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Direct Application of MDMA to the Brain is not Neurotoxic

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There was an interesting theory a few years ago concerning crosstalk between dopaminergic and serotonergic systems in the brain. Specifically, the theory held that under normal physiological conditions, dopamine never travels beyond the synapse. However, under conditions that engender supraphysiological dopamine concentrations--such as those created by amphetamines and aryl-substituted amphetamines--significant extrasynaptic dopamine is seen. Could extrasynaptic dopamine be taken up by serotonergic neurons via SERT and oxidized to cytotoxic quinone-like species such as 4-(2-aminoethyl)cyclohexa-3,5-diene-1,2-dione? This might explain why SERT blockers like fluoxetine seem to ameliorate MDMA neurotoxicity. This model, however, does not explain why non-catecholaminergic amphetamines like PCA and fenfluramine are selective 5-HT neurotoxins.
 
Was fenfluramine demonstrated to be neurotoxic? I can't remember... will go look after breakfast :)
 
Yeah, that model sounds basically like the intergrated hypothesis Riemann. In my mind, SERT blockers protect against MDMA mediated neurotoxicity, because the stop MDMA from working, though the fact that they can stop damage when given afterwards (6 hours was the final time it reached signficance) does lend some support to the metabolite theory.

From what I've seen Fenfluramine isn't honest to god neurotoxic, it just causes SERT internalization. Cause it doesn't cause free-radicles.
 
I like SSRIs for preventing neurotoxicity because MAO is primarily found inside the terminal.


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Now, in regards to your/theDEAs theory on MDMA being the thing that MAO-B chews on, heres a couple of facts thats might make you think, might not though.
  • [+] and [-]MDMA have the same affinity for MAO-B[1]
  • [+]MDMA is far more neurotoxic[2]
On the otherhand
  • [+]MDMA releases dopamine far more than [-]MDMA[3]
  • ...and hence [+]MDMA induces hyperthermia, and [-]MDMA doesn't.[4]
 
I don't think MAO-B attacks MDMA, I still think it likes a metabolite of MDMA. I do think there are a lot of "what-ifs" though. MDA is closer to dopamine so if MDxx compounds are directly attacked by MAO-B then MDA would logically be a better fit. A better fit means more toxic metabolites... Is this why MDA is more toxic? I don't know, but I don't think MAO-B directly acts on MDxx compounds. That methylenedixoy bridge seems too bulky. For this reason I don't think MDMA is able to enter the axon terminal. However, remove the bridge to form a 3,4,dihydroxy compound and I see a better likelyhood of this happening. The closer it is to dopamine obviously the easier time it will have being transported into the terminal and the easier time MAO-B will have getting ahold of it.

There's lots of good toxic possibilities with 3,4,dihydroxy DA-like compounds, both in the deamination (OH radicals) and in the metabolic products themselves, not to mention the possibility that MDxx compounds are only a few steps away from dopamine going downward. Take away an O, and one or two CH (one for MDA, two for MDMA) and you have DA.

Someone should run the CSF HVA, DOPAC and DOPAL numbers after MDMA and see how much they spike and if they correlate to the "missing" metabolites of MDMA.


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So hyperthermia is induced by DA rather than by 5HT?

How come serotonin syndrome is associated with hyperthermia or is this just misinfo?
 
A lot of things can produce hyperthermia, you definatly can get hyperthermia with serotonin syndrome.

But Nah, MDMA gets into terminals man, how else does it act? I mean, in like, synaptosomes, there is no metabolism of any consequence. And really, MDMA is no longer than 5-HT, and 5-HT has an indole nitrogen as a source of electrons, just like MDMAs oxygens.
 
There are some really interesting structure activity relationships in the para- and meta-substituted amphetamines. The more electron-withdrawing the para-substituent, the more serotonergic the amphetamine, e.g. amphetamine, 4-FP, p-CA, ... I wonder what the meta-substituent dictates? Is it just along for the ride? What about something like 3,4-dichloroamphetamine or 3,4-dichloromethamphetamine?
 
But Nah, MDMA gets into terminals man, how else does it act?
Click to expand...

