Research Highlight:

DAT Leak: A link to ADHD?

Original Research Article:
MS Mazei-Robison, E Bowton, M Holy, M Schmudermaier, M Freissmuth, HH Sitte, A Galli and RD Blakely (2008). Anomalous Dopamine Release Associated with a Human Dopamine Transporter Coding Variant. J. Neurosci. 28 (28): 7040-7046.

The dopaminergic system has long been thought to be involved in the etiology of attention-deficit hyperactivity disorder (ADHD).  The dopamine transporter (DAT), as a target for ADHD medication, has been characterized for common genetic variants, and yielded several interesting targets for further study.  In a paper published recently in the Journal of Neuroscience (and later featured as an “Editor’s Choice” in Science), a team of neuroscientists at Vanderbilt University characterized the human dopamine transporter (hDAT; SLC6A3) containing an A559V mutation.

Mazei-Robison et al. expressed the hDAT A559V mutation in HEK-293T and found that overall protein expression and cell-surface expression were similar to wildtype hDAT.  Using amperometry, the authors found that while levels of dopamine uptake in these cells was comparable to wildtype hDAT, efflux of dopamine was 300% normal.  Combining amperometry with whole-cell patch-clamp recording, the authors also found that hDAT A559V exhibited increased sensitivity to intracellular Na+ which contributed to greater dopamine efflux when depolarized.

Perhaps the most intriguing result from this study was the author’s finding that dopamine efflux through hDAT A559V could be blocked by amphetamine (AMPH), which normally enhances dopamine efflux in wildtype hDAT.  Because this mutation was originally identified in two male probands with ADHD that were treated with AMPH, this unexpected result suggests a possible mechanism for the efficacy of AMPH as a treatment.  Furthermore, the authors found that baseline dopamine efflux in hDAT A559V mimicked the level of efflux seen in AMPH-treated wildtype hDAT.  These data strongly suggest that dopamine efflux may be linked to ADHD in a heritable manner, and provide a specific target for further research into therapeutics for the disorder.