The Neuropharmacology of Hallucinogens V2

[5-HT2]

Thanks for those points 5-HT2. I agree with your point about a combination of 2nd messenger sysmtes. I perhaps wonder if it was the ratio of PLA2/PLC that denoted potency. With a higher ratio meaning more potency. Perhaps PLC activation inhibits EPSPs (increase calcium influx, PKC activation, channel phosphorylation and inhibition)

There is definitely evidence that PKC activation inhibits excitatory synaptic transmission. Activation of PKC via the 5-HT2A receptor reduces sodium current, though it is unknown whether it is due to phosphorylation of the sodium channels themselves (Serotonin receptor activation inhibits sodium current and dendritic excitability in prefrontal cortex via a protein kinase C-dependent mechanism.
J Neurosci. 2002 Aug 15;22(16):6846-55.). In addition, PKC is involved in 5-HT2A receptor internalization (Internalization and recycling of 5-HT2A receptors activated by serotonin and protein kinase C-mediated mechanisms. Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14470-5.).

which PLA2 activation potentiates EPSPs... LSD has the highest PLA2/PLC ratio....

Perhaps we should do a little meta-analysis of the literature and see whether the ratio of PLA2/PLC is correlated with potency of hallucinogens. Then again, I would be surprised if Nichols hasnt already done this, and if the results were positive, he probably would have reported them by now. Maybe e-mailing him first would be a good idea.

P.S. Last time we talked on this subject, you were reading the Ion Channels of Excitable Membranes.... Now I'm reading it...

Great book. The second half is pretty hardcore and I sometimes had trouble following all the math, but I definitely got a lot out of it.

 

[ice-9]

excellent job

 

[BilZ0r]

Perhaps we should do a little meta-analysis of the literature and see whether the ratio of PLA2/PLC is correlated with potency of hallucinogens. Then again, I would be surprised if Nichols hasnt already done this, and if the results were positive, he probably would have reported them by now. Maybe e-mailing him first would be a good idea.

Been there, done that. The problem is, I believe the work done by Nichols and Kurrasch-Orbaugh on the PLC/PLA2 work he did on hallucinogens, but he didn't do very many, 5-MeO-DMT, psilocin and maybe DOM and some of his weird moth and fly phenethylamine hallucinogens, along with things like lisuride, tryptamine non-hallucinogenic compounds. The problem is, finding reliable drug discrimination results to compare it with. still....

 

[Riemann Zeta]

Excellent review article. Even published, highly regarded academic texts such as Cooper, et al (2003) and Feldman, et al (1997) do not go into this much detail concerning 5-HT2A receptors. You should submit this to a real journal, like JPET, Mol. Pharmacol, or Pharmacol. Rev.

P.S. Props for mentioning 'Ion Channel of Excitable Membranes,' it is one of my favorites. If you like that style, and are interested in a more clinical approach to ionotropic receptors, check out 'Ion Channels & Disease' by Ashcroft (1999).

 

[BilZ0r]

For one, none of those journals would publish reviewes from people who didn't work in the field... but even if they wanted to, there is no point.. Apart from my 'putting it all together section', there is hardly anything new there in comparison to Nichols 2004 - Hallucinogens.

I also realise that I need to put in my "putting it all together" section, a wee bit possibley disucssion the effects of increased assynchronous transmission...

 

[5-HT2]

The idea that hallucinogens work at least in part by inhibiting firing of the raphe nuclei was once seen as a major hypothesis, but now seems unlikely. Although it seems conclusive that indole hallucinogens inhibit raphe firing via activating 5-HT1A receptors, recent evidence suggested that the mixed excitatory/inhibitory effects of phenethylamine hallucinogens on raphe firing actually leads to an increase in total 5-HT release as measured by in vivo microdialysis (Martin-Ruiz et al., 2001; Puig et al., 2003).

Be careful here. Release of 5-HT was increased only when the DOI was applied LOCALLY in medial prefrontal cortex. When it was administered systemically, serotonin release was inhibited.

 

[Schizomanic]

Great work, I can tell YOU don't have ADD! And if you do, bravo...

 

[Meshuggah]

Excellent work.

 

[BilZ0r]

Be careful here. Release of 5-HT was increased only when the DOI was applied LOCALLY in medial prefrontal cortex. When it was administered systemically, serotonin release was inhibited.

GOD DAMN IT. You know, when I wrote that (it was one of the last things I added in), I specifically checked that, cause I was like "That's odd, all those old papers showed that PEAs decreased 5-HT turnover, I better just check that it is not local administration" and I checked, and I thought I read IV... but you're right.

I see, its because when they record pyramidal cell firing they inject DOI.

 

[BilZ0r]

Right, so I changed that bit to:

Originally posted by bilz0rs shitty article
The idea that hallucinogens work at least in part by inhibiting firing of cells in the raphe nuclei was once seen as a major hypothesis, but now seems unlikely, thought it may in some way modulate the subjective effect hallucinogens produce.

