Dopaminergic dysfunction in attention deficit hyperactivity disorder (ADHD), differences between pharmacologically treated and never treated young adults: A 3,4-dihdroxy-6-[18F]fluorophenyl-l-alanine PET study
Introduction
Attention deficit hyperactivity disorder (ADHD), the most frequently diagnosed psychiatric disorder in childhood, was considered a rare phenomenon in adulthood. Today, the prevalence is estimated to be 1–5% (Kessler et al., 2006). The pathophysiology of this disorder still remains unclear. Neuroimaging data indicate that the dopaminergic system, especially variations in the density of presynaptic dopamine transporter (DAT) and postsynaptic dopamine (DA) receptors play a role in the pathogenesis of ADHD (Dougherty et al., 1999, Krause et al., 2000, Lou et al., 2004). It is likely that presynaptic DA metabolism, as measured by the radiolabelled dopamine precursor 3,4-dihdroxy-6-[18F]fluorophenyl-l-alanine (FDOPA), is also involved (Ernst et al., 1998, Ernst et al., 1999).
While the efficacy of methylphenidate (MP), a DAT inhibitor, is not in question, there is preclinical evidence that early MP treatment may have long-term effects on DA metabolism (Brandon et al., 2003). We therefore evaluated the data of this FDOPA PET study with regard to previous treatment. Two groups of ADHD patients were studied in a cross-over design: one group treated in childhood and/or adolescence with MP and one untreated group of ADHD patients. We envisaged that DA turnover rate would be different between untreated and treated ADHD patients compared to controls, but we did not specify the direction of the difference. Major differences were expected in the striatum the region with the highest dopamine decarboxylase activity and the highest DAT density, however, in a volume of interest analysis we did not restrict our analysis to the striatum and in a second approach we employed a whole-brain analysis with the option to investigate possible alterations in every part of the dopaminergic system.
Section snippets
Participants
The study protocol was approved by the local Institutional Review Board (Ethics Committee) of the University of Ulm, and legal authorities. After complete description of the study to the participating ADHD patients and healthy control subjects, written informed consent was obtained. Twenty-one male patients with ADHD participated in the study. Data sets of 20 were included in the analysis. One untreated ADHD patient was not able to stay in the scanner for the required 90min and the scan had to
Results
The data obtained in this study are presented in two parts, an analysis of the VOI in the striatum and extrastriatal areas and a comparison of the two different patient groups with the healthy control group using SPM2.
Discussion
This whole brain FDOPA-PET study further confirms a dopamine dysfunction in young adult ADHD patients. MP treatment seems to specifically and significantly down regulate FDOPA influx in all studied regions behalf the caudate nucleus where the influx was comparable with regard to the healthy control group or the untreated subjects. This makes an unspecific withdrawal effect of MP unlikely, since a similar effect in all regions should have been expected. The statistic parametric mapping analysis
Conclusions
The present data confirm a dysregulated dopamine metabolism in young male adults with ADHD. The mesolimbic, mesocortical and nigrostriatal tracts of the dopaminergic system seem to be affected. Furthermore the data suggest that MP treatment could lead to a reduced turnover rate in the dopaminergic system. The blockade of the DAT, enhancement of the tonic dopamine level in the synaptic cleft and probably the consecutive stimulation of the autoreceptors on the presynaptic dopaminergic neuron seem
Acknowledgments
This study was supported by an unrestricted research grant from UCB, Kerpen, Germany. We thank Dr Sabine Krämer, MD, Frankfurt, and Dr Dieter Claus, MD, Wiesbaden, for informing their ADHD patients about this study. Special thanks go to the medical students Miriam Lange and Felicitas Neumann for taking care of the patients and healthy subjects. Further thank goes to the staff and technicians of the Department of Nuclear Medicine, Ulm without them the realization of the study would not have been
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