A. Objective

Attention deficit hyperactivity disorder (ADHD) is a heritable neurodevelopmental disorder with a reported male predominance that persists into adulthood and leads to significant morbidity in affected individuals. ADHD is currently hypothesized to reflect central dopaminergic dysfunction. Evaluation of human dopaminergic dysfunction using in vivo neuroimaging has been limited to studies of receptor localization and quantification, and dopamine synthesis, rather than direct measurement of the functional status of receptor signaling. There exists a need to thoroughly elucidate mechanisms underlying aberrant dopaminergic neurotransmission downstream of receptor activation in signaling processes. We have developed an in vivo method to measure neuroreceptor-initiated signal transduction involving activation of phospholipase A(2) to release the second messenger, arachidonic acid (AA). We propose to use positron emission tomography (PET) to quantitatively image dopamine-initiated signal transduction via AA in ADHD patients and healthy volunteers, in subjects administered the dopaminergic agonist, apomorphine, and to measure regional cerebral blood flow (rCBF) as well. We hypothesize that signaling and flow responses to apomorphine will be elevated, demonstrating hypersensitivity of the dopamine signaling mechanism.

B. Study population

30 male patients with a clinical diagnosis of attention deficit hyperactivity disorder (ADHD) and 36 age matched healthy volunteers, will be recruited for this study (see justification for recruitment of males only in Study Design and Methods).

C. Design

All subjects will have up to four study-related visits to the Clinical Center in Bethesda over a one-year period, including an overnight stay. Participants will also be asked to complete an initial comprehensive telephone questionnaire to elicit whether they meet criteria for study participation, followed by on-site visits to NIH to complete a modified battery of neuropsychiatric screening tests related to symptom presence and severity. Questions relating to medical, family, psychiatric and developmental histories and lifestyle will be asked. In addition, visits will include a physical exam as well as blood and urine collection, and structural magnetic resonance imaging (MRI) of the head. Subject participation will culminate with sequential subcutaneous administration of a single dose of control vehicle solution (control) followed by the dopamine agonist apomorphine (after appropriate pre-medication with the anti-emetic, trimethobenzamide) or two sequential injections of vehicle for PET scans with attendant radiolabeled compounds.

D. Outcome Parameters

This study has four specific aims. First, regional cerebral blood flow will be quantified in response to an acute challenge with apomorphine s.c. and compared between study groups (ADHD/non-ADHD). Second, dopamine D(2)-like receptor signal transduction will be evaluated by PET in response to an acute challenge with apomorphine s.c. and compared between study groups (ADHD/non-ADHD). Third, baseline esterified and unesterified serum fatty acids will be compared between patients and control subjects. Lastly, we will examine the acute effect of apomorphine in the stimulation of serum growth hormone in all subjects, as confirmatory evidence for stimulation of central dopaminergic receptors.