People have been taking hallucinogenic drugs for thousands of years. Now scientists think they've figured out a key mechanism that allows tiny amounts of substances like LSD to have a powerful effect on the brain.
Hallucinogens Recruit Specific Cortical 5-HT2A Receptor-Mediated Signaling Pathways to Affect Behavior
Javier González-Maeso,1,7 Noelia V. Weisstaub,3,4,5,7 Mingming Zhou,4 Pokman Chan,1 Lidija Ivic,1 Rosalind Ang,1 Alena Lira,4 Maria Bradley-Moore,4 Yongchao Ge,1,2 Qiang Zhou,1 Stuart C. Sealfon,1,2,∗ and Jay A. Gingrich4,5,6
1 Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA
2 Center for Translational Systems Biology, Mount Sinai School of Medicine, New York, NY 10029, USA
3 Department of Biological Sciences, Columbia University, New York, NY 10032, USA
4 Department of Psychiatry, Columbia University, New York, NY 10032, USA
5 Sackler Institute Laboratories, New York State Psychiatric Institute, New York, NY 10032, USA
6 Lieber Center for Schizophrenia Research, New York State Psychiatric Institute, New York, NY 10032, USA
∗Corresponding author
Stuart C. Sealfon
Summary
Hallucinogens, including mescaline, psilocybin, and lysergic acid diethylamide (LSD), profoundly affect perception, cognition, and mood. All known drugs of this class are 5-HT2A receptor (2AR) agonists, yet closely related 2AR agonists such as lisuride lack comparable psychoactive properties. Why only certain 2AR agonists are hallucinogens and which neural circuits mediate their effects are poorly understood. By genetically expressing 2AR only in cortex, we show that 2AR-regulated pathways on cortical neurons are sufficient to mediate the signaling pattern and behavioral response to hallucinogens. Hallucinogenic and nonhallucinogenic 2AR agonists both regulate signaling in the same 2AR-expressing cortical neurons. However, the signaling and behavioral responses to the hallucinogens are distinct. While lisuride and LSD both act at 2AR expressed by cortex neurons to regulate phospholipase C, LSD responses also involve pertussis toxin-sensitive heterotrimeric Gi/o proteins and Src. These studies identify the long-elusive neural and signaling mechanisms responsible for the unique effects of hallucinogens.
Intresting... anyone care to provide a summery of that summery
From what I understood, some hallucinogens flip "on" the serotonin 2a (5-HT2a) receptors. However, there are other substances which flip "on" the 5-HT2a receptors that don't cause hallucinations. After "treating" mice with hallucinogens last year, some scientists believe there may be two ways to turn on the 5-HT2a switch... to the "right" and to the "left." They want to do further research on this idea to obtain a better understanding of the neurological effects hallucinogens have on the body and to determine whether or not understanding said neurological effects will help better treat schizophrenia and other mental disorders.
^^ If they're going to try and explain mental disorders by examining hallucinogenic serotonin agonists, I guess they'd had to put the current dopamine theory aside. That's where anti-pscychotics such as chlorpromazine base their action on. And I believe there has been made a clear pharmacological distinction between mental disorders and hallucinogenic action in the early days(somewhere on the fifties-sixties).
The thing about hallucenagenics is that the weirdest ones are insanely (lol, no pun intended) simillar to our natural brain chemistry. Serotonin is chemicaly simillar to LSD. It's classed as an indole.
On the subject, in case one is listening to music and doesn't want to turn it off to listen to an *.mp3, here is an article describing the 5-HT2A receptor switch theory. I'll quote parts of the article so y'all don't have to read the whole thing if you don't have time.
Quote:
How drugs cause hallucinations
Jan. 31, 2007
Special to World Science
Scientists say they have partly explained what causes the mind-bending effects of hallucinogens—drugs, such as LSD, mescaline, and psilocybin, that trigger states akin to dreaming or madness...
The findings also offer a path to understanding the function of drugs used to treat brain disorders, sometimes with no clear understanding of how they work, the researchers said...
Hallucinogens—sometimes taken ritually to induce what users feel are mystical experiences—are known to act on brain molecules called 5-HT2A receptors...
Yet hallucinogens, also called psychedelics, present a puzzle. They “unlock” the same receptors as serotonin, or similar non-hallucinogenic chemicals. So why do they cause such different effects?...
The researchers found that LSD produced an array of electrical and cell signaling responses in the cortex very different from those induced by the nonhallucinogen...
The receptor seems to be “like a switch that can go on in more than one direction,” he explained.
When the mind-bending drug activated the receptor, it not only triggered the typical changes in the cell, it caused additional cell responses, he said... LSD seemed to cause a characteristic chain reaction of brain chemistry involving a class of molecules called G proteins...
G proteins can be linked to signaling receptors, such as HT2A. When a signal arrives, the proteins can change the cell in ways that, for example, make either it more or less prone to pass on similar signals in the future...
...one type of G protein was activated by both non-hallucinogens and hallucinogens; but only the latter also switched on a second type...
The significance of the difference is unknown. But it was particularly noticeable in a special layer of cells in the cortex, called Layer 5, Sealfon said. This is often described as the “output” layer of the cortex: it essentially gathers up decisions made in that structure and relays them on to other brain regions, including centers that execute physical movements.
Layer 5 also has extensive interconnections to other parts of the cortex... It’s also hypothesized to contribute to a certain filtering function, in which it helps squelch unimportant information so that this doesn’t overwhelm other brain areas that don’t need it. Hallucinogens may thus disrupt this filtering, Sealfon speculated. “You have a sensory overload, a less filtered experience of your sensory input.”
I recommend you pay serious attention to the underlined information. This terribly reaks of Dr. C. D. Broad's theory, as outlined by Aldous Huxley in "The Doors of Perception." Written in 1954, a selected passage reads:
Quote:
"...Each person is at each moment capable of remembering all that has ever happened to him and of perceiving everything that is happening everywhere in the universe. The function of the brain and nervous system is to protect us from being overwhelmed and confused by this mass of largely useless and irrelevant knowledge, by shutting out most of what we should otherwise perceive or remember at any moment, and leaving only that very small and special selection which is likely to be practically useful." According to such a theory, each one of us is potentially Mind at Large. But in so far as we are animals, our business is at all costs to survive. To make biological survival possible, Mind at Large has to be funneled through the reducing valve of the brain and nervous system.
02-02-2007, 19:17
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