Attention-deficit hyperactivity disorder (ADHD) is the most frequent psychiatric disease in children affecting about 3 million children in the USA. Yet we know very little about the pathophysiology of the disease or of the effects of chronic treatment with psychostimulant drugs (which have been used for ADHD for more than 40 years) in the human brain. This places a sense of urgency on identifying the neurochemical changes occurring in ADHD and their response to treatment. There is mounting evidence that brain dopamine (DA) dysfunction is involved in ADHD and that psychostimulant-induced elevations in brain DA are involved in its treatment. Here we hypothesize that ADHD subjects have a deficit in DA cell function, which results in too little extracellular DA and leads to synaptic adaptations (decreases in DA transporters (DAT) that remove synaptic DA) to compensate for this deficit. We also postulate that while acute treatment temporarily compensates for this deficit, chronic treatment could further exacerbate the DA changes. We propose to test these hypotheses in never-medicated adults with ADHD. We will use positron emission tomography (PET) to measure DAT using [11C]cocaine (DAT radioligand) and to assess DA cell function using the dopamine D2 receptor radioligand [11C]raclopride with and without a challenge dose of methylphenidate (drug that increases DA by blocking DAT). We propose to test ADHD subjects (n = 35) at baseline and after 12-14 months treatment with psychostimulant medication. Normal controls (n = 35) will be similarly evaluated and will be retested 12-14 months later to assess reproducibility. The working hypotheses for this proposal are: (1) Never-medicated ADHD subjects will have lower than normal function of DA cells (seen as decreased extracellular DA) and a compensatory reduction in DAT. (2) Chronic treatment of ADHD subjects with psychostimulant medication, which increase extracellular DA, will result in an increase of DAT and reductions in extracellular DA (when tested off medication). Despite the high prevalence of ADHD and its multiplicity of adverse consequence, the diagnosis of ADHD has remained controversial. This controversy is driven by a lack of understanding of the biological basis of the disorder and the fact that the most frequently used medications in the treatment of ADHD (methylphenidate and amphetamine), have reinforcing effects and can be diverted for drug abuse. After a half-century of clinical recognition and treatment of ADHD, a better understanding of the neurochemistry underlying this disease and the potential effects that chronic stimulant treatment may have on the human brain is long overdue.
