Author Topic: Trip Tolerance: Neurons Swallowing own Receptors  (Read 3833 times)

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Ganesha

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More
« Reply #20 on: April 06, 2004, 10:06:00 PM »
My opinion on that matter is that DMT and 5-MeO-DMT are too short-acting to affect the receptor down-regulation, which only comes into play when the receptors are stimulated for longer time-periods.

You can always prolong the action of (5-MeO)-DMT by simply smoking more. How is duration of action related to the receptor down-regulation?


7is

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Some references
« Reply #21 on: April 07, 2004, 01:37:00 AM »
Hi, I uploaded all the articles mentioned in this thread to my site (and some bonus articles too)  :)  They are all named by the name of the study. Sorry that I dont have enough time to post more details.

http://nic-nac-project.de/~tajkor/1/


longimanus

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DMT and 5-HT2A downregulation
« Reply #22 on: April 07, 2004, 05:44:00 PM »
You can always prolong the action of (5-MeO)-DMT by simply smoking more. How is duration of action related to the receptor down-regulation?

 DMT DOES affect the 5-HT receptors` sensibility (i.e. activates the internalization process) and it doesn`t matter how much you smoke (or inject). That`s what Strassman`s articles say:

...Adrenocorticotropic hormone (ACTH), prolactin, cortisol, and heart rate responses decreased with repeated DMT administration...

 Which means that tolerance of the physical effects of DMT occurs. But (what is the most interesting characteristic of DMT) the strength of the behavioral effects produced by certain dose of the drug remains constant with the number of ingestions.

Lilienthal

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ACTH, prolactin, cortisol, and heart rate...
« Reply #23 on: April 07, 2004, 06:17:00 PM »
ACTH, prolactin, cortisol, and heart rate response could be a 'psychological response' to the strange effects of these drugs. The 'tolerance' then could be a simple customization to the starnge effects of these drugs. At least for cortisol I know that it is a  stress marker.

longimanus

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ACTH, PRL, MAP, HR... and something about cortisol
« Reply #24 on: April 08, 2004, 11:32:00 AM »
1. Who said ACTH, prolactin, cortisol and heart rate response are psychological response?

 2. A citation

Human psychopharmacology of N,N-dimethyltryptamine
Strassman, Rick J.
Behavioural Brain Research 73(1996)121-124

Medline (PMID=8788488)



...ACTH and PRL responses did decrease over the course of the morning, suggesting tolerance development. This differential tolerance development was interpreted as being mediated by independantly regulated desensitization of relevant 5-HT receptor mechanisms...

 Not that I`m sure it`s true but...

 3. Now about cortisol (hydrocortisone). It`s used as an antiinflamatory agent. W. Burroughs had used cortisone as a substitute for opiates. Actually it`s not an opiate but 1 mg i.v. feels better than benzodiazepines.

Nicodem

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10 minuteus vs. 2h makes a difference
« Reply #25 on: April 08, 2004, 11:50:00 AM »
Who said ACTH, prolactin, cortisol and heart rate response are psychological response?

Well, I guess they were dettermined from blood samples and not from intraspinall liquid or whatever connected with brains.

I agree with Lily, the physiological tolerance for DMT does not necessarily mean the receptors get internalized. As the psychoactivity remains the same I would say it is proof enough that doesn’t happen. Actually, if for example, the 5-HT1A serotonin autoreceptors are more sensitive for the desensitization we could expect an even stronger effects after continuous exposure. That would really be a funny phenomenon. ;)
Besides if somebees would read at least the abstracts of the papers Rhodium cited they would already find the answer. It does seam that the 5-HT2A R gets desensitized also at short exposures, but trough a different mechanism (which is obviously only short lived). However they do not get internalized. There are other much more temporary desensitization mechanisms known. For example, if I remember correctly, the nicotinic receptors can be temporarily desensitized by phosphorylation on the intracellular side if too much of the agonist sticks around for more than just a moment.

This is from the abstract of the first ref in the first post of this thread!
Mechanisms of Ligand-Induced Desensitization of the 5-HT2A Receptor. JPET 300 (2002) 468-477. (

http://jpet.aspetjournals.org/cgi/content/abstract/300/2/468

)

5-HT-induced desensitization of the 5-HT2A receptor involved receptor internalization through a clathrin- and dynamin-dependent process because it was prevented by concanavalin A, monodansylcadaverine, and by expression of the dominant negative mutants betta-arrestin (319–418) and dynamin K44A. Although short-term (i.e., 10 min) 5-HT and ketanserin exposure resulted in the same degree of desensitization, ketanserin-induced desensitization was not prevented by these agents and did not involve receptor internalization. In contrast, prolonged ketanserin exposure (i.e., 2 h) resulted in 5-HT2A receptor internalization through a clathrinand dynamin-dependent process, as was observed after agonist treatment.


longimanus

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desensitization -> tolerance
« Reply #26 on: April 10, 2004, 10:08:00 AM »
OK, I was really wrong when mixed the terms "desensitization" and "internalization" - it`s a mistake that should be avoided.
 So, it`s obvious that DMT doesn`t activate the process of internalization because it`s too short acting. But its exposure should produce very similar degree of desensitization as should the 2h exposure of ketanserin:
 ...short term (i.e., 10 min) 5-HT and ketanserin exposure resulted in the same degree desensitization..."
(from

None

(http://jpet.aspetjournals.org/cgi/content/abstract/300/2/468)
 
 And if some of the 5-HT2A R-s are desensitized it will be very hard for the same dose of DMT to activate the same number of receptors. That means that we need additional quantities of DMT to activate the same number of receptors. That means we have suceeded to produce tolerance, haven`t we?
 And, why do you, Nicodem, think that the constant psychoactivity is enough to proove that the receptors are not affected? The effects of a certain drug on one`s psyche is not determined only by the effects of this drug on the receptors he/she has in his/her body. z.B., look at the poor little rats - both, male and female, have the same set of receptors but...
 DOI:

10.1016/S0376-8716(01)00185-5


 DOI:

10.1016/S0091-3057(02)00853-5


Nicodem

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And, why do you, Nicodem, think that the ...
« Reply #27 on: April 10, 2004, 10:49:00 AM »
And, why do you, Nicodem, think that the constant psychoactivity is enough to proove that the receptors are not affected?

I was reffering to the R. Strassman paper on DMT discused before. It is quite obvious that if taking close spaced DMT doses the first would have the higher psychological impact (the most traumatic I mean), but if tolerance would develop after a few hits you would have big difficulties to trip out. So it seams obvious to me that the dessensitization that develops on 10 minute DMT trips is short lived (I compared it to the nicotinic receptor phosphorylation dessensitization). You also have to include the possibility that the 5-HT1A autoreceptors could dessensitize as well, meaning that it would compensate for the 5-HT2A dessensitization (5-HT1A agonism inhibit 5-HT release).