5-HT2A Receptor-Mediated Signaling Pathways Responsible for Effects of Hallucinogens

[5-HT2]

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.

http://www.neuron.org/content/article/abstract?uid=PIIS0896627307000281

 

[egor]

^^ wish I could read it beyond the summary, sounds like a very interesting topic.

 

[Trogdor]

Here, have a listen to this:

http://www.bluelight.ru/vb/showthread.php?t=290839

 

[boywonder]

http://www.npr.org/templates/story/story.php?storyId=7102284

Leave it to NPR to dig stuff up like this! I get most or all of my everyday news from there. Great unbiased perspectives IMO.


I always thought it was interesting how the binding of LSD to serotonin receptors somehow translates into the amazing experience that it is. This new info seems to be a breakthrough, I'd love to hear some thoughts on this.

 

[Dondante]

Great article! If anybody really wants it, PM me with an email and I'd be glad to send a copy.

 

[5-HT2]

It's too bad they didn't do drug discrimination studies; that would have made the paper significantly stronger and probably gotten it into a better journal, perhaps even Cell. Right now, they only have head twitch as behavioral validation, and it's hard to interpret what aspect of the psychopharmacology it reflects.

 

[phosphorylase]

wow, this is a pretty big discovery; completely knocks out the thalamocortical gating hypothesis if they're right. you're right though, they should really do some discrimination studies.

 

[Dondante]

I missed that in my first read through. Wow, thanks for poining it out.

Neuronal Target of HCs
Our findings also bear on the hypothesized role of thalamic
2AR in the mechanism of action of HCs. Previous studies
have suggested that 2AR expressed on thalamocortical
axon terminals activates glutamate release in the cortex
(Marek et al., 2001; Scruggs et al., 2000, 2003). Our
htr2A/:Emx1-Cre+/ rescue line shows a selective restoration
of 2AR expression in the cortex. As 2AR expression
is not restored in the thalamus, 2AR should not be
expressed on the cortical terminals of thalamic neurons
in these mice. The expression of 2AR in the cortex neurons
alone was sufficient to elicit HC-specific behavioral and
signaling effects (Figure 8). In contrast, 2AR restoration
exclusively to the thalamus did not restore HC-induced
behaviors (data not shown). Although previous studies
implied that the effects of HCs require the release of glutamate
(see above), our data suggest that the circuit involved
in this effect is a cortical-cortical circuit and does
not require activation of a thalamocortical pathway.

I was going to say I was disappointed because I liked the gating theory, but it seems the gating theory still holds ... just in a different region of the brain.

Because layer V functions as the ‘‘output’’ layer of the cortex (Sapienza
et al., 1981), it has been hypothesized that layer
V neurons engage in ‘‘gating’’ functions that are of critical
importance to the proper balance between cortical-subcortical
communications (Barkai and Hasselmo, 1994). It
is reasonable to suspect that 2AR-mediated HC signaling
may perturb the normal gating functions of layer V cortex,
disrupt cognition and sensory processing, and lead to the
characteristic HC effects on behavior.

 

[5-HT2]

I also think doing duration discrimination or peak procedure studies on these mice would be very interesting.