From: bagg@ellis.uchicago.edu (matthew john baggott)
Newsgroups: alt.drugs
Subject: Re: LSD the poop is straight
Date: 21 Nov 92 22:21:18 GMT
Reply-To: bagg@midway.uchicago.edu
Organization: University of Chicago Computing Organizations

In article <1992Nov19.182245.20320@u.washington.edu> lamontg@stein.u.washington.edu (Lamont Granquist) writes:
>f0358@desire.wright.edu writes:

>>Lysergic-acid diethylamide
>>
>>When ingested into the human body, LSD act as 5-HT (Serotonin) autoreceptor
>>inhibitor, thus it is a 5-HT agonist.  LSD increases the level of active 5-HT
>>molecules by disaffecting their autoreceptors (a safeguard type feature in the
>>brain which reduces levels of certain neurotransmitter and the like). 

That "thus" in the first sentence should be an "and."  I'm not certain
what "disaffecting" should be (autoreceptors' only true loyalty is
to the laws of chemistry & physics) for the second sentence to be
true.

The autoreceptors in question are 5-HT1As.  5-HT2s, which are not
autoreceptors and which hallucinogens agonize, seem to be the more
important ones for hallucinogenic activity. Hallucinogens need not 
affect 1As directly (some definitely don't).  However, 5-HT2 receptor 
activation seems to facilitate presynaptic 1A function (such that,
for example, hallucinogen use produces rapid 5-HT2 downregulation
which, in turn, decreases 5-HT1A function).  So hallucinogens would
inhibit autorecetpor activity, but not necessarily directly.

>LSD also has effects on 5-HT1C receptors, and its not entirely sure what the
>specific receptor mechanism is -- there's also the question of why the
>psychological effects seem to last much longer than the presence of the LSD
>molecule.  One thing that is fairly sure is that LSD shuts down the firing of
>the seratonin neurons in the raphe, though.

It is difficult to separate 1Cs from 2s because of their great similarity.
However, hallucinogens seem to be all 2 & 1C agonists.  Molecules which (like
LSD) are partial 2 agonists, and which (unlike LSD) are 1c antagonists
are not hallucinogenic.

I believe that the effects of DOI (and probably LSD) on firing in the
raphe nucleus are not blocked by 5-HT2 antagonists (like ketanserin),
implying that these effects are not mediated by 5-HT2 receptors.
Oddly enough, ritanserin (which antagonizes 2 and 1C) doesn't block
'em either.  That's kind of mysterious to me.

>  5-HT has been implicated in
>>certain behaviors, notably dreaming and sleep, which explains the hallucinatory
>>effect.  We are in effect dreaming while completely awake and aware.

>Actually, a better explanation is the increased firing of the locus coereleus
>by its disinhibition due to the neurons in the raphe slowing down (since you
>are inhibiting an inhibitory neuron the result is excitation...).  The l.c.
>has been associated with being a "sensory highway" in the brain, and has also
>been associated with feelings of anxiety, and theorized that its invovled
>with depression.  My guess is that the hallucinations and stimulatory effects
>of LSD come from potentiating the l.c., while the effect on the 5-HT neurons
>in the raphe is responsible for its entheogenic effect on the mind.

This isn't the full story since this decrease in firing (in the raphe) is still
produced by hallucinogens even after chronic treatment with hallucinogens.
Since tolerance does develop to hallucinogens, we would have
expected to see it in the firing.  Of course, rate of firing and amount
of 5-HT released _are_ two different things.  Besides, tolerance may
occur via another route.  

>>I for one have never actually hallucinated in that I have seen things that were
>>in fact not there.
>
>Yup, you've only had *psychedelic* experiences.  To have a *hallucinogenic*
>experience you're supposed to take Ketamine (so I've read).

High doses of LSD or mushrooms will produce full-blown hallucinations.
Mushrooms can have some toxicity at high doses, although many people
still seem to find it easier to achieve hallucinations with them than with
LSD.

>-- 
>Lamont Granquist  lamontg@u.washington.edu
>  "When dogma enters the brain, all intellectual activity ceases."
>                                      -- Robert Anton Wilson

     --Matt
Newsgroups: alt.drugs