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IRA FLATOW, host:

This is Talk of the Nation Science Friday. I'm Ira Flatow. A bit later in the hour, Mars and Mercury, but first, researchers have discovered a rare genetic mutation in two brothers with attention deficit hyperactivity disorder or ADHD. And the mutation throws a chemical pathway in their brains into reverse. In normal brains, vacuum cleaners like proteins called transporter suck up the chemical messenger dopamine after it has sent its message from one neuron to the next. But the mutation makes the transporter seem to run backwards, leaking out extra dopamine which they should be holding in instead. It's almost like the brain is almost on stimulants like amphetamines. This discovery raises a lot of questions about ADHD and the drugs used to treat them.

And joining me now to talk about these neurochemical pathways and how they can go awry as research published in a journal of neuroscience is my guest Doctor Randy Blakely. He is professor of pharmacology and psychiatry at Vanderbilt and is also a director of the Senate for Molecular Neuroscience there. He joins us by phone from Nashville. Welcome to the program Doctor Blakely.

Doctor RANDY BLAKELY (Professor of Pharmacology and Psychiatry, Vanderbilt; Director of the Senate for Molecular Neuroscience): Hi, Ira.

FLATOW: What is going on here?

Dr. BLAKELY: Well, this is a very unusual change in this key brain protein that, as you said, sweeps away dopamine from the extracellular space outside the neuron, a nerve cell after it's been released. And normally, those levels of dopamine when they're released are extremely tightly controlled, if you don't get enough dopamine, certain circuits in the brain will cause you to freeze up, and we know that from Parkinson's disease. And if there's too much dopamine, you can become agitated after - a little bit extra dopamine can sharpen your attention. But a little more, and you can become agitated and hyperactive and even generate signs of paranoia and mood disorders and delusions. And that's all controlled by this dopamine transporter protein. And it's extremely important that it work properly. And in the past, we've always thought about changes in this protein being sort of a gain or loss, but we've never seen a change in this protein that would make it run in reverse. And this really struck us when we first found this, now, about a year ago and the lessons we learned from this change in this protein just continue to astound us.

FLATOW: So it is like then that the dopamine is not being removed in the brain as sort of on a perpetual high, so to speak.

Dr. BLAKELY: That's right. That's what we suspect. We lack the tools still to go in to the brains of these kids, of course, and actually see this happening. We have to infer what is happening from studies in brain cells in the laboratory. But everything that we do to this molecule in the laboratory to tell us that the protein is not working the way...

FLATOW: Yeah.

Dr. BLAKELY: The normal protein does.

FLATOW: But it also is very mysterious because we know that if we give kids or people with ADHD more of the stimulant, it actually calms them down. I mean, doesn't that just fly in the face of what we're seeing here?

Dr. BLAKELY: Well, it did up until we found this mutation. So one of the amazing things that this mutation has thought us is that when this transporter is stuck in reverse, then the drugs actually act in a way that makes sense. So in the past, we've thought the actions of amphetamine, for example, would do just as you said, they would be - have this stimulating action because they would cause dopamine, this stimulant brain chemical, to come out. But when we tested this mutated protein in the laboratory, it's stuck in this reverse mode already and when we give it amphetamine, it actually turns it off at a single molecule level. So we - all of a suddenly we realize that maybe this reversed mode of transport might give us some better clues to how this drugs actually do provide therapeutic benefit to people with ADHD.

FLATOW: And as you say, it's hard to know - hard to do any testing in people.

Dr. BLAKELY: That's right. And - but there are some approaches that use some sophisticated brain imaging tools and there's advances being made in that every day, and we certainly are excited to try to contribute to that.

FLATOW: Now we know there are other diseases like bipolar disorder that involve dopamine pathways. Is there any help here for those kinds of illnesses?

Dr. BLAKELY: There is a possible link. These changes as you mentioned at the beginning of your program are extremely rare. We found this change in these two brothers, and it's essentially only in that family that we've found this mutation.

FLATOW: Mm hmm.

Dr. BLAKELY: But another group in Germany a few years ago reported the very same mutation in a girl with bipolar disorder. Now they didn't follow this up because it was such a singular observation, and they really weren't studying how the protein worked so they left it behind. But when we rediscovered this in these two boys, all of a sudden we now realized that this is actually the first time a mutation like this has been discovered twice.

FLATOW: Right.

Dr. BLAKELY: And it's in these two disorders that, as you say, have a link to dopamine action.

FLATOW: So what about all these children who have ADHD, but do not have this genetic mutation. Can we say anything about their brains?

Dr. BLAKELY: That's a great question and it's one we're - we try to be very cautious about. You're right, the findings right now is limited to this one family, to these two boys. But remember that these drugs that act on the dopamine transporter in such a beneficial way both in our cells in the laboratory and also in people are in quite widespread use, and we wonder whether or not there are other ways to put the dopamine transporter in reverse that are not genetically determined.

FLATOW: Yeah.

Dr. BLAKELY: So in this particular case, we have found the rare case that might actually end up proving a larger rule.

FLATOW: You mean, it might be something environmentally.

Dr. BLAKELY: I think that's an open possibility. It could be something environmental. It could be a convergence of a number of other genetic changes that are in other proteins. My colleagues here at Vanderbilt have found several other proteins that caused the dopamine transporter to move in reverse and of course those come under our examination now.

FLATOW: So where do you go from here?

Dr. BLAKELY: Well, that's the - as I was alluding to, I think these other proteins may - their genes may in fact have risk for - may cause risk for ADHD, and so we need to look...

FLATOW: Right.

Dr. BLAKELY: At those genes carefully, and you know part of the effort that we're engaged in is try to narrow down all the genes in the genome that contribute to the way the brain works.

FLATOW: Right.

Dr. BLAKELY: And we just need clues.

FLATOW: Yeah.

Dr. BLAKELY: And this is an important clue that sort of orients us toward a signaling network that we think might contribute to how dopamine is controlled.

FLATOW: So there might be other genes that control dopamine. Is that what you're saying? Are you trying to discover that?

Dr. BLAKELY: Yes. I think that, that would control dopamine because they're controlling the way the dopamine transporter runs in either the forward or the reverse direction. And that's not something we thought to look for before. We've always thought about how much dopamine might be released by a neuron or how much a responding cell might pick up of that dopamine. But this status of this dopamine transporter getting stuck in reverse is a totally new phenomenon for us and it's one that now establishes a whole research paradigm for us that we want to go after this other proteins for.

FLATOW: Interesting. How important is dopamine itself in the brain?

Dr. BLAKELY: A dopamine is a critical brain chemical that essentially, if you didn't make dopamine, you would be a Parkinsonian. You would look as if, you were frozen in space.

FLATOW: Mm hmm.

Dr. BLAKELY: You couldn't initiate movements, it's critical for brain reward circuits. And I think, with respect to today's program what's most important is at the last 10 to 15 years, we've learned how important it is for attention, and learning, and memory. So, the deficits in dopamine signaling or the changes that go array in the signaling pathway of dopamine, we think, can contribute to some of these learning disabilities and attention deficits, they're part of ADHD.

FLATOW: I will have to check back with you later, Dr. Blakely.

Dr. BLAKELY: Thank you very much, Ira.

FLATOW: Thank you for taking time to meet with us.

Dr. BLAKELY: Bye-bye.

FLATOW: Dr. Randy Blakely is professor of pharmacology and psychiatry at Vanderbilt in Nashville. He's also director of the Center for Molecular Neuroscience there.

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