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The negative correlation accounted for about half of the overall variance across studies. This suggests that the higher striatal dopamine transporter density in ADHD may be the consequence of previous treatment with stimulants and hence be the result of an adaptive response of the brain to the continuous dopamine transporter blockade with psychostimulants. This suggests that a high dopamine transporter level is not part of the key ADHD pathophysiology but is secondary to years of psychostimulant treatment and reflects an adaptive brain response to the long-term blockade of dopamine transporters by psychostimulants. This notion of an adaptation to psychostimulants is in line with the finding that methylphenidate is effective in improving clinical symptoms of ADHD in the short term but that long-term effectiveness is limited; larger doses are often required to maintain clinical effectiveness, and clinical effectiveness appears to wane after years of medication

Enhanced striatal dopamine transporter density in patients receiving long-term treatment, however, could reflect a secondary adaptive brain response to the chronic striatal dopamine transporter blockade, i.e., adjustment to chronically elevated striatal dopamine availability through up-regulation of dopamine transporter levels. There is evidence in favor of this theory from a small prospective study, which showed that after 1 year of stimulant medication the striatal dopamine transporter levels of ADHD patients in fact increased (47). Furthermore, there is evidence indicating that cocaine—which is a stimulant drug that, like methylphenidate, blocks dopamine transporters— not only blocks the acute regulatory effect of the dopamine transporter on synaptic dopamine levels but also may exert the opposite effect: insertion of dopamine transporters from the endosomic recycling pool into the plasma membrane

High dopamine transporter expression has also been shown in postmortem analyses of brain tissue from human cocaine addicts, and synaptosomes prepared from this tissue exhibit greater dopamine uptake than synaptosomes from age-matched cocaine-naive individuals

Methylphenidate-associated changes have also been observed in brain function and structure. Functional MRI studies in patients with ADHD have shown that single and long-term doses of methylphenidate up-regulate and normalize typically low frontostriatal brain activation (49–54). Because striatal dopamine transporters are located exclusively on dopamine-synthesizing neurons, their measurement is a specific marker of dopaminergic neuron integrity in the basal ganglia. The notion of adaptive brain changes

in response to long-term psychostimulant treatment is also in line with the results of several structural imaging studies showing that patients with ADHD receiving long-term medication have more normal structure and morphometry in the basal ganglia than medication-naive patients (55, 56). These findings are further confirmed by a recent metaanalysis of whole-brain structural imaging studies, which showed that the lower basal ganglia gray matter volume in ADHD patients, relative to that in comparison subjects, is dependent on long-term medication (9). The percentage of patients receiving long-term medication was linearly associated with basal ganglia size, such that studies in which more than 70% of the patients were medicated did not show striatal abnormalities, while the greatest deficits were observed in studies of medication-naive patients.

It is, however, also possible that lower dopamine transporter density and lower dopamine release in medication- naive ADHD patients reflect prefrontal pathology, well demonstrated in neuroimaging results for ADHD (5), since frontostriatal glutamatergic circuits regulate striatal dopamine release.

The meta-analysis and meta-regression analysis show that striatal dopamine transporter levels in ADHD depend on chronic psychostimulant treatment, so that medication- naive patients have low striatal dopamine transporter levels, whereas patients receiving long-term medication have high levels. Consequently, the previously reported high dopamine transporter density in ADHD patients may potentially represent up-regulation secondary to chronic administration of psychostimulants, rather than primary pathophysiology of ADHD. Future prospective studies using randomized controlled trials in large groups of drugnaive individuals with ADHD will be needed to definitively clarify the long-term effect of psychostimulants on striatal dopaminergic neurotransmission.