From: bagg@ellis.uchicago.edu (matthew john baggott)
Subject: Re: Ecstasy
Reply-To: bagg@midway.uchicago.edu
Organization: University of Chicago
Date: Thu, 28 Jan 1993 00:09:07 GMT

In article <1993Jan22.181434.6764@mnemosyne.cs.du.edu> aankrom@nyx.cs.du.edu (Anthony Ankrom) writes:

> I have to beg to differ with the figures presented here by this poster. I
>would like to see reference citings, becuase the articles that I have read
>have NEVER reported the 80% loss in serotonergic neurons. I only regret
>that I cannot cite these references myself.

You could get as high as an 80% decrease in the density of 5-HT uptake
sites at 2 weeks after 20 mg/kg s.c. MDMA given twice a day for four days 
in some of the rats, but there'd be a lot of variability in the 
individuals.  And it would be a pretty punishing regimen, although
part of why MDMA neurotoxicity is popular is that the rats don't die
as much on it (as compared to methamphetamine).

One neat recent-ish study was done by Kathy Cunningham.  She failed to
find neurotoxicity in rats after intraraphe microinjections of MDMA.
She used as high a dose as possible while avoiding doses that
produced non-specific tissue damage.  Some neurotoxin MDMA makes!
Her data suggests systematic effects of MDMA may be important in 
producing axonal degeneration.   One candidate is body temperature which 
correlates with axonal degeneration.

The real cause for concern, IMHO, isn't the 5-HT axonal degeneration,
but the inclusions which develop in the neuronal perikarya in the
dorsal raphe nucleus of monkeys given high doses.  These have been
found by Ricaurte and are currently kind of puzzling.

>                                             If I recall, the neurotoxicity
>has to do with the serotonergic neurons taking up dopamine into the
>serotonergic neurons which somehow cannot properly metabolise it.

This is one theory and is based upon the fact that the release of DA
seems important for the neurotoxicity.  If you block the release of
DA, you block the neurotoicity.  However, that phenomenon fails to
demonstrate that DA or some metabolite is the neurotoxin.

>                                                                  I have
>heard that the potential for neurotoxicity of MDMA and PCA and
>fenfluramine can be reduced by taking a subtherapeutic dose of a sertonin
>uptake inhibitor, such as Prozac, as long as up to 6-8 hours after taking
>said drug(s). Taking the prozac can subdue the effects of the drug as
>well. 

You heard correctly.  See Schmidt _JPET_ 240: 1-7.

> One disparity that I have wondered about is whether or not the
>neurotoxicity  that is being quoted is that of MDA or MDMA. They
>supposedly work in the brain via different mechanisms.It would seem odd
>that they would display similar neurotoxicities.

Both have appreciable affinities for lots of different receptors.
MDMA doesn't seem to do much at of interest at most of them,
although its alpha-2 adrenergic binding might play a role in
its cardiovascular effects.  MDA, on the other hand, does something
interesting at receptors, like produce hallucinations.  So far so
different.  However, both also do something interesting at the
reuptake transporter and probably inside the 5-HT neuron as well.
Thus, they have overlapping mechanisms.

>
>St. Anthony
>

      --Matt