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Further discussion on MDMA-induced (and related componds) neurotoxicity.

aced126

aced126

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So, if we assume the theory that dopamine is taken up into the serotonergic neuron, causing oxidative stress and so forth. My question is, why would there even be dopamine there? Surely there would be a much greater concentration of serotonin in the synaptic cleft?
 
Normally there isn't all that much extrasynaptic spillover of dopamine, but MDMA increases dopamine release and blocks reuptake. And it is true that there would normally be enough serotonin floating around to block dopamine from binding to the serotonin transporter. But MDMA depletes serotonin, so as its acute effects wear off there is more opportunity for dopamine to bind to SERT.
 
I think what serotonin2A was getting at is this probably only happens with substances that interact with VMAT because they will do the best job of depleting serotonin. But from my understanding I did see a study proving that dopamine uptake into the serotonin nerve terminal is possible, I believe the study was with lymphocytes. There is quite a good bit of evidence that something is being taken up into the nerve terminal and then a fair bit of evidence that some of that something is dopamine (and possibly a hepatic MDMA metabolite/MDMA itself), the researcher Dave Nichols had the theory that it was dopamine I believe because apparently non-neurotoxic MDMA analogues have been shown to be neurotoxic if combined with (if I remember right) dopamine releasers.

So with that in mind I think the theory of dopamine uptake into the nerve terminal is two fold: 1. Low serotonin 2. High dopamine. And also a possible 3. Available serotonin transporters to uptake dopamine.

I had this whacky idea (that serotonin2A kinda shot down) that because MDMA is an agonist at 5HT2B it might possibly increase the number of available SERTs, or that the number of SERTs might increase to compensate for the large amount of serotonin that was in the synapse. But apparently transporters are trafficked very slowly across the membrane so this would be something that is more chronic than acute if it did happen, so maybe by the time that SERTs were increased there would be more normal levels of serotonin and dopamine.

*waits for serotonin2A*
 
How does MDMA "deplete" serotonin. Where is the serotonin going? Surely it's just staying there in the synaptic cleft.
 
SEROTONIN I have ideas! So if we are to assume that dopamine uptake is most likely to occur after serotonin concentrations have dropped via binding to receptors (rather than via MAO-A), then might we assume that - 1. Neurons that have more 5HT1 receptors might sustain more damage because serotonin has higher affinity for 5HT1>5HT2 and therefore you might find less serotonin available to compete for the SERT around 5HT1 dense areas because it binds and leaves the synapse faster there
2. The damage might be worse in areas with auto receptors/the damage might be worse pre synaptically because the auto receptors there would tone down the release of serotonin and therefore there would be a more damaging ratio of dopamine to serotonin.
3. The damage would be worse in any place where there are more serotonin receptors than usual because serotonin could leave the synapse faster via binding.

I suppose you could possibly test this theory of increased receptor binding increasing the harmful dopamine to serotonin ratio by up regulating an animals serotonin receptors (maybe just 5HT2A so as to try not to involve auto receptors and make things complicated) very heavily before MDMA administration to see if that group sustained more damage, though I guess there might be other factors.
 
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An ongoing discussion involving similar ideas is occurring in the large MDMA Neurotoxicity thread. Shouldn't we have this discussion in the same place rather than spreading this over multiple threads?
 
That thread was for a long term comedown sufferer who got anxiety from reading about MDMA neurotoxicity so let's not post there and make his anxiety worse lol, but anyways this thread is a bit more technical and specific anyhow
 
aced126 said:
How does MDMA "deplete" serotonin. Where is the serotonin going? Surely it's just staying there in the synaptic cleft.
Click to expand...

1. MDMA is causing serotonin to leak out of vesicles, so the amount available for release decreases. 2. MDMA denatures tryptophan hydroxylase. It therefore takes some time to refill the vesicles.

The released MDMA goes into the synapse but it eventually diffuses away.
 
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Hey Serotonin, do you think that serotonin binding to receptors is a big source of serotonin disappearing from the synapse, and also do you think that the damage might be worse pre-synaptically because of how auto receptors might tone down serotonin release resulting in a more harmful dopamine to serotonin ratio?
 
