Attention deficit hyperactivity disorder: binding of [99mTc]TRODAT-1 to the dopamine transporter before and after methylphenidate treatment

Abstract

Involvement of the dopaminergic system has been suggested in patients suffering from attention deficit hyperactivity disorder (ADHD) since the symptoms can be successfully treated with methylphenidate, a potent blocker of the dopamine transporter (DAT). This study reports the findings on the status of the DAT in adults with ADHD before and after commencement of treatment with methylphenidate, as measured using [99mTc]TRODAT-1. Seventeen patients (seven males, ten females, aged 21-64 years, mean 38 years) were examined before and after the initiation of methylphenidate treatment (3x5 mg/day). All subjects were injected with 800 MBq [99mTc]TRODAT-1 and imaged 3 h p.i. Single-photon emission tomography (SPET) scans were acquired using a triple-headed gamma camera. For semiquantitative evaluation of the DAT, transverse slices corrected for attenuation were used to calculate specific binding in the striatum, with the cerebellum used as background [(STR-BKG)/BKG]. Data were compared with an age-matched control group. It was found that untreated patients presented with a significantly increased specific binding of [99mTc]TRODAT-1 to the DAT as compared with normal controls [(STR-BKG)/BKG: 1.43+/-0.18 vs 1.22+/-0.06, P<0.001]. Under treatment with methylphenidate, specific binding decreased significantly in all patients [(STR-BKG)/BKG: 1.00+/-0.14, P<0.001]. Our findings suggest that the number of DAT binding sites is higher in drug-naive patients suffering from ADHD than in normal controls. The decrease in available DAT binding sites under treatment with methylphenidate correlates well with the improvement in clinical symptoms. The data of this study help to elucidate the complex dysregulation of the dopaminergic neurotransmitter system in patients suffering from ADHD and the effect of treatment with psychoactive drugs.

Atomoxetine Increases Extracellular Levels of Norepinephrine and Dopamine in Prefrontal Cortex of Rat A Potential Mechanism for Efficacy in Attention Deficit/Hyperactivity Disorder

“…Catecholamines, particularly DA, are highly involved in ADHD and enhancement of DA and NE neurotransmission in the PFC by psychostimulants and NE uptake inhibitors may play a pivotal role in the efficacy of these drugs in ADHD (Spencer et al 1995;Biederman and Spencer 1999;Arnsten et al 1996). The observed increase in DA transporters in brains of ADHD patients (Dougherty et al 1999;Krause et al 2000;Dresel et al 2000) presumably results in decreased DA neurotransmission which may be offset by drugs that enhance dopamine neurotransmission. However, DA transporters in ADHD patients have not been shown to be increased in cortical areas due to the difficulty of imaging the low levels of DA transporters in those regions.…”

Association and linkage of allelic variants of the dopamine transporter gene in ADHD

“…8 Several lines of evidence imply that dysregulation in DA transmission, particularly altered DAT1 function, is likely to be involved in the pathophysiology of ADHD: (1) Increased striatal DAT1 density has been found in imaging studies in both adults [9][10][11] and in children with ADHD; 12 however, van Dyck et al 13 did not replicate these findings likely due to a different tracer with less binding specificity for DAT1. (2) Stimulants, effective in the treatment of the core symptoms of ADHD, are known to interact with DAT1; 14 striatal DAT1 availability is lowered effectively in children and adults with ADHD by methylphenidate in clinical doses.…”

“…(2) Stimulants, effective in the treatment of the core symptoms of ADHD, are known to interact with DAT1; 14 striatal DAT1 availability is lowered effectively in children and adults with ADHD by methylphenidate in clinical doses. 9,11 (3) Complete disruption of the DAT1 gene in mice (Dat1-knockout (KO) mice) alters DA tone and signaling and leads to spontaneous locomotor activity in novel environment and lack of locomotor habituation; [15][16][17] furthermore, Dat1-KO mice show deficits in learning, memory and social interactions leading to the hypothesis that Dat1-KO mice represent a model for ADHD. 18,19 The DAT1 gene, encoding 620 amino acids, comprises 15 exons that span more than 52 kb of genomic DNA on human chromosome 5p15.33.…”

Role of Dopamine D4 Receptors in Motor Hyperactivity Induced by Neonatal 6-Hydroxydopamine Lesions in Rats

“…However, the pathophysiology of these models may be dissimilar, and may or may not reflect mechanisms underlying clinical ADHD. Notably, the 6-OHDA lesioning model involves neonatal removal of DA with overgrowth of serotonin projections to forebrain (Kostrzewa et al 1998), whereas the DAT knockout mouse involves a loss of the major mechanism for inactivating DA (Gainedtinov et al 1999)-a mechanism that may be overexpressed in clinical ADHD (Dougherty et al 1999;Dresel et al 2000).…”