So, you want to know exactly how Dexedrine works? This research shows exactly what its doing in our brains to release all that dopamine! This is stunning new research and will go a long way to assuring us about dexedrine's true properties and end they myths about it.So, you want to know exactly how Dexedrine works? This research shows exactly what its doing in our brains to release all that dopamine! This is stunning new research and will go a long way to assuring us about dexedrine's true properties and end they myths about it.

"A multi-institutional team of neuroscientists led by Aurelio Galli, Ph.D., at Vanderbilt University and Jonathan Javitch, M.D., Ph.D., at Columbia University has clarified the action of .... amphetamine."
Illuminating amphetamine’s molecular action (http://exploration.vanderbilt.edu/news/news_galli.htm) explains in detail, with animation, how amphetamine (for us its dex-amphetamine) releases all that dopamine! It is no longer a mystery. Though the thrust of their research is in treatment of drug abuse, they also point out that it has implications for all the psychoactive drugs used to treat depression, anxiety and ADHD.

So all my google searches and endless hours of reading have finaly paid off and now I get to answer back to all those people who tell me that "You don't even know what it does!"

cheers...
katatak :cool:

Well, this is more like a clarification of what was already known. It was already known that they blocked reuptake and simultaneously caused dopamine to leave the cell through the reuptake site. What they didn't know was how exactly it caused the reuptake sites to work in reverse.

I worry, however, that the animation on that site was likely not made by the authors but by a computer engineer who had misunderstood the paper. I haven't read the actual paper yet, I'm trying to find it on PLoS, but if they're saying that amphetamine actually enters the cell, it's a very radical finding. Plus the animation says that the calcium ions enter the cell due to a change in membrane potential. This is incorrect, the calcium ions entering the cell should cause a change in membrane potential. It seems likely that the animator simply misunderstood the paper.

That being said, that phosphorylation causes reuptake sites to work in reverse is fascinating. The real question still remains how amphetamine causes this. An increase in calcium ions is unlikely to be the sole cause. It is more likely that the influx of calcium ions merely stimulates the general release of dopamine by increasing the voltage potential, as is already known. The real question becomes: Is the phosphorylation an adaptation by the cell that occurs when voltage potential reaches a certain point, or does amphetamine cause this through a specific process, maybe by activating a particular protein-linked receptor?

Ok, never mind, read through the abstract and the relevant parts of the paper. It turns out that basically everything in the little animation on that site is pretty much...how can I put this...it's roughly on par with the historical accuracy of Disney movies.

The paper itself is quite interesting, however. Apparently what happens is that amphetamine binds to a receptor on the cell, the PKC site, which both increases the membrane potential of the cell as I mentioned above, but also activates a particular protein enzyme inside the cell. This enzyme then attaches phosphor to the end of the uptake site, and this phosphorylation is what causes the transporter to act in reverse.

What is interesting is that this process doesn't seem to affect the ability of these transporters to take the dopamine back into the cell. The question then becomes whether amphetamine also blocks reuptake, or if the release of dopamine is simply strong enough as to make reuptake irrelevant.

Again, I repeat, the animation on that page, and the simply summary of that page itself, is simply inaccurate and does not represent what the paper itself says. Those who are interested should read the paper in its entirety here:

http://biology.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pbio.0020078

I liked both links, as they present an opportunity to look those data over and hopefully learn something.

I especially like it when people point me in the direction of articles I probably wouldn't have found on my own.

I do have to say though,that I've never seen researchers presented in quite that way in terms of their pics.

Thanks again to both of you.

mctavish23
Robert

The animation, looks like someone hand drew the track to a rollercoaster, then stuck some blue tubes in the middle which are held together by loose fitting dental floss. Really, that picture explains nothing to me visually. From an artistic perspective, it's not pretty at all.

