2C-I and 5-HT2 receptors

[rincewindrocks]

Study Abstract

I think I understand the basic idea, which is just that 2C-I acts as a seratonin agonist, providing further evidence for seratonin as a major factor in psychdelic drug action. If Im wrong, please correct me.

 

[BilZ0r]

2C-I is a serotonin agonist, yes. All classical psychedelics are 5-HT2A receptor agonists (and most effect other receptors). Drugs that block 5-HT2A receptors (relatively) selectively, block the hallucinogenic effect of classical hallucinogens.

There is no question anymore that hallucinogens are hallucinogenic because they activate the 5-HT2A receptor

http://www.erowid.org/psychoactives/pharmacology/pharmacology_article2.shtml
Read up.

 

[rincewindrocks]

I just posted it cause this was the first hard evidence in study form that I had seen. I had assumed it was a seratonin agonist, but had nothing scientific to back me up before.

 

[BilZ0r]

^ Well that study doesn't show that it as an agonist, very clearly, just that it has affinity.

this study tries to say that they are ANTAGONISTS. But who knows what G-proteins the 5-HT2A receptors are linked to when they are expressed on Xenopus eggs. So I don't really care about that study.

 

[gerrym]

Dopamine, acetylcholine

Where do dopamine and acetylcholine fit in with regards to hallucinogenic drugs? Dopamine and norepinephrine (not just serotonin) are also known to be released, especially with the hallucinogenic amphetamines. Dopamine of course plays a role in psychoses.

Treatment with the older antipsychotics which antagonise dopamine results in cholinergic overload which is often treated with centrally-acting anticholinergics such as benzhexol and orphenadrine. These anticholinergics are euphoric and in high doses hallucinogenic. (Incidentally, the newer atypical antipsychotics are also potent 5-HT2 blockers.)

There is complex interaction between serotonin, norepinephrine and dopamine receptors. This is an interesting article which describes this in the context of atypical antipsychotics being used as augmenting agents with serotonin uptake inhibitors:

http://www.psychiatrist.com/supplenet/v66s08/v66s0805.pdf


gerrym
New Zealand

 

[BilZ0r]

Dopamine and norepinephrine (not just serotonin) are also known to be released, especially with the hallucinogenic amphetamines

Really? Are they? Do you have a citation?

Everything interacts with everything, it's the nature of the brain. Functionally important interactions? No, I doubt it. Anti-cholinergic hallucinations are in no way like those induced by classical serotonergic hallucinogens. Likewise, Anti-cholinergic hallucinations are not antagonist by atypical antipyschotics.

 

[gerrym]

Really? Are they? Do you have a citation?

Perhaps "play a role" was a better term than "released" Out of interest, this is from TOXINZ, our National Poisons Centre database here in NZ, on hallucinogenic amphetamines:



MECHANISM OF ACTION


Indirect sympathomimetic action through:

The inhibition of presynaptic vesicular storage and catecholamine reuptake

The reduction of catecholamine metabolism, via monoamine oxidase inhibition[88]


A stimulating effect on several central cortical centres including the:

Cerebral cortex

Medullary respiratory centre

Reticular activating system


Direct action on both alpha- and beta-adrenoreceptors


Hallucinogenic activity is thought to be due to:

Stimulation of serotonin and dopamine receptors in the CNS[89]

Methoxylation and methylenedioxylation of the catechol ring (metabolism of mescaline-like attachment that is present in hallucinogenic amphetamines)[90]


[88] Schmidt CJ, Wu L, Lovenberg W. Methylenedioxymethamphetamine: a potentially neurotoxic amphetamine analogue. Eur J Pharmacol 1986; 124: 175-8.
[89] Trulson ME, Crisp T, Henderson LJ. Mescaline elicits behavioral effects in cats by an action at both serotonin and dopamine receptors. Eur J Pharmacol 1983; 96: 151-4.
[90] Schmidt CJ. Acute administration of methylenedioxymethamphetamine: comparison with the neurochemical effects of its N-desmethyl and N-ethyl analogs. Eur J Pharmacol 1987; 81-8.

