DAT mutation (reverse flow) and ADHD

[Ham-milton]

I had a chance to have an email chat with Dr. Randy Blakely, the lead author from the Vanderbilt study about the mutation leading to reversed DAT transport in ADHD'ers, but it's only lead to more questions.

The biggest of which is how amphetamine and methamp- which actually reverse DAT transport- alleviate the problems.

Is it possible that when amphetamine binds in these mutated transport proteins it is reversing them- but instead of making them pump backwards (which is really forwards for these) they pump forward?

And then what about the DARIs? They also help- and just as well as the releasers. If the problem is just too much DA in the synaptic cleft, then they should make it even worse, no? Would a backwards leaking DAT cause more or less DA than a DARI?

If DAT is just turned off that might actually result in less, right?

Huh, maybe by going through this bit by bit I answered my own question. Is this plausible?

 

[Beenhead]

Interesting, is he on Pub Med? Its always nice to speak with a Ph.D

 

[Ham-milton]

No, I heard him on Talk of the Nation (where I first heard of the study) went and read the press release (copied it to DITM) and then emailed him with the questions I had about it.

Maybe they all secretly hate me for it, but I've never got gotten really good, quality responses when I've had questions about a study that was done.

 

[ebola?]

(I used to research AD(H)D.)

I would love to see the primary study. While statistical correlates between physiology and the disorder have been discovered, they are by no means reliable indicators of the "disorder". We also lack reliable diagnostic tools, and the official criteria for the disorder (DSM-IV-TR) are quite vague. This exacerbates things.

I would imagine that a subset of people w/ ADD have these abnormal transporters.

ebola

 

[vecktor]

I haven't got time to look this up. it occurred to me that there might be a bit of a problem if the ADHD sufferers had been medicated over a period of time with methylphenidate or similar because it has been shown that exposure to DAT binding agents whether they are substrates or inhibitors alters the balance of DAT types, the difference probably being due to phosphorylation though it might be through post transcriptional modification. additionally the number of cycles DAT has done alters it in a subtle way which I do not understand.

there is also evidence that there is a high affinity binding site on DAT which most DAT ligands other than dopamine bind to with high affinity, and there is another close site which binds dopamine with high affinity. either that or there are two or more discrete populations of DAT.

 

[negrogesic]

So in this case backwards + backwards equals forwards? This sounds a bit strange, but perhaps it is possible. I suppose this could explain why DARI/NERI's like MPH can cause sedation in those with ADHD, if it is causing dopamine/norepinephrine to be pumped out of the synaptic cleft. Or, perhaps because of this mutation, those with ADHD are tolerant to the effects of the extra dopamine in the synpatic cleft, and instead of reversing flow, mph/amp simply adds more dopamine to alleviate the symptoms?

What about the norepinephrine transporter, would there potentially be a similar mutation?

As vecktor pointed out, have these individuals been previously treated with DARI's like methylphenidate?

Edit: whoops

 

[Ham-milton]

I'm not sure. That's what I came up with to answer my question though.

These people most likely have been, but the mutation has been reported in a bipolar patient from europe where those drugs are used pretty infrequently (and bipolar disorder isn't one you see stimulants indicated for- quite the opposite.

 

[ebola?]

>>I suppose this could explain why DARI/NERI's like MPH can cause sedation in those with ADHD>>

Well, only the minority of those with ADD exhibit this effect.

 

[Ell]

>>I suppose this could explain why DARI/NERI's like MPH can cause sedation in those with ADHD>>

Well, only the minority of those with ADD exhibit this effect.

Couldn't the minority just be those with severe enough ADHD where there is a significantly noticeable back-flow of DA into the synaptic cleft? It's possible that many more have a back-flow, just not nearly as severe or noticeable. Possibly, more noticeable and concentrated the back-flow, the more intense the ADHD.

Wasn't the flow discovered through "listening" in on DA as it passed across the synapses and estimating how much was going in which direction? Having to measure molecular flow with the naked ear (albeit with a measuring device) would be extremely subjective.

While the underlying idea is the there, the numbers might not be.

It would make sense that a DARI would work better than a DAT, since once the DARI came into effect and started inhibiting the dopamine in the cleft from passing back, after a few hours, it would defuse back through the synapse and with another dose administered, undergo normal inhibition.

 

[ebola?]

>>Couldn't the minority just be those with severe enough ADHD where there is a significantly noticeable back-flow of DA into the synaptic cleft? It's possible that many more have a back-flow, just not nearly as severe or noticeable. Possibly, more noticeable and concentrated the back-flow, the more intense the ADHD.>>

This is indeed possible, but I find it more parsimonious to suppose that a disorder so vaguely defined and heterogeneous in its presentations is heterogeneous in its causes.

 

[grue]

One line I tend to hear is that inattention (which may as well be a completely different etiology for most intents and purposes) usually does not respond as well to methylphenidate as to amphetamines. That might be interesting in this context. Were the people tested hyperactive?

I'm pretty severely inattentive unmedicated, without hyperactivity. When I took it (methylphenidate), I felt extraordinarily sedated, and that the drug would be perfect for hyperactive little shits. Amphetamine OTOH is enlivening* and works well for me.

I agree with ebola that there doesn't seem to be too many consistent neurological markers for the disorder, which to my mind may as well be called a "syndrome" rather than a disorder, as any number of things could cause a persistent inability to focus and some of the other symptoms common to the problem. Head injury, sustained methamphetamine neurotoxicity, pre-Parkinsonism, genetics ...

Hence, as with all things that we call mental illness, IMO in most situations the only final way to diagnose is via self-reporting, and I don't see this changing for a long time.

* enlivening especially early on. I feel that the mood/motivational boost, which tends to develop rapid tolerance, is just as, if not more therapeutic for me than the more persistent concentrative, but somewhat dulling effect. I hope to see if I can delay tolerance to this effect with memantine, which seems to have been successful for a few people.

 

[LuxEtVeritas]

there is a whole school of thought of the many subsets of ADD/ADHD (with a fairly wide variance) and their unique profile and characteristics so indeed a one size fits all is not remotely valid