The animation is also about as basic as it gets. These poor red and blue dots, stuck forever in a tight holding pattern. :)

The thing is, I've seen pretty good animations before on other sites, where they were clearly reviewed by the relevent experts. I understand what those little squiggly lines are supposed to be on this animation, it's just that virtually every part of it is wrong...not just like "agree to disagree" issues, but like fundamentally wrong from a neurological perspective. It would be like claiming that hydrogen and oxygen combine to form Miller Lite.

Also, if anyone is looking over this and thinking "I'm confused," don't worry. This isn't exceptionally important for understanding how amphetamines work, it's just one of those incredibly technical details that answers an obscure question about the exact particular mechanism that us neuropharm nerds have wet dreams over.

Now, one possible benefit might be if this leads to development of PKC antagonist drugs that might be able to halt an overdose, much the way that naloxone is sometimes used to halt heroin overdoses. This could be useful in the event of an accidental overdose or any kind of bad reaction. The other main benefit might be if it allows for the development of new ADD drugs, but given that the ones that we have work fairly well with few side effects, this is less of a concern for me.

It would be like claiming that hydrogen and oxygen combine to form Miller Lite.

Well, Miller Lite is pretty much the same thing. :D

By the way...what is that dental floss?

I think that those are supposed to be the peptide chains that attach to the uptake sites, the ends of which get phosphorylated.

But it's really hard to tell, that's a pretty crappy animation, second only to the crappiness of the summary that's displayed while it plays.

Well, this is more like a clarification of what was already known. It was already known that they blocked reuptake and simultaneously caused dopamine to leave the cell through the reuptake site. What they didn't know was how exactly it caused the reuptake sites to work in reverse.I share your reservations Hyperion, we only see about a third of what happens.

Is Dopamine produced by the cell we're seeing?
Is that a reuptake pathway we're seeing or just the release mechanism?
Dopamine is active when it is in the intracellular space. What is its normal route of egress?
My impression is that a reuptake pathway is the method of washing a neurotransmitter away. Where is that pathway?
I thought the release of a neurotransmitter was a one way trip -- it is active as long as it is in the intracellular area then gets washed away or remains (this would be where Ritalin works because it is a reuptake inhibitor)
Why is Ritalin not called what it really is, an SDRI; Selective Dopamine Reuptake Inhibitor?

I worry, however, that the animation on that site was likely not made by the authors but by a computer engineer who had misunderstood the paper. Computer engineer? Not very likely. This was done by an experienced Flash animator so you are likely right that there are flaws in the conceptualization. That said, I'm glad its there because it allows me to begin to grasp all of this.

I haven't read the actual paper yet, I'm trying to find it on PLoS, but if they're saying that amphetamine actually enters the cell, it's a very radical finding. Plus the animation says that the calcium ions enter the cell due to a change in membrane potential. This is incorrect, the calcium ions entering the cell should cause a change in membrane potential. It seems likely that the animator simply misunderstood the paper.

That being said, that phosphorylation causes reuptake sites to work in reverse is fascinating. The real question still remains how amphetamine causes this. An increase in calcium ions is unlikely to be the sole cause. It is more likely that the influx of calcium ions merely stimulates the general release of dopamine by increasing the voltage potential, as is already known. The real question becomes: Is the phosphorylation an adaptation by the cell that occurs when voltage potential reaches a certain point, or does amphetamine cause this through a specific process, maybe by activating a particular protein-linked receptor?Perhaps the amphetamine does exactly what our brain cells should be doing but aren't. That would put it in the class of drugs like thyroxin (thyroid replacement) which merely do what are own bodies cannot do. That would certainly explain its relative non-toxicity (say compared to another drug like nicotine which is actually a poison).

I'm so glad this has gotten people talking. There is a more recent paper on a related subject which I cannot find right now. (I hate when I can't find something I just read ! )


Cheeers,
Katatak

Is Dopamine produced by the cell we're seeing?
Yes. That's not in question.