TheBlackPirate, I'm certainly okay with a mega thread, I think that would be a great idea, but would you want to start it in neuroscience and pharmacology or MED forums? Personally I think it's better suited to neuroscience and pharmacology, plus there are way too many people with anxiety that don't need to read about this in MED
 
Cotcha Yankinov said:
Hey Serotonin, do you think that serotonin binding to receptors is a big source of serotonin disappearing from the synapse, and also do you think that the damage might be worse pre-synaptically because of how auto receptors might tone down serotonin release resulting in a more harmful dopamine to serotonin ratio?
Click to expand...

A significant amount of serotonin is released from varicosities, which is a volume transmission type of signaling. In other words, the serotonin signaling isn't always confined to synapses but rather can influence downstream neurons at some distance from the terminal. So serotonin is released and then it diffuses some distance until it binds to a receptor (possibly repeatedly). Eventually the serotonin is picked up by SERT.

In general, receptor binding doesn't reduce the concentration of transmitter in the synapse. The receptor concentration is very small compared to the number of transmitter molecules released. But even the amount of transmitter that is bound hasen't really "disappeared" -- the transmitter molecules are still present, and once they dissociate from the receptor then they are available for binding. Eventually the transmitter disappears due to transporter uptake, degradation, or by diffusion out of the synapse).

During the period when neurotoxicity develops (after the acute effects of MDMA wear off), 5-HT release is declining, so you would think that there would be relatively little autoreceptor activation.
 
serotonin2A said:
1. MDMA is causing serotonin to leak out of vesicles, so the amount available for release decreases. 2. MDMA denatures tryptophan hydroxylase. It therefore takes some time to refill the vesicles.

The released MDMA goes into the synapse but it eventually diffuses away.
Click to expand...

I'm confused by the underlined part. Did you mean to say "the released 5HT goes into the synaptic cleft but eventually diffuses away"? If so, why doesn't the dopamine diffuse away too? I guess my question is that if there is dopamine ready to be uptaken, why isn't there at least as much if not more serotonin to be uptaken?
 
^I suspect that something to consider is that you might only need a teensy bit of dopamine uptake to harm a nerve terminal while normally tons of serotonin is uptaken, so even if there are 10 serotonin molecules for every 1 dopamine that still might be enough to cause harm.


So Serotonin2A, since it sounds like neurotransmitters can travel from synapse to synapse, do you suspect that damage might be worse at serotonin nerve terminals near dopamine rich areas (assuming a dopamine rich area means that there is more synapse to synapse diffusion of dopamine)?
 
aced126 said:
I'm confused by the underlined part. Did you mean to say "the released 5HT goes into the synaptic cleft but eventually diffuses away"? If so, why doesn't the dopamine diffuse away too? I guess my question is that if there is dopamine ready to be uptaken, why isn't there at least as much if not more serotonin to be uptaken?
Click to expand...

Yes, should be 5-HT. Sorry

To answer your question, when the MDMA is working, it gradually drains 5-HT out of vesicles. Then when the MDMA wears off, when 5-HT cells fire and the vesicles dock, but they don't release very much 5-HT. Normally this would be fixed by making more 5-HT, but tryptophan hydroxylase activity is also impaired. So the net effect is that extracellular 5-HT levels decrease.

It isn't necessarily the case that there is no serotonin blocking dopamine uptake. There certainly might be some. But it may not take all that much dopamine in serotonergic terminals to cause oxidative stress. So if more DA gets in than normal, into a terminal that is already stressed due to hyperthermia and oxidative stress due to MDMA metabolites, then that will contribute to degeneration.
 
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Do you think there will tend to be more dopamine near serotonin synapses that are located in dopamine rich areas (and therefore those areas will sustain more serotonin damage)?

I'm also under the impression that 5HT2A and D2 can co-localize on terminals, do you think this might have any implications for the pattern of serotonin damage? Or would that D2 only be activated by dopamine that is diffusing out of dopamine neurons and therefore there would still be average concentrations of dopamine in that nerve terminal even though there's a D2 receptor?

