Mechanism of the 5-hydroxytryptamine 2A receptor-mediated facilitation of synaptic activity in prefrontal cortex
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Classic hallucinogens such as lysergic acid diethylamide are thought to elicit their psychotropic actions via serotonin receptors of the 5-hydroxytryptamine 2A subtype (5-HT 2A R). One likely site for these effects is the prefrontal cortex (PFC). Previous studies have shown that activation of 5-HT 2A Rs 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-HT 2A Rs inactivation and 5-HT 2A R rescue over a 5-HT 2A R knockout genetic background, to distinguish between competing hypotheses accounting for these effects. The results from these experiments do not support the idea that 5-HT 2A Rs elicit the release of an excitatory retrograde messenger nor that they activate thalamocortical afferents, the two dominant hypotheses. Rather, they suggest that 5-HT 2A Rs facilitate intrinsic networks within the PFC. Consistent with this idea, we locate a discrete subpopulation of pyramidal cells that is strongly excited by 5-HT 2A R activation.
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Psychedelics primarily act on 5-HT2ARs expressed on glutamatergic pyramidal cells in cortical and deep cortical layers (V and VI).
“Psychedelics primarily act on 5-HT2ARs expressed on glutamatergic pyramidal cells in cortical and deep cortical layers (V and VI) (86, 87).”
From Psychedelics and Neuroplasticity: A Systematic Review Unraveling the Biological Underpinnings of Psychedelics. (2021) · cites this paper as [86]
This increases AMPAR density, resulting in more extracellular glutamate and BDNF release in the cortex.
“This increases AMPAR density, resulting in more extracellular glutamate and BDNF release in the cortex (86, 91).”
From Psychedelics and Neuroplasticity: A Systematic Review Unraveling the Biological Underpinnings of Psychedelics. (2021) · cites this paper as [86]
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- Authors
- Béïque, J.-C., Imad, M., Mladenovic, L., Gingrich, J. A., & Andrade, R.
- Affiliations
- Wayne State University (US)
- Department of Pharmacology,
- Columbia University (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2007-06-05
- Volume
- 104
- Issue
- 23
- Pages
- 9870-9875
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1887564
- OpenAlex
- W2120918936
- Cited by
- 229
- References
- 33
- Citations by year
- 2026: 10 · 2025: 13 · 2024: 10 · 2023: 18 · 2022: 14 · 2021: 10 · 2020: 15 · 2019: 3 · 2018: 8 · 2017: 11 · 2016: 19 · 2015: 12 · 2014: 11 · 2013: 20 · 2012: 11
- FWCI
- 13.10
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (MH 43985, R29MH043985, R01MH043985)
- Topics
- Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- 5-HT2A receptor, serotonin receptors, hallucinogens, lysergic acid diethylamide, prefrontal cortex, glutamatergic neurotransmission, spontaneous synaptic activity, pyramidal neurons, thalamocortical afferents, retrograde signaling, receptor knockout
- MeSH terms
- Animals, Carbachol, Synaptic Transmission, Serotonin, Prefrontal Cortex, Pyramidal Cells, Mice, Knockout, Patch-Clamp Techniques, Receptor, Serotonin, 5-HT2A, Mice, Phospholipase C beta
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