Monday, September 1, 2008

ADHD Protein on "Speed"?

ADHD treatment options and resources

New mutation found on an "ADHD gene"

I was going to post some more information on the second ADHD gene on the list, but I recently came across a very interesting article on genetic mutations and ADHD, which can be found here.
The original study was recently published in the July 9, 2008 issue of the Journal of Neuroscience by the groups of Aurelio Galli and Randy Blakely. Several subtypes of ADHD are thought to be caused by an imbalance in the levels of of dopamine, an extremely important chemical found in the brain and nervous system that regulates proper neural functioning. There is an ideal balance between the amount of dopamine that is stored in neurons and the amount that is present in the "gaps" between different neuron cells.

It is here, that a critical protein comes into play. A special protein called the Dopamine Transporter (DAT) protein acts as a type of "shuttle" or "ferry" that helps balance dopamine levels inside and outside of the neuronal cells by aiding in the transport of dopamine in and out of the cells. This protein is actually "coded" for by the third ADHD gene on the list of a recent post.

It is strongly suggested that individuals diagnosed with ADHD have lower than normal levels of this dopamine in the gaps between neuron cells. As a result, a number of ADHD drugs focus on this DAT "shuttle" in an attempt to manipulate its ability to clear dopamine to the cells (think of the analogy of building a dam to trap and collect a stream of water in a region where it is scarce). In essence, this helps "fix" the problem of the low dopamine levels in this space, which is associated with ADHD.

Here is where it gets interesting. A rare mutation causes this shuttling DAT protein to essentially run in reverse at high speeds. Instead of "mopping up" dopamine and carrying it into the surrounding neurons, this mutated form of the protein essentially "squeezes" dopamine out of the cells and into the open space. This mutant protein actually functions in a very similar way to amphetamines such as the popular ADHD drug Adderall (which, incidentally, is chemically similar and has a similar, but much more benign, mode of function as the drug "Speed"). Here lies the paradox-- we would think that this mutated transporter protein, which behaves like a drug used to treat ADHD would be beneficial for ADHD individuals. However, the opposite is true. Individuals which possessed this mutation exhibited noticeable ADHD behavior.

Further complicating the issue is the fact that Adderall, while behaving much like this mutation by making the DAT shuttle run backwards, actually blocks some of the key negative effects of the mutation. Think of it as an almost homeopathic-like solution, treating "like" with "like". Ritalin, another ADHD medication which, in turn, can counteract the ability of Adderall to make this shuttle protein move backwards. For sake of brevity, I will save this discussion for a later post in the near future!

Finally, it is also interesting to note that this DAT mutation is very rare. Outside of this study, only one other case had been seen by the researchers, that of a bipolar girl. I found this interesting because it is sometimes difficult to distinguish differences between ADHD and pediatric bipolar disorders. The overlap of this mutation between the two disorders may lend some credence to underlying genetic mechanisms that both disorders seem to share.

ADHD treatment options and resources

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