavior have reported modest associations. For example, Fossella et al 1 described the influence of four genes related to dopamine function on measures of executive attention and report small effect sizes. Furthermore, their effects were subtle in that not all aspects of executive attention were affected and that genes had differential effects. 1

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Mechanism of action of methylphenidate: Insights from PET imaging studies

Cited by 311 publications

References 38 publications

Attention-Deficit/Hyperactivity Disorder and Attention Networks

Attention-Deficit/Hyperactivity Disorder and Attention Networks

Dopamine Transporter Genotype and Methylphenidate Dose Response in Children with ADHD

Differential effects of DRD4 and DAT1 genotype on fronto-striatal gray matter volumes in a sample of subjects with attention deficit hyperactivity disorder, their unaffected siblings, and controls

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