Mechanism of hallucinogens' effects discovered

[ITENRELUD]

The brain mechanism underlying the mind-bending effects of hallucinogens such as LSD, mescaline, and psilocybin has been discovered by neuroscientists. They said their discoveries not only shed light on the longtime mystery of how hallucinogens work, but that the findings also offer a pathway to understanding the function of drugs used to treat neuropsychiatric disorders, which are now being used largely without an understanding of their fundamental mechanism.

Stuart Sealfon, Jay Gingrich, and colleagues published their findings in the February 1, 2007 issue of the journal Neuron, published by Cell Press.

Researchers have long known that hallucinogens activate specific receptors in the brain, called 5-HT2A receptors (2ARs), that are normally triggered by the neurotransmitter serotonin. Neurotransmitters are chemicals that one brain cell launches at receptors on another to trigger a nerve impulse in the receiving cell. However, a fundamental mystery has been why other compounds that activate the same receptors are not hallucinogenic.

In their studies, the researchers compared the differences between the effects of LSD and a nonhallucinogenic chemical that also activates 2AR receptors on the mouse neural machinery. Since the animals could not report the kinds of perception-altering effects that humans experience on hallucinogens, the researchers determined hallucinogenic properties by measuring a head twitch response the mice characteristically showed when under hallucinogens but not when under nonhallucinogens.

The scientists concentrated their studies on the cortex of the brain, which earlier studies had shown to be the center for action of the hallucinogens. Their analysis revealed that LSD produced genetic, electrophysiological, and internal cellular signaling responses that were distinctively different from those induced by a nonhallucinogenic compound.

They also explored whether 2ARs were central to the hallucinogenic effect of LSD by producing mice lacking the receptors, but in which receptor activity could be selectively restored in the cortex. The researchers found that mice without functioning receptors showed no hallucinogenic response to LSD, but restoring the receptors rendered LSD hallucinogenic in the animals.

The researchers wrote that "These studies identify the long-elusive neural and signaling mechanisms responsible for the unique effects of hallucinogens."

They also concluded that "The strategy we developed to elucidate [hallucinogen] action should be applicable to [central nervous system]-active compounds, with therapeutic potential in other disorders. Thus, our findings may advance the understanding of neuropsychiatric disorders that have specific pharmacological treatments whose mechanisms of action are not fully understood."

http://www.eurekalert.org/pub_releases/ ... 012507.php

[Lasipallo]

Transcriptome fingerprints distinguish hallucinogenic and nonhallucinogenic 5-hydroxytryptamine 2A receptor agonist effects in mouse somatosensory cortex.

Gonzalez-Maeso J, Yuen T, Ebersole BJ, Wurmbach E, Lira A, Zhou M, Weisstaub N, Hen R, Gingrich JA, Sealfon SC.

Department of Neurology, Mount Sinai School of Medicine, New York, New York 10029, USA.

Most neuropharmacological agents and many drugs of abuse modulate the activity of heptahelical G-protein-coupled receptors. Although the effects of these ligands result from changes in cellular signaling, their neurobehavioral activity may not correlate with results of in vitro signal transduction assays. 5-Hydroxytryptamine 2A receptor (5-HT2AR) partial agonists that have similar pharmacological profiles differ in the behavioral responses they elicit. In vitro studies suggest that different agonists acting at the same receptor may establish distinct patterns of signal transduction. Testing this hypothesis in the brain requires a global signal transduction assay that is applicable in vivo. To distinguish the cellular effects of the different 5-HT2AR agonists, we developed an assay for global signal transduction on the basis of high throughput quantification of rapidly modulated transcripts. Study of the responses to agonists in human embryonic kidney 293 cells stably expressing 5-HT2ARs demonstrated that each agonist elicits a distinct transcriptome fingerprint. We therefore studied behavioral and cortical signal transduction responses in wild-type and 5-HT2AR null-mutant mice. The hallucinogenic chemicals (+/-)-2,5-dimethoxy-4-iodoamphetamine (DOI) and lysergic acid diethylamide (LSD) stimulated a head-twitch behavioral response that was not observed with the nonhallucinogenic lisuride hydrogen maleate (LHM) and was absent in receptor null-mutant mice. We also found that DOI, LSD, and LHM each induced distinct transcriptome fingerprints in somatosensory cortex that were absent in 5-HT2AR null-mutants. Moreover, DOI and LSD showed similarities in the transcriptome fingerprints obtained that were not observed with the behaviorally inactive drug LHM. Our results demonstrate that chemicals acting at the 5-HT2AR induce specific cellular response patterns in vivo that are reflected in unique changes in the somatosensory cortex transcriptome.

