LSD, serotonin and dopamine

[specialspack]

Something Nichols said at the Basel conference - this was in the Hefter forum session if anyone else remembers - about LSD acting first via serotonin receptors, and then via domapine.

He discussed some rat experiments where blocking either the 5-HT activity during the initial part of the ... the "experience" in rats was enough to stop any effects from LSD, or by blocking the the dopamine mediated activity in a later time (I think the total duration was around three hours, and the switch from serotonin to dopamine came around 30-60 mins).

Does this make sense to anyone - I don't know if this was published material he was talking about.

 

[lifeisforliving]

^ Could it be that the stimulation of the serotonin system resulting in more cellular activity that responded with a dopamine response? Or did they speak of LSD actually binding the receptors for dopamine or somehow releasing dopamine?

 

[narrative0]

He was probably talking about this:


http://www.ncbi.nlm.nih.gov/entrez/..._uids=15723230&query_hl=7&itool=pubmed_docsum

 

[BilZ0r]

Well it's complicated.

In humans during normal recreational use, LSD must only reach a tiny occupancy at dopamine receptors.

That LSD drug discrimination paper cited above uses some pretty fucked up doses... 0.16mg/kg are you serious? I mean, I know that that is a pretty common dose in rodents, but it's got to cause spillover into all kinds of receptors that it would never hit in humans.

 

[specialspack]

^ Could it be that the stimulation of the serotonin system resulting in more cellular activity that responded with a dopamine response? Or did they speak of LSD actually binding the receptors for dopamine or somehow releasing dopamine?

Hmm, I don't remember clearly. Presumably that paper will have the details.

Bilz0r... I'm confused so spell it out for me - the DA affinities are at least as great as those for 5-HT2A (which, according to Nichols et al is the main locus for psychedelic activity) so why shouldn's such a tiny occupancy be involved?

 

[ChuangTzu]

Bilz0r, regardless, I find it interesting that despite the high doses given to the rats, discrimination is still blocked by a dopamine antagonist, but not a 5HT2a antagonist. Nichols discusses this in a section of his review article Hallucinogens [Pharmacology & Therapeutics 131-181 (2004)].

 

[5-HT2]

I would like to point out, as I have in the past, that the affinity of LSD for DA receptors is HIGHLY controversial. Also, even if it has a high affinity, if it has little efficacy as an agonist, then it doesn't matter. Also, I agree with Bilz0r's impressions of the appropriateness of the dose of LSD they used.

 

[VelocideX]

specialspack - a larger bar on that graph means a smaller binding strength.

 

[BilZ0r]

Yeah, the lower the Ki, the higher the affinity.. i.e. LSD has the highest affinity for 5-HT1A and 5-HT6 receptors.

Bilz0r, regardless, I find it interesting that despite the high doses given to the rats, discrimination is still blocked by a dopamine antagonist, but not a 5HT2a antagonist. Nichols discusses this in a section of his review article Hallucinogens [Pharmacology & Therapeutics 131-181 (2004)].

Yeah.. but drug discrimination experiments are fucked, 5-MeO-DMT more potently generalizes to 5-HT1A receptor agonists. Who knows whether it's a neural effect, or just because of it's effects on blood pressure, or whatever.

And I mean, the LSD discrimination was still fucked around by classical 5-HT2A receptor ligands... I don't fully understand the article, but I can't really see how it proves it's point.

 

[ChuangTzu]

^^Right, but it's still more interesting than if things had gone as we'd expect. Of course, the only psychedelic studies that actually mean anything are the ones involving human subjects. Unless you actually care about head twitch responses in rats or hyperthermia in rabbits...

 

[TioMoco]

I've dosed 50+ times in my misspent youth and really enjoyed it, and always felt amazingly refreshed for the next few days after a trip.

In the last two years, I have been diagnosed with mild BP2 and started on an SSRI and also some Seroquel, to help me sleep.

The first couple of times I tried the Seroquel, I would get this sensation very similar to some of what I felt on the acid - a brightening of colors and sounds, and some other sensations that are hard to describe right now.

I suspect that the serotonergic effects of Lexapro and Seroquel are related to some of the clearheadedness and sense of balance that I would get for a few days after I dosed.

I don't recall feeling as good after eating fungus as I did after dosing, so maybe the mechanisms are less closely related than most people think (tripping is tripping).

I am also taking Ritaling for my recently diagnosed ADD symptoms (that I've had forever) and am finding that the dopamine activity of the methylphenidate has been so kind to my brain, that I actually have little desire to drink anymore and even opioids seem unappealing.

I'm thinking that I have my serotonin and dopamine issues addressed, as I'm feeling better than I have in 20 years. Lexapro, Seroquel and Ritalin (and ganja) are now enough to keep me satiated and I feel a peace that I thought would never come back.

Can someone map the activity of Lex and quetiapine on that chart to see what the overlap might be??? If I recall, Stephen Stahl's book on atypical anti-psychotics maps the activity of quetiapine on these receptors, but I can't find my copy right now.



tioMoco