When you first ingest a psychedelic drug, you soon discover that you develop tolerance to its effects very quickly, a single dose of a tryptamine or phenethylamine can block almost all the effects of any psychedelic for a day or two, as well as attenuating the effect of any taken within 1-2 weeks. Why is that? Why is it so effective? Was D.A.R.E. right after all, and you really
did etch away the braincells with that Acid blotter?
Nope, not by far - read on... The effects of the "classical hallucinogens" (largely the Phenethylamines and the Tryptamines) are all chiefly mediated by them binding to and activating the 5-HT
2A receptor (they are 5-HT
2A agonists), which is a member of the neurotransmitter receptors in the body and brain which binds Serotonin (or 5-HT, from its chemical name 5-Hydroxy-Tryptamine). This receptor is very easily deactivated, probably because it is not used to a large extent (to the best of my knowledge) during everyday brain-activity, something that for simplicitys sake can be verified by the fact that you usually never get religious experiences while standing in line in the store, nor are the clouds constantly on the morph.
When the 5-HT
2A receptor becomes more stimulated than it is used to (as in you ingesting ANY active amount of a psychedelic drug), the neurons on the recieving end of the synapse responds to this with "receptor internalization", the nerve cell actually drawing the receptor into the cell membrane, so that all its contact with the surface is lost.
You can draw an analogy with the eyes of a snail - when its eye is poked or otherwise disturbed, it almost instantly retracts the telescopic eye and turns the eye tube inside out, so that it becomes buried inside the head, safe from eye-poking scientists. In the same way the serotonin neurons become stressed by being poked with 5-HT
2A agonists and retracts its receptors so that any further poking does not lead to the activation of the receptor, which would otherwise force the neuron to fire repeatedly, sending away an electrical pulse of a few tens of millivolts - it doesn't sound like much, but for a cell which may have a diameter of only 0.05-0.1 millimeter (that's 1/2500 to 1/5000 of an inch), that is
hard work. If you had to make 20 push-ups every time the phone rang, you would also soon disconnect the phone if you got a series of prank calls (which is very close to what serotonin neurons would consider 5-HT
2A agonist drugs to be). They are small, but very clever - after all, they are
brain cells by profession.
When the receptors internalized, the nerve cell cannot become activated by any 5-HT
2A agonists, regardless of how much of it you ingest - the drug cannot reach, and thus not activate the receptor. That you still feel
something even if you would take a trip every day for a week is because not 100% of the receptors are internalized, and that most drugs affect a whole range of other receptors, but to a lesser extent. There are also a few other mechanisms contributing to the development of tolerance to psychedelics, but this is by far the most important one, and the most fantastic of them all. A short period after the drug has left the body, the 5-HT
2A receptors either return to the surface, or if the repair machinery in the neuron determines that any of them were damaged, they are broken down to their constituents again and are thus salvaged for spare parts, so that new 5-HT
2A receptors can be built and re-installed, allowing the serotonergic neuron to return to exactly the same pristine state it was before the weekend.
To study this more in-depth, I have linked a few articles of interest below - most (if not all?) of them should be free to download, otherwise just tell me, and I'll upload them to my page.
Further Reading on 5-HT2A Desensitization:Mechanisms of Ligand-Induced Desensitization of the 5-HT2A Receptor J. Pharm. Exp. Ther. Vol. 300, Issue 2, 468-477, February 2002
(
http://jpet.aspetjournals.org/cgi/content/abstract/300/2/468)
Differences in Rapid Desensitization of 5-HT2A and 5-HT2CJ. Pharm. Exp. Ther. Vol. 299, Issue 2, 593-602, November 2001
(
http://jpet.aspetjournals.org/cgi/content/abstract/299/2/593)
Dynamin-dependent, Arrestin-independent Internalization of 5-Hydroxytryptamine 2A (5-HT2A) Serotonin ReceptorsJ Biol Chem. 2001 Mar 16;276(11):8269-77
(
http://www.jbc.org/cgi/content/abstract/276/11/8269)
The Interaction of a Constitutively Active Arrestin with the Arrestin-Insensitive 5-HT2A Receptor Induces Agonist-Independent InternalizationMol. Pharmacol., May 1, 2003; 63(5): 961-972.
(
http://molpharm.aspetjournals.org/cgi/content/abstract/63/5/961)
Cell-Type Specific Effects of Endocytosis Inhibitors on 5-HT2A Receptor Desensitization and ResensitizationMol. Pharmacol., Vol. 60, Issue 5, 1020-1030, November 2001
(
http://molpharm.aspetjournals.org/cgi/content/abstract/60/5/1020)
Receptor Internalization ProcessSource: Roth Lab: Functional Studies of 5-HT Receptors
(
http://kidb.cwru.edu/rothlab/regulation.htm)
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