Hallucinogens Recruit Specific Cortical 5-HT2A Receptor-Mediated Signaling Pathways to Affect Behavior
Open accessAbstract
Hallucinogens, including mescaline, psilocybin, and lysergic acid diethylamide (LSD), profoundly affect perception, cognition, and mood. All known drugs of this class are 5-HT(2A) 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 G(i/o) proteins and Src. These studies identify the long-elusive neural and signaling mechanisms responsible for the unique effects of hallucinogens.
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Via activation of 5-HT2AR, psychedelics activate intracellular signaling pathways such as PLC, PLA, and Src.
“Via activation of 5-HT2AR, psychedelics activate intracellular signaling pathways such as PLC, PLA, and Src (88–90).”
From Psychedelics and Neuroplasticity: A Systematic Review Unraveling the Biological Underpinnings of Psychedelics. (2021) · cites this paper as [90]
Activation of Src is suggested to be essential for psychedelics' hallucinogenic effects, as its inhibition prevented hallucinogenic effects of LSD.
“Activation of Src is suggested to be essential for psychedelics' hallucinogenic effects, as its inhibition prevented hallucinogenic effects of LSD (90).”
From Psychedelics and Neuroplasticity: A Systematic Review Unraveling the Biological Underpinnings of Psychedelics. (2021) · cites this paper as [90]
These analogs produce antidepressant-like effects without causing increases in the head-twitch response.
“These analogs produce antidepressant-like effects without causing increases in the head-twitch response, a behavior associated with classical psychedelics (González-Maeso et al., 2007).”
From Psychedelics and Neural Plasticity: Therapeutic Implications (2022) · cites this paper as González-Maeso et al., 2007
Hallucinogenic effects at 5HT2A receptors may also entail activation of the pertussis toxin-sensitive heterotrimeric Gi/o proteins.
“Hallucinogenic effects at 5HT2A receptors may also entail activation of the pertussis toxin (PTX)-sensitive heterotrimeric Gi/o proteins [33].”
From Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans. (2021) · cites this paper as [33]
Several recent studies of drugs acting at cell surface receptor targets show that the activation mechanisms responsible for their cellular and systemic effects are more complex than accounted for by their classical pharmacological profiles.
“Several recent studies of drugs acting at cell surface receptor targets show that the activation mechanisms responsible for their cellular and systemic effects are more complex than accounted for by their classical pharmacological profiles (30 -32).”
From Cytokine Response Is Determined by Duration of Receptor and Signal Transducers and Activators of Transcription 3 (STAT3) Activation (2013) · cites this paper as [32]
Temporal pattern encoding relieves the cellular information bottleneck, where many stimuli must signal through few intracellular pathways to generate diverse and specific cellular responses, but complicates the relationship between synthetic target modulators and their cellular and clinical effects.
“Temporal pattern encoding relieves the cellular information bottleneck, where many stimuli must signal through few intracellular pathways to generate diverse and specific cellular responses (30 -32) but complicates the relationship between synthetic target modulators and their cellular and clinical effects.”
From Cytokine Response Is Determined by Duration of Receptor and Signal Transducers and Activators of Transcription 3 (STAT3) Activation (2013) · cites this paper as [32]
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References 67 · Cited by 925
- Authors
- González-Maeso, J., Weisstaub, N. V., Zhou, M., Chan, P., Ivic, L., Ang, R., Lira, A., Bradley-Moore, M., Ge, Y., Zhou, Q., Sealfon, S. C., & Gingrich, J. A.
- Affiliations
- New York State Psychiatric Institute (US)
- Icahn School of Medicine at Mount Sinai (US)
- Columbia University (US)
- Corresponding author
- Sealfon, Stuart C.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2007-02
- Volume
- 53
- Issue
- 3
- Pages
- 439-452
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W2009134620
- Cited by
- 925
- References
- 67
- Citations by year
- 2026: 73 · 2025: 84 · 2024: 86 · 2023: 72 · 2022: 70 · 2021: 62 · 2020: 58 · 2019: 40 · 2018: 42 · 2017: 37 · 2016: 42 · 2015: 28 · 2014: 29 · 2013: 41 · 2012: 23
- FWCI
- 38.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5k08mh001711-02)
- National Institute of Mental Health (K08 MH01711)
- National Institute on Drug Abuse (T32DA007135, T32DA07135, P01DA012923, P01-DA12923)
- 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 › Cognitive Neuroscience › Hallucinations in medical conditions
- Keywords
- hallucinogens, 5-HT2A receptor, serotonin receptor agonists, mescaline, psilocybin, LSD, lisuride, cortical neurons, phospholipase C signaling, heterotrimeric G proteins, Src kinase, psychoactive effects
- MeSH terms
- Amphetamines, Animals, Autoradiography, Behavior, Animal, Binding, Competitive, Cells, Cultured, Cerebral Cortex, Electrophysiology, Hallucinogens, Ketanserin, Lisuride, Male, Serotonin Antagonists, Signal Transduction, Serotonin Receptor Agonists, In Situ Hybridization, Fluorescence, Receptors, Dopamine D1, Receptors, Dopamine D2, Pyramidal Cells, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, Receptor, Serotonin, 5-HT2A, Mice
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