Posted by MB on July 25, 2003, at 21:56:47
In reply to Re: nah, this is important. wouldnt do something like, posted by stjames on July 21, 2003, at 14:44:22
> In over 200 doses I have no neurotoxicity. Given that ecstacy has been around for decades, you would think this "neurotoxicity" would be well reported.
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Here's an article for you.
MB-------------------------------
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 slide.
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.
poster:MB
thread:243723
URL: http://www.dr-bob.org/babble/20030723/msgs/245346.html