Is that a reuptake pathway we're seeing or just the release mechanism?
Reuptake pathway. The normal release mechanism is usually different, where the dopamine is stored inside the cell in packets called vesicles. The vesicles attach to the cell membrane and then empty their contents into the synapse. This occurs in response to the voltage potential of the cell, which is determined by the actions of other neurotransmitters which contact receptors on a completely different area of the cell..."upstream" of this transmission. Transmitters hitting the dendrites of the cell cause the voltage potential to change, and when it reaches a certain point, the vesicles release the neurotransmitter from the axon into the synapse. It was already known that amphetamines could cause the reuptake sites to also release dopamine into the synapse, but nobody knew how. These researchers have shown that the release is independent of voltage potential and can be mediated by receptors on the axon itself. This does raise the question of whether electrochemical transmissions can travel "upstream," as it were, with the "female" dendrites of one cell telling their "male" axons attached to them when to release their chemicals, rather than being a purely one-way signal from the axons of one cell to the dendrites of another.


Dopamine is active when it is in the intracellular space. What is its normal route of egress?
Either through the reuptake transporters, back into the original cell axon, or they are metabolized by monoamine oxidase and excreted.



My impression is that a reuptake pathway is the method of washing a neurotransmitter away. Where is that pathway?
That pathway is on the original cell that produced and released the dopamine. Let's call that cell "A." It is released by a "male" arm of that cell called an axon, and right next to that axon is the "female" part of cell "B," that has receptors on it. There is a small space between the axon of A and the dendrite of B, called the "synapse." Dopamine is released into the synapse from A's axon, where it then contacts the receptors on B's dendrite. There are also reuptake sites on A which transport the dopamine back into cell A, where it can be reused. It is only "washed away" in the sense that it is pulled out of the synapse and no longer activating the receptors on B.



I thought the release of a neurotransmitter was a one way trip -- it is active as long as it is in the intracellular area then gets washed away or remains (this would be where Ritalin works because it is a reuptake inhibitor)
Yes and no. It only transmits the signal from A to B, and so in that sense the signal itself is one way. However, it then re-enters cell A through the reuptake transporter and it can be reused. If you block the reuptake transporters, more of it remains in the synapse. Some of the dopamine will also be broken down by an enzyme called monoamine oxidase, which does destroy it and make it no longer active.

Why is Ritalin not called what it really is, an SDRI; Selective Dopamine Reuptake Inhibitor?
Same reason amphetamine isn't called that, because it simply isn't one. It isn't an SDRI for two reasons. One is that it's not selective for dopamine, they also affect norepinephrine. The second is because their action isn't purely by inhibiting reuptake, they also cause more dopamine and norepinephrine to actually be released into the synapse. There is also some evidence that they might bind to the dopamine receptors on the dendrite at higher doses, but this is not thought to contribute significantly to the effects.

Computer engineer? Not very likely. This was done by an experienced Flash animator so you are likely right that there are flaws in the conceptualization. That said, I'm glad its there because it allows me to begin to grasp all of this.
No, no, no. Don't use that animation to try to grasp this. It's fundamentally flawed even on the basics. For starters, amphetamine doesn't enter the cell. The animation is not an accurate representation of either what was previously known or what is in the paper.

Perhaps the amphetamine does exactly what our brain cells should be doing but aren't
Most likely. We know that ADD is most likely related to a lack of dopamine and norepinephrine in the prefrontal cortex. It is possible that this is due to excess reuptake, or possibly an internal defect in the dopamine producing cells that causes them to release too little dopamine. It is entirely possible, for example, that ADD patients' dopamine neurons do not properly phosphorylate the reuptake sites, causing too few of them to release extra dopamine when needed, and that by doing this, the amphetamines are correcting for this problem.

Regardless, we know that lack of these neurotransmitters is implicated in ADD, and we know that these drugs increase the levels of these neurotransmitters. We also know that these drugs correct many of the symptoms of ADD. To that extent, we don't need new studies to tell us that these drugs are causing our brains to behave as they should. What is interesting about this new study is not that it shows some amazing new discovery, but that it builds on what we already know with one more small piece of the puzzle.