Subject: MDMA Neurophamacology
From: [email-masked] (Lamont Granquist)
Date: 23 Jun 1994 09:26:59 GMT
Newsgroups: alt.drugs,alt.psychoactives,sci.med.psychobiology

Check this out for accuracy -- ignore spelling errors, i haven't bothered
to run it through a spell-checker yet, which should catch them...

If anyone has any suggestions of good introductions to neurpharm for the
"public" along the lines of Synder's book, i'd appreciate it.

MDMA Neuropharmacology

     MDMA is primarily a seritonergic (5-HTergic) drug.  Serotonin
(5-hydroxytrytamine, 5-HT) is one of the major neurotransmitters in the
brain, and is synthesized from tryptophan through the intermediate
5-hydroxytryptophan.  It is synthesized in 5-HT neurons, and stored in
synaptic vesicles.  These vesicles release their 5-HT into the synaptic
cleft in response to the firing of the 5-HT neurons.  In the synaptic
cleft the 5-HT neurotransmitter excerts its action on both pre- and
post- synaptic receptor sites (sites on the 5-HT neuron itself, and on
the neuron which it is communicating with.)  5-HT is then taken back
into the 5-HT neuron via the synaptic membrane 5-HT transporter (aka
"reuptake pump"), where it is again stored in the synaptic vesicles.
5-HT is metabolized primarily by monoamine oxidase (MAO) into
5-hydroxyindileacetic acid (5-HIAA).
     Serotonin is thought to be responsible for many psychological (and
physiological) states including mood and sleep.  It has been particularly
associated with major depression and obsessive compulsive disorder, and
drugs to treat these disorders tend to effect 5-HT (although things are
not quite clear-cut).
     MDMA blocks the reuptake of 5-HT, similarly to SSRI (serotonin
specific reuptake inhibiting) anti-depressants such as fluoxetine (Prozac),
sertraline, and paroxetine.  Unlike those drugs, however, MDMA appears
to enter the neuron, either through passive diffusion or directly
through the reuptake transporter, and causes the release of 5-HT.  This
release is calcium-independent (i.e. independent of the firing of the
5-HT neuron) and appears to come from cytoplasmic stores rather than
from synaptic vesicles.  The released 5-HT then enters the synaptic cleft
through the 5-HT transporter.  MDMA thus acts on 5-HT similarly to the way
amphetamines act on dopamine.
     It is thought that this efflux of 5-HT into the synaptic cleft, and
the subsequent action of this 5-HT on pre- and post- synaptic binding
sites is central to MDMA's neuropharmacology.  MDMA, however, has 
micromolar potency for the serotonin 5-HT2, muscarinic M1, alpha-2 adrenergic
and histamine H1 receptors.  Agonist (stimulation rather than blocking)
properties at the 5-HT2 receptor have been found to fairly universally be
associated with "classical" psychedelic drugs such as LSD, psilocybin and
mescaline.  It is possible that some of MDMA's "psychedelic" effect occurs
because of interactions with this receptor.  The alpha-2 adrenergic receptor
may be associated with some of the carciovascular effects of MDMA.
     MDMA also releases dopamine which may be central to both its
psychological action and to its neurotoxicity in animal studies.  Pre-
treatment of an animal with a drug which blocks dopamine release will
also block MDMA neurotoxicity.  Also, serotonin specific releasing agents
which are non-dopaminergic have been synthesized and been found to be
devoid of MDMA's neurotoxicity in animals, they have also been found to
be devoid of MDMA's psychological effects.  MDMA tends to indirectly
*inhibit* the firing and release of dopamine in nigrostriatal dopamine
neurons (neurons projecting from the substantia nigra to the striatum) due
to local 5-HT release.
     MDMA doses of 20mg/kg in animals can reduce levels of tryptophan
hydroxylase, which is the rate-limiting enzyme in 5-HT synthesis.  It is
thought that this occurs because of oxidative stress which MDMA places
on the neuron.  This oxidative stress might occur through several
possible channels (the metabolism of MDMA into a toxic Quinoid, 5-HT
derived toxins, 5-HT mediated cellular events, or temporary inhibition
of monoamine oxidase) and the exact mechanism is presently unknown.  It is
thought that this oxidative stress also leads to the neurodegenerative
destruction of 5-HT axons which is observed to occur with large doses of
MDMA in animals.  Anti-oxidants, anti-dopaminergic agents, agents which
block intracellular calcium increases and pre- or post- treatment (up to
6 hours) with fluoxetine all block MDMA's neurotoxicity.  Research
ontinues on the exact mechanism of MDMA-induced toxicity.
     In summary, MDMA effects 5-HT similarly to the way that amphetamines
effect dopamine, by inhibiting the reuptake and causing the release of 5-HT.
This effect is somewhat similar to the effect that SSRI anti-depressant
drugs have.  It also effects the 5-HT2 (psychedelic) and alpha-2 adrenergic
(cardiovascular) receptor sites.  Also, its effects on dopamine appear, at
this point, to be involved both with its neurotoxicity and psychological
effects.  For more information, see:

     Rattray-M. "Ecstasy: towards an understanding of the biochemical
     basis of the actions of MDMA."  Essays in Biochemistry.  26:77-87.
     1991.

And for general info:

     Synder, Solomon H. "Drugs and the Brain."  Scientific American Books.
     1986.  (slightly out of date, but a good introduction).

     Cooper-JR, Bloom-FE, Roth-RH.  "The Biochemical Basis of Neuro-
     Pharmacology."  Oxford Uniersity Press.  1991 (6th ed).  (the bible
     for grad students)

-- 
Lamont Granquist ([email-masked])
"And then the alien anthropologists - Admitted they were still perplexed - But
on eliminating every other reason - For our sad demise - They logged the only
explanation left - This species has amused itself to death" -- Roger Waters