Genetics of childhood disorders: XXIV. ADHD, part 8: hyperdopaminergic mice as an animal model of ADHD.

(amphetamine) induces a calming effect when used in hyperactive children. It is still not known how these drugs work to increase alertness in normal individuals as well as distractible and overactive children. Numerous studies have shown that psychostimulants exert their pharmacological actions through interaction with plasma membrane monoamine transporters, namely, the dopamine, serotonin, and norepinephrine transporters. The normal function of these transporters is to provide rapid removal of neurotransmitters from the synaptic cleft to permit repetitive synaptic firing. Inhibition of the transporter would prevent the normal reuptake and would lead to markedly elevated extracellular monoamine levels. Because dopamine has been strongly implicated in the control of locomotion, particular attention has been given to the interaction of these drugs with the dopamine transporter (DAT). The elevation of extracellular dopamine levels is believed to be the primary mechanism by which psychostimulants are able to regulate locomotion. This concept, as well as the proven therapeutic efficacy of psychostimulants in attention-deficit/hyperactivity disorder (ADHD) patients, has provided the basis for the hypodopaminergic hypothesis of the disorder and suggested a possible connection between DAT and ADHD. Many attempts to clarify the status of the dopamine system in patients with ADHD have been largely unsuccessful. This is generally thought to be due to the fact that many of the current approaches in clinical research, such as the analysis of plasma, urine, cerebrospinal fluid, or computer imaging techniques, provide equivocal estimates of the extracellular levels of dopamine in the major motor areas of the human brain. The hypodopaminergic hypothesis of ADHD, therefore, remains a theoretical concept inferred from an oversimplified understanding of the mechanism of action of psychostimulants in normal subjects. The hypothesized connection between DAT function and ADHD has continued to spark considerable interest. There has been a reported association between a polymorphism in the DAT gene and ADHD. Specifically, a significant association was found by Cook and associates between ADHD and the 480-bp DAT1 allele (48-bp repeat sequence). Other groups of researchers later confirmed these observations in additional cohorts of patients and concluded that the 480-bp allele of DAT1 is preferentially transmitted to ADHD probands. More recently, four different analytical strategies were used to examine the association and linkage of the DAT gene and ADHD in children. Waldman and associates replicated Genetics of Childhood Disorders: XXIV. ADHD, Part 8: Hyperdopaminergic Mice as an Animal Model of ADHD