Mechanism of the 5-hydroxytryptamine 2A receptor-mediated facilitation of synaptic activity in prefrontal cortex

Classic hallucinogens such as lysergic acid diethylamide are thought to elicit their psychotropic actions via serotonin receptors of the 5-hydroxytryptamine 2A subtype (5-HT₂AR). One likely site for these effects is the prefrontal cortex (PFC). Previous studies have shown that activation of 5-HT₂ARs...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 104; no. 23; pp. 9870 - 9875
Main Authors Béïque, Jean-Claude, Imad, Mays, Mladenovic, Ljiljana, Gingrich, Jay A, Andrade, Rodrigo
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 05.06.2007
National Acad Sciences
Subjects
Agonists
Animals
Behavioral neuroscience
Biological Sciences
Brain
Carbachol - pharmacology
Carbohydrates
Hallucinogens
Mice
Mice, Knockout
Neurology
Neurons
Patch-Clamp Techniques
Phospholipase C beta
Prefrontal cortex
Prefrontal Cortex - physiology
Pyramidal cells
Pyramidal Cells - drug effects
Pyramidal Cells - metabolism
Receptor, Serotonin, 5-HT2A - metabolism
Receptors
Serotonin - pharmacology
Serotonin receptors
Studies
Synaptic Transmission - drug effects
Synaptic Transmission - physiology
Transfection
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Summary:Classic hallucinogens such as lysergic acid diethylamide are thought to elicit their psychotropic actions via serotonin receptors of the 5-hydroxytryptamine 2A subtype (5-HT₂AR). One likely site for these effects is the prefrontal cortex (PFC). Previous studies have shown that activation of 5-HT₂ARs in this region results in a robust increase in spontaneous glutamatergic synaptic activity, and these results have led to the widely held idea that hallucinogens elicit their effect by modulating synaptic transmission within the PFC. Here, we combine cellular and molecular biological approaches, including single-cell 5-HT₂ARs inactivation and 5-HT₂AR rescue over a 5-HT₂AR knockout genetic background, to distinguish between competing hypotheses accounting for these effects. The results from these experiments do not support the idea that 5-HT₂ARs elicit the release of an excitatory retrograde messenger nor that they activate thalamocortical afferents, the two dominant hypotheses. Rather, they suggest that 5-HT₂ARs facilitate intrinsic networks within the PFC. Consistent with this idea, we locate a discrete subpopulation of pyramidal cells that is strongly excited by 5-HT₂AR activation.
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Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved April 23, 2007
Present address: Department of Neuroscience, Johns Hopkins University School of Medicine, 918 Preclinical Teaching Building, 725 North Wolfe Street, Baltimore, MD 21205.
Author contributions: J.-C.B., M.I., and R.A. designed research; J.-C.B., M.I., L.M., and R.A. performed research; J.A.G. contributed new reagents/analytic tools; J.-C.B., M.I., and R.A. analyzed data; and J.-C.B. and R.A. wrote the paper.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0700436104