PMID: 14523084 [PubMed - indexed for MEDLINE]

PubMed

[kasipallo willer]

Jälkimmäinen artikkeli löytyy kokonaisuudessaan täältä:
http://www.jneurosci.org/cgi/content/full/23/26/8836.

Mielenkiintoinen tutkimus, mutta luulis nykytekniikalla pystyttävän tutkimaan reseptorivasteita myös in vitro hermokantasolulinjoilla(neural embryonic stem cells). Myös tässä tapauksessa, missä 5-HT2A-agonistien erilainen affiniteetti 5HT2A-reseptorissa aiheuttaa erilaisen vastekuvion.

IMO ei nimittäin oo mitenkään kauheen eettistä käyttää rekombinanttihiiriä, joiden hermostollisiin rakenteisiin ollaan kajottu noinkin(5HT2A-reseptoreja koodaavien geenien knockout) perustavanlaatuisella tavalla. Muutenkin nisäkkäiden( ja erityisesti kädellisten(ei tosin tässä tapauksessa)) käyttö fysiologisissa tutkimuksissa on vähän erikoinen valinta tiedostavilta tutkijoilta, ihan kuin tieteenteon itseisarvo ajaisi aina tiedostavan yksilön omien tarpeiden ja elämisen oikeutuksen ohitse.

btw. _syön_ kyllä lihaa =)

[Kalastaja]

btw. _syön_ kyllä lihaa =)

Eli tieteelle ei saa uhrata eläimiä, mutta sinun makuhermoillesi kyllä? :)


Scientific American julkaisi muuten tässä jokunen päivä sitten aiheesta jutun. En osaa sanoa ilmestyikö tuo jopa lehdessä, vai vaan netissä.

How Hallucinogens Play Their Mind-Bending Games
----------------------------------------

Kattavin vertaisarvioitu paperi psykedeelien vaikutuksista on tietenkin Nicholsin käsialaa.

David E. Nichols.
Hallucinogens.
Pharmacology & Therapeutics. 2004. 101(2) pp. 131– 181

http://www.maps.org/w3pb/new/2004/2004_ ... 2684_1.pdf

[LD50]

btw. _syön_ kyllä lihaa =)

Eli tieteelle ei saa uhrata eläimiä, mutta sinun makuhermoillesi kyllä?

OWNED! Loistavaa kettuilua.

En voinut vastustaa.

[Ahab]

Kattavin vertaisarvioitu paperi psykedeelien vaikutuksista on tietenkin Nicholsin käsialaa.
David E. Nichols. Hallucinogens. Pharmacology & Therapeutics. 2004. 101(2) pp. 131– 181
http://upload2.net/page/download/FxD5z9 ... 4.pdf.html
Pahoittelen säälittävää ilmaisjakelijaa, mutta eiköhän sen tuolta saa kuitenkin ladattua helpommin kuin haettua kirjastosta.

Tuo ei taida olla enää saatavilla. Olisiko mahdollista pistää sen uudestaan tuonne?

Kelasin noiden perusteella että jos ihmiseltä (tai joltain eläimeltä) estäisi tuon 5HT2A-reseptorin toiminnan ja tutkisi näkeekö koehenkilö silloin unia (tai vaipuuko hän ollenkaan REM-tilaan) voisi paljastua jotain siitä että tekeekö DMT ne unet. Tai joku muu endogeeninen hallusinogeeni. Tai ainakin paljastuisi että riippuuko unien näkeminen tuon reseptorin toiminnasta. Vai menikö tuo ajatus ollenkaan nappiin? Vai onko tuollainen tutkimus jo tehty?

[Kalastaja]

http://www.maps.org/w3pb/new/2004/2004_ ... 2684_1.pdf
----


Bluelightin BilZ0rin artikkeli erowidin sivuilla kannattaa myös katsastaa. Aika paljon helpommin lähestyttävä.

The Neuropharmacology of Hallucinogens: a technical overview
http://www.erowid.org/psychoactives/pha ... cle2.shtml

[Touchet]

James Kentin signaaliteoria

[Aukikco]

Toi Kentin teksti oli kyllä hyvä, tuntuu paikkaansapitävältä oivallukselta. Silti, on myös vahvasti fiilis "tuossa nyt taas yksi osa-alue kokonaisuudesta" :)

[Touchet]

Kent on nyt laajentamassa teoriaansa, esikatseluversio löytyy täältä: http://www.tripzine.com/pit/html/multi-state-theory.htm