Also, in the same sense that a mechanism of toxicity is compounds gaining access to the cell through the transporter, can some compounds gain access through a receptor if a receptor can be recycled with something still bound to it (I'm thinking of irreversibly binding things), and if dopamine can bind to a SERT when serotonin concentrations are low, then might dopamine be able to bind to a serotonin receptor and then if the receptor is recycled and pulled back into the cell, the dopamine might cause damage via uptake into the cell via a receptor essentially? Same question goes for other compounds that are actual serotonin agonists that can be harmful once inside the cell, maybe they can cause harm by being bound to the receptor when it happens to be recycled as well?
 
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Cotcha Yankinov said:
Do you think there will tend to be more dopamine near serotonin synapses that are located in dopamine rich areas (and therefore those areas will sustain more serotonin damage)?

I'm also under the impression that 5HT2A and D2 can co-localize on terminals, do you think this might have any implications for the pattern of serotonin damage? Or would that D2 only be activated by dopamine that is diffusing out of dopamine neurons and therefore there would still be average concentrations of dopamine in that nerve terminal even though there's a D2 receptor?

Also, in the same sense that a mechanism of toxicity is compounds gaining access to the cell through the transporter, can some compounds gain access through a receptor if a receptor can be recycled with something still bound to it (I'm thinking of irreversibly binding things), and if dopamine can bind to a SERT when serotonin concentrations are low, then might dopamine be able to bind to a serotonin receptor and then if the receptor is recycled and pulled back into the cell, the dopamine might cause damage via uptake into the cell via a receptor essentially? Same question goes for other compounds that are actual serotonin agonists that can be harmful once inside the cell, maybe they can cause harm by being bound to the receptor when it happens to be recycled as well?
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Hi CY,

Internalization would be an inefficient way to bring dopamine into cells. Internalized receptors are isolated in vesicles, and so any bound dopamine would be trapped inside the vesicle for a relatively long period (compared with SERT uptake). It is also a low-throughput mechanism--there are far fewer receptors that internalize compared with the capacity for SERT to transport things.

But we know that SERT blockade inhibits the neurotoxicity, so that also suggests that receptor internalization is probably not terribly important for MDMA induced terminal loss.
 
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Cotcha Yankinov said:
Hey Serotonin, do you think that serotonin binding to receptors is a big source of serotonin disappearing from the synapse, and also do you think that the damage might be worse pre-synaptically because of how auto receptors might tone down serotonin release resulting in a more harmful dopamine to serotonin ratio?
Click to expand...

Most of these conversations are happening in Neuroscience and Pharmacology and this topic is an advanced topic. Also, obviously this could placate the concerned people in MDMA & Empathogenic Drugs considering modern research has demonstrated normal MDMA users won't suffer significant neurotoxicity and ecstasy abusers recover nearly 100% once they discontinue use.

Let's request a "Big and Dandy MDMA Pharmacology and Purported Toxicity" thread in Neuroscience and Pharmacology and then request MDMA & Empathogenic Drugs links this in the sticky threads.
 
TheBlackPirate said:
Let's request a "Big and Dandy MDMA Pharmacology and Purported Toxicity" thread in Neuroscience and Pharmacology and then request MDMA & Empathogenic Drugs links this in the sticky threads.
Click to expand...

Sounds like a plan, idk about the "purported toxicity" part though. Maybe let a mod decide the name of the thread?
 
serotonin2A said:
Yes, should be 5-HT. Sorry

To answer your question, when the MDMA is working, it gradually drains 5-HT out of vesicles. Then when the MDMA wears off, when 5-HT cells fire and the vesicles dock, but they don't release very much 5-HT. Normally this would be fixed by making more 5-HT, but tryptophan hydroxylase activity is also impaired. So the net effect is that extracellular 5-HT levels decrease.

It isn't necessarily the case that there is no serotonin blocking dopamine uptake. There certainly might be some. But it may not take all that much dopamine in serotonergic terminals to cause oxidative stress. So if more DA gets in than normal, into a terminal that is already stressed due to hyperthermia and oxidative stress due to MDMA metabolites, then that will contribute to degeneration.
Click to expand...

I don't get why then that non-neurotoxic MDMA analogues can be neurotoxic when administered with a dopamine releasing agent. Surely the DRA would drain all the dopamine while the 5HT is being drained as well, so that when both the 5HT releaser and DRA are gone, there is both a lack of 5HT and DA?

So really the key cause of neurotoxicity is TPH inhibition, but not the inhibition of tyrosine hydroxylase?
 
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