At the transporter, and this is why fluoxetine will stop a roll. It bumps MDMA off SERT becuase fluoxetine has a higher affinity. In theory, if MDMA acted inside of the terminal fluoxetine should intensify a roll, but it does the exact opposite. MDMA can't be both a vesicular 5HT releaser AND a SERT blocker, so I'm picking SERT blocker. If MDMA were a vesicular 5HT releaser, how would it differ from reserpine in effect?


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Huh?
Fluoxetine stops a role because MDMA a) is being recycled via exocytosis from the terminal, and b) doesn't all act at once, its floating around in the extracellular fluid.

Amphetamines aren't vesicular monoamine releasers, they are cytoplasmic monoamine releasers. And its quite easy from them to be both reuptake inhibitors and releasers. While the compound is bound to the reuptake transporter, no endogenous transmitter can bind, and while the amphetamine is being transporter, and afterwards, while the transporter is momentarily left facing inwards, the amphetamine is also acting as a reuptake inhibitors. Chance are, the amphetamine also results in the transporter being phosphorylated, which reduces its inward transportation rates.

amphetamines differ from reserpine because reserpine is a) a VMAT inhibitor, not a substrate b) has no (real) action on monoamine transporters.

I mean, as I said before, how does MDMA cause the massive release of neurotransmitter that it does, if it was just a reuptake inhibitor.
 
I mean, as I said before, how does MDMA cause the massive release of neurotransmitter that it does, if it was just a reuptake inhibitor.
Click to expand...

It's not just a reuptake inhibitor, I think it causes SERT to work backwards. Probably the same mechanism of action as cocaine. If cocaine were just a DA transport blocker it would be as euphoric as bupropion (ie, not very).


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It does cause the SERT to work backwards, just like all amphetamines, by PKC mediated phosphorylation. Cocaine doesn't cause any release, its just a reuptake inhibitor. Its the probably noradrenergic component of coke that causes it to be more pleasureable that bup.

Don't take this the wrong way, but I think you need to do some reading man. I made this little collection for you man. Start with Rothman to make yourself happy that amphetamines and reuptake inhibitors work differently, then read Kantor et al., then Giambalvo.

I know none of its proof, because its about Meth and not MDMA, but seeing that MDMA activates PKC in synaptosomes in a SERT dependent manner, and thats been shown to be enough to mediate amphetamine-like release, I'm sold.
 
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Yep, cocaine is just a monoamine reuptake inhibitor. It is more euphoric than bupropion because of its (1) significantly higher affinity for the DA transporter and (2) extremely rapid pharmacokinetic profile. Basically, a high dose of intranasal cocaine will take DA transporter occupancy from 0 to 75-80% in a matter of seconds/minutes. Bupropion will take DA transporter occupancy from 0 to 15-25% in a matter of hours/days. I have a sneaking suspicion that coke inhibits the Na+ uptake pore of the various monoamine reuptake transporter proteins, preventing the monoamines from being taken up rather indirectly. This is similar to hyperforin, the active compound in St. John's Wort, except to a much greater extent.
 
But occupancy is just a matter of dose. The rate thing I agree about though.

Meanwhile, I don't think the transporter has a sodium pore to block. Its a transporter, not a pore, and I don't think coke binds to the sodium site much, because coke competes with dopamine for binding in isolated membranes.
 
There is still debate about the structure and kinetics of the neurotransmitter transporters. The classical model of transmitter reuptake holds that transportation of the transmitter across the membrane is coupled to the cotransportation of several ionic species (Na+, Cl-, H+) in discrete stoichiometry. This model, however, is starting to be supplanted by a far richer model, according to which, transporters--like ion channels--have multiple states of conduction and allow dynamic flow of ions through an aqueous pore. Check out Lin, et al (1996), Quick (2003).
 
You coulda linked you lazy bastard! lol. Yeah, I've read that Quick one before. Its just talking about coupled vs uncoupled transporter. Thats quite relavent to amphetamine action (possibley), but it still doesn't point to ion channel like kinetics. There was a review on findings like that in TIPS or TINS at the start of the year I think.

This this review, which I still haven't worked my way through, and although it humors that ion channel idea, it doesn't really sell it.
 
Is MAOB expressed inside 5-HT neurons? I was under the impression it was only inside glial cells
 
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