Last Updated on Friday, 10 July 2009 22:11

MDMA and Neurotoxicity

This next section of the slideshow deals with MDMA neurotoxicity. If you have understood everything so far, you should have no trouble with this section.

1) The current theory

The most current theory of how MDMA causes neurotoxic damage in laboratory animals goes like this:

After MDMA depletes serotonin, the reuptake transporters are left vacant and exposed. When this happens, dopamine enters the transporter and gets taken up into the serotonin axon, where it isn't supposed to be. Studies have shown that dopamine itself is toxic to serotonin cells. But if that weren't enough, MAO comes along and breaks it down into hydrogen peroxide, which is also toxic to the cell. (Yes, the same hydrogen peroxide they put in hair bleach!) The hydrogen peroxide then "oxidizes" certain parts of the cell which don't normally get oxidized ("oxidize," as used here, basically means to break down with oxygen). Researchers sometimes refer to this as oxidative stress, and a number of studies have looked at anti-oxidants like Vitamin-C as a possible agent to prevent MDMA's neurotoxicity (see our section about pre-loading on our neurotoxicity page for more info on this).

Once again . . . To re-cap we have (1) serotonin depletion causing the uptake transporters to become empty. Then (2) dopamine, which exists in higher levels in the synapse now, enters the uptake transporter. (3) This dopamine is broken down by MAO into hydrogen peroxide. (4) The dopamine is toxic to the cell and so is the hydrogen peroxide, by producing oxidative stress.

How did they come up with this theory? And is there evidence for it?

The researchers who first devised this theory (Jon E. Sprague, Shannon L. Everman and David E. Nichols) called it an "integrated hypothesis." They looked at a decade worth of MDMA research and tried to put the pieces together. They came up with this theory in the summer of 1997 and it was published in 1998. To date, it is still the dominant theory of how MDMA causes axon damage in laboratory animals, and would most likely apply to humans as well, should neurotoxic damage in humans be proven conclusively.

Technical details

Below are some rather techincal explanations of how they came up with this theory. If you're not interested in such detail, go on to the next image. Looking at past studies of MDMA neurotoxicity, it is clear that dopamine plays a crucial role. For example, in 1988, it was discovered that pre-treating rats with a-methyl-p-tyrosine, a substance which inhibits the synthesis of dopamine, prevents MDMA neurotoxicity (Stone et al.). Also, in 1990 a study showed that if you destroy all of the rat's dopamine terminals before giving them MDMA (thus eliminating all their dopamine), they sustain no serotonin axon loss (Schmidt et al.). Furthermore, in the same year they also discovered that if you give the rats L-DOPA, a dopamine precursor, they sustain more neurotoxic damage when given MDMA. And another study in 1991 demonstrated a linear correlation between the amount of dopamine release and the extent of MDMA-induced axon loss in rats (Nash and Nichols).

In 1987 researchers discovered that MDMA itself releases dopamine (Schmidt et al., Steele et al.). Then they discovered in 1996 that serotonin release also increases dopamine release (Gudelsky and Nash). It does this because one of the serotonin receptors (receptor 2A), when activated by serotonin, stimulates the synthesis and release of dopamine (Nash; Schmidt et al., 1990). Also, drugs which block the 2A-receptor have been shown to reduce extracellular dopamine levels.

They also discovered that dopamine actually can get uptaken into the serotonin terminal (Faraj et al, 1994) and that the terminal dose, in fact, contain a type of MAO known to metabolize dopamine (MAO-B).

To further support the theory, in 1995 they discovered that MAO-B inhibitors (L-deprenyl or MDL-72974) reduce neurotoxic damage in rats given 40mg/kg of MDMA.

2) "All shrivelled up."

This is what a damaged serotonin axon terminal might look like under a microscope using the "Fink-Heimer" silver staining method, or another one called "immunohistochemical" staining.

3)How does Ecstasy cause the release of serotonin?

We've been neglecting this question for a long time, because we didn't want to present too much information all at once, and there wasn't any pressing need early on to show this. However, we'll show you now. MDMA enters the serotonin axon terminal by going through the uptake transporters! Researchers say MDMA has a greater affinity for the transporter than serotonin (just like prozac does). This means that the MDMA will be the first thing to get into the axon terminal. Once there, it interacts with the vesicle, causing it to pour it's serotonin into the synapse. The important thing to be aware of is that the MDMA does its thing only after entering the serotonin axon terminal via the uptake transporters. This is important, as we will soon see.

4) MDMA Makes the Serotonin Transporters Work In Reverse!

A new theory is gaining wider acceptance among researchers about exactly how MDMA causes serotonin to be released into the synapse after it enters the axon. It is no longer assumed that the MDMA somehow interacts with the vesicle, causing it to pour its serotonin into the synapse.

Rather, the MDMA is thought to make the transporters work backwards, transporting serotonin from inside the axon to the synapse!

Here's the theory:

Once the MDMA enters the transporter, it falls off inside the axon terminal, and leaves the transporter in such a state that a serotonin molecule now binds to the place where the MDMA fell off. The transporter then spins around and deposits the serotonin molecule into the synapse, where another MDMA molecule binds to where this serotonin molecule used to be.

This all happens through a four-step process:

1. MDMA is released from the transporter into the axon when the transporter undergoes a change in "configuration." (The transporter is basically a group of proteins that can change configuration, or "shape." Depending on its configuration, certain molecules are more likely to bind to it. This is called "affintity." When a molecule with a high affinity binds to a transporter, it changes the transporter's configuration, which eventually causes the molecule to unbind or "fall off," possibly on the other side. This is what makes the transporter capable of "transporting" molecules between the synapse and the axon.)

2. The transporter now has the correct configuration to attract and bind cytoplasmic serotonin inside the axon.

3. The bound serotonin is then transported out of the presynaptic cell, and when the transporter changes configuration again, the serotonin falls off into the synapse.

4. The transporter is now in the correct configuration to attract more MDMA in the synapse, and the whole process is repeated.

Remember, serotonin is produced inside the axon (through the conversion of 5-htp), and under normal circumstances it enters the vesicles, which release it, over time, into the synapse. The reuptake transporters then bring some of the serotonin back into the axon, where it enters the vesicles again and is recycled. On MDMA, however, most of the serotonin enters the synapse directly through the reuptake transporters (in the opposite direction from what is normal).

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Full credit to Emanuel Sferios and DanceSafe for the creation of all images and associated text.

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