Claude de Contrecoeur wrote:
>>>> How MDMA may enhance Sociability:An Hypothesis.
> ----------------------------------------------------------------------------
The sociabilising action of MDMA is,very probably, related to its
indirect blockade of
> serotonin
> neurotransmission in a brain structure called the MEDIAN RAPHE NUCLEUS.
It's my understanding that MDMA has the effect of increasing serotonergic
transmission through an effect on the Serotonin Transporter. It acts at
serotonergic sites the way methamphetamine acts at noradrenergic sites,
and cocaine at dopaminergic sites - it sort of forces the transporter
into reverse, so that unpackaged, newly synthesized neurotransmitter
(5HT, DA, or NE) is forced out through non-exocytotic mechanisms,
probably being carried out of the cell by the reuptake transporter
instead of into the cell. There is much evidence to support this in
methamphetamine and cocaine research (blocking NET or DAT will block the
respective effects, and microdialysis has shown increased extracellular
DA after cocaine ingestion), and recent work, along with many subjective
case studies (i.e. the rec.drugs.psychedelic newsgroup) suggests that
prozac and the other 5HT reuptake inhibitors will block the effects of
MDMA.
When the Median
> Raphe Nucleus is inactivated then sociability,spontaneously,appears.In fact,both
> GAMMA-OH(gamma-hydroxybutyrate) and MDMA could act at a common site modulating
> oxytocinergic neurotransmission(Oxytocin is postulated to be of crucial importance in
> the expression of sociable states).
First, I admittedly don't know the distribution of tocinergic cells,
other than the PVN of the hypothalamus. So my question is, are there
connections between MR and PVN? I have been injecting WGA-HRP into areas
near the MR for my own project and have accidentally hit it once or
twice, but don't recall seeing any anterograde hypothalamic labelling
(there may have been a retrograde cell or two but it wasn't very well
labelled at any rate). Is there evidence for this projection, or is
there evidence for tocinergic cells in the MR itself? Or to anyplace it
projects?
The expression of "sociable states" connects with oxytocin and
vasopressin, but so far in a very limited number of rodent species (voles
for instance). Experiments on higher animals haven't demonstrated the
same effect, so species differences seems to play a BIG role.
The following hypothesis could link the effects on
> sociability of these two molecules.Basically this hypothesis states that MDMA might be
> an
> indirect tyrosine hydroxylase activator(Gamma-OH is a direct tyrosine hydroxylase
> activator) by suppressing the action of serotonin at post-synaptic 5-HT-IA
> heteroreceptors,thus enhancing the activity of tyrosine hydroxylase in some
> unidentified locus normally controlled by the release of serotonin from the Median
> Raphe Nucleus.
What does TH have to do with tocinergic systems? If TH is being
activated, and indirectly increasing release of DA/NE/EPI (which I don't
think is a given fact either), why couldn't you just say that the
stimulant effect is what's increasing sociability. Considering that X is
usually taken in a fun,upbeat setting (rave, for instance) or with good
friends or loved ones, you could argue that someone is already inclined
to being in a good mood. The stimulation provided by MDMA/GHB is just
amplifying that good mood. It doesn't have to be increasing the desire
for social contact (what I presume you mean by sociability) directly.
Of course, this assumes that MDMA does suppress 5HT transmission.
There is one molecule, called NAN-I9O ,which could help in evaluating
> this hypothesis.GAMMA-OH is a pure sociabiliser while MDMA and MDMA-mimetics are
> partial sociabilisers.At lo
> w doses of MDMA the sociabilising action of this substance is masked by a
> pro-serotoninergic action as MDMA is,also, a serotonin releaser.This effect of MDMA
> produces a psychotropic action similar to the serotoninergic thymoanesthesisers such
> as fluvoxamine,citalopram,sertraline,etc.
I've never seen nor heard of people saying they felt emotionally flat
after taking X, even low dose first time users. Where did this
information come from (a published primary paper would be nice)?
At higher dosage the sociabilising action of
> MDMA becomes manifest.Subjectively speaking 2.5gr of GAMMA-OH are equivalent to 2OOmgr
> of MDMA.
Are you suggesting that the neurotoxic effects of MDMA (reducing
serotonergic nerve terminal counts) are what's responsible for this
sociability effect? At higher doses, you'll just amplify the effect of
MDMA on SERT. Eventually, assuming the mech. of action is similar to
cocaine, you'll wind up removing 5HT from the terminal vesicles by
pushing the vesicular monoamine transporter (or the vesicular 5HT
transporter if it isn't VMAT) into reverse the way SERT already is being
pushed. This forces more 5HT release.
Haloperidol Imgr does not block the sociabilising actions of Gamma-OH
while it
> blocks
> the dopaminergic effects of a dose of 2OOmgr of Amineptine,a dopamine re-uptake
> blocker.Haloperidol might block the sociabilising effects of MDMA.This is not clear
> yet and should be studied.
While MDMA has some overlap effect on NET at higher doses, I haven't seen
whether it affects DAergic terminals. I also don't know whether Vitamin
H :) affects 5HT uptake at all. Presumably, if there isn't overlap by
haloperidol, it shouldn't block any effects of MDMA.
Andrew Ray
Emory University Neuroscience Program
aray at emory.edu