 

[gerrym]

Here are a couple of recent studies implicating D2/D3 involvement in effects produced by LSD. In one of these studies, effects were biphasic, the later dopamine-mediated phase not reversed by a 5HT2A antagonist but reversed by haloperidol:

Minuzzi L, Nomikos GG, Wade MR, Jensen SB, Olsen AK, Cumming P. Interaction between LSD and dopamine D2/3 binding sites in pig brain. Synapse. 2005 Jun 15;56(4):198-204.

Marona-Lewicka D, Thisted RA, Nichols DE. Distinct temporal phases in the behavioral pharmacology of LSD: dopamine D2 receptor-mediated effects in the rat and implications for psychosis. Psychopharmacology (Berl). 2005 Jul;180(3):427-35. Epub 2005 Feb 19.


gerrym
New Zealand

 

[5-HT2]

Really? Are they? Do you have a citation?

These effects of psychedelics are not surprising, due to the presence of the 5-HT2A receptor on cell bodies and axon terminals of catecholaminergic and (I think) cholinergic neurons. They have also been observed by several different groups:

[1], [2], [3]

 

[BilZ0r]

^ Oh yeah, I mean, I know the heteroreceptor role... but I though they guy was talking about amphetamine like actions (which he was)

gerrym: Those ciations are talking and MDMA, not 2C-I... or DOI, or the subjectively, "pure" hallucinogens in the phenethylamine spectrum.

 

[gerrym]

Yes, I was talking more generally about non-specific hallucinogens

BilZ0r, I have seen your article 'The Neuropharmacology of Hallucinogens' and I'm impressed. I've bookmarked it. You seem quite knowledgeable. I need your opinion on something. This is slightly off-topic for this thread; though this also brings up the subject of 5-HT2 and its blockade:

I regularly use benzylpiperazine (BZP) recreationally when attending dance parties, as a stimulant, to stay awake and keep dancing, and sociabiliser, which it has been doing a good job of until recently.

I started taking olanzapine 10mg/d as an augmenting agent to my SNRI antidepressant venlafaxine. Since starting olanzapine, my response to BZP has been significantly attenuated, as though I have taken little, even with increased dosage.

Now, when I dose up on BZP and attend dance parties, I have much less energy in me to dance than previously. The BZP is not as stimulating and the effects are fairly short-lived. What might be going on here pharmacologically? 5-HT2 and/or dopamine blockade? BZP is pharmacologically very similar to d-amphetamine, and the data I have read suggest a combination of serotonergic, noradrenergic and dopaminergic properties.

Would you say my description of what is happening is typical of someone who has been preteated with an atypical antipsychotic? I want to give whoever made olanzapine a knock to the head

gerrym
New Zealand

 

[illuminati boy]

While olanzapine (AKA Zyprexa) has a complicated pharmacology, its primary therapeutic actions are at Dopamine and Serotonin sites. Specifically it is a blocker at D2 and 5HT2A sites which will greatly attenuate the effects of drugs that target these pathways. Among other things, olanzapine is also pretty notable for causing pronounced sedation. While I must confess less of a familiarity with the psychopharmacology of BZP and related agents, it would seem plausible that olanzapine could cut down on stimulant effects by 1. making you more sedated generally and 2. directly impacting the dopamine and serotonin effects from any compounds ingested.

Olanzapine is a very potent compound that will pretty much kill the effects from most 5HT2A drugs and their cousins… but it is often quite effective for those who may need to take it for pronounced mood or thought disorder(s).

I hope this might have been helpful. If you wish to discuss this further, you may want to split this line of discussion into a separate thread.

I B

 

[BilZ0r]

^ Yeah, the 5-HT2A receptor is very important in the action of serotonergic amphetamines like BZP. You block it, you block a lot of the pro-dopaminergic effects.

 

[gerrym]

Haha. Clever olanzapine. I might look up its plasma elimination half-life in the data sheet and maybe miss a dose or two before taking BZP.

 

[illuminati boy]

Plasma concentrations are not the whole story when one is / has been regularly taking a medication such as olanzapine. Even if one were to suddenly discontinue their medications (which is probably not advised to say the least), it could take more than just a few days before ones response to something like BZP might be comparable in effect to before one started a medication such as olanzapine.

But just FYI the metabolites are effectively inactive and the parent drug has a 21-54 Hour ½ life… or so my handy dandy prescriber’s guide tells me anyway.

I B