And in the History of Mechanistic Research (end of 2nd paragraph) I put

Originally Posted when I wrote the first section
Furthermore, the effects LSD induces on the raphe were not proportional to the behavioural effects, the effects of the raphe outlasted the behavioural effects and tolerance to LSD-induced behavioural effects was not proportional to the tolerance induced in the raphe (Trulson et al., 1981). Finally it was shown that the effect indole hallucinogens have on the raphe was mediated by 5-HT1A autoreceptors (Trulson et al., 1981), and that non-hallucinogenic compounds can have the same effect (Rogawski & Aghajanian, 1979). Although this makes the idea that hallucinogens mediate their action via inhibiting raphe cell firing extremely unlikely, it is not impossible that lowered 5-HT release in part mediates hallucinogen action, as systemically applied phenethylamine inhibit some raphe neurons (Aghajanian et al., 1972), and decrease 5-HT turnover (Anden et al., 1974).

 

[Riemann Zeta]

I know, real journals don't publish anything unless someone with a PhD is a coauthor (if you have a PhD, mea culpa); as a graduate student, I know this all too well. Nevertheless, your article is well written and contains a wealth of useful information for prospective psychonauts--it is rare to see electrophysiological discussions in the popular press.



P.S. One nitpicking item: on pg. 4, the subtitle is "Modern mechanistic of hallucinogen research," instead of 'mechanisms.'

 

[BilZ0r]

I'd ask you this by a private message Riemann, but you don't seem to accept them... What is your area of study?

 

[Blowmonkey]

*Bump*

This would go great in the new "Advanced Drug Discussion" forum.

 

[fastandbulbous]

Damn fine

Very nice. I've just read it, and even though I'm a bit slow at the moment due to having a cold, it has helped me pin down some of the points I was still a bit fuzzy about (I will re-read it when I'm virus free).
The one thing that I found was excellent was that it pulled together three different types of hallucinogen into one overall scheme (5-HT acting hallucinogens such as the phenethylamines/tryptamines/ergolines, NMDA antagonists such as the arylcycloalkylamines and GABA acting hallucinogens - ibotenic acid/muscimol) Whereas I had a fair idea about the 5-HT and NMDA based hallucinogens, I'd always been at a bit of a loss to intergrate ibotenic acid/muscimol into the big picture.


PS. One last thing; you've made me realize just how lazy and complacent I've become in the 15 years since I left university academia

PPS. On the editing/proof reading front, you might want to alter the styructural diag of DOI, as you haven't shown the alpha-methyl group (as it is, it's the structure of 2C-I)

 

[Church]

This is excellent, excellent work, BilZ0r! Congratulations indeed.

 

[gloggawogga]

Moving this one over to the new AD forum

 

[Ernestrome]

The history of mechanistic hallucinogen research
Once serotonin’s (5-HT) presence was demonstrated in the brain in 1953 (Twarog & Page, 1953) it was not long until the chemical similarity between LSD and 5-HT was noted and in the same year, Gaddum (1953) demonstrated that LSD antagonized the action of 5-HT in peripheral tissues. Soon afterwards two groups independently proposed the hypothesis that the hallucinogenic action of LSD was due to its ability to block central 5-HT receptors (Gaddum & Hameed, 1954; Woolley & Shaw, 1954). This idea held sway, even after it was shown that the brominated LSD analogue BOL, which was a potent 5-HT antagonist, was devoid of hallucinogenic action (Cerketti & Rothlin, 1955; Woolley & Shaw, 1954), that BOL could block the hallucinogenic effects of LSD and that several other LSD analogues, which were weaker 5-HT antagonists, were more potent in regards to their hallucinogenic action (Gogerty & Dille, 1957; Votava et al., 1958). Anden et al., (1968) was the first to suggest that the primary action of hallucinogens was as a 5-HT receptor agonist, and with the body of evidence already mentioned this idea was rapidly excepted by most. Recent evidence from cortical brain slices has shown that hallucinogens are 5-HT receptor partial agonists (Marek & Aghajanian, 1996), although there is still some debate as to whether all hallucinogens are partial agonists (Villalobos et al., 2004).

Fantastic. I hope corrections won't seem pedantic, the bold word should be accepted.

 

[Xherrus]

Entheogen is derived from the Greek, enthos, which means “god within”...

A somewhat pedantic correction. There's no such word as "enthos"; the word entheogen is composed like so.

"en-" (in, within)
+ "-theo-" (god, spirit)
+ "-gen" (create, generate)

So you could say:
Entheogen is derived from the Greek, basically meaning “[something that] creates the god/spirit within.”

Great work, BilZ0r, by the way.

 

[BilZ0r]

entheo... I didn't mean to have the S.... I left of the gen, because it was preaty obvious...

 

[samantha]

wow!!! impressive. I'll read it carefully during daytime and comment on it later. Excellent job! wow!