The long-term goal of this proposal is to examine the molecular basis by which the coding variant Ala559Val (A559V), present in the hDAT gene in children with attention deficit hyperactive disorder (ADHD), contributes to the ADHD phenotype. Since ADHD has been linked to hyperactivity of the dopaminergic system, the hypothesis is that the hDAT coding variant A559V mediates changes in the sensitivity of hDAT for intracellular signals that are involved in reverse transport of DA. These changes may promote a state of DAT that would result in increased dopamine (DA) efflux and, as a consequence, increased extracellular DA levels. Importantly, the single nucleotide polymorphism, A559V, is the first mutation in DAT with an anomalous function to be linked to ADHD. Thus, the mechanism by which A559V produces changes in DA signaling by altering extracellular DA levels may be a potential target for the design of small molecules that could provide a novel approach to the treatment of ADHD. Because ADHD is frequently treated with amphetamine, the proposal will also evaluate how the A559V hDAT is distinct from the wild type hDAT in its response to amphetamine.[unreadable] [unreadable]