Dopamine Transporter Efflux in ADHD

Elevated dopamine efflux through the dopamine transporter may underlie some forms of attention-deficit hyperactivity disorder (ADHD), according to MazeiRobison et al. The authors identified a mutant form of dopamine transporter in two siblings with ADHD and expressed the mutant and wild-type forms in HEK-293T cells. Although expression levels and dopamine uptake were similar for mutant and wildtype transporters, the mutant transporter exhibited greater dopamine efflux under both basal and depolarized conditions, due to a greater sensitivity to intracellular sodium concentration and a higher affinity for intracellular dopamine. A role for increased dopamine efflux in ADHD was unexpected, because a common treatment for the disease is amphetamine, which also increases efflux through the wild-type transporter. Remarkably, however, amphetamine reduces efflux through the mutant receptor. Although the mutation described is extremely rare, alterations in dopamine efflux through the transporter due to mutations in transporter regulatory proteins may underlie other forms of the disease.