5-Hydroxytryptamine 2A serotonin receptors in the primate cerebral cortex: Possible site of action of hallucinogenic and antipsychotic drugs in pyramidal cell apical dendrites

Jakab, Robert L.; Goldman-Rakic, Patricia S.

doi:10.1073/pnas.95.2.735

Cited by 536Neurotransmitter Receptor Influence on BehaviorPsychedelics and Drug StudiesNeuroscience and Neuropharmacology Research

5-Hydroxytryptamine 2A serotonin receptors in the primate cerebral cortex: Possible site of action of hallucinogenic and antipsychotic drugs in pyramidal cell apical dendrites

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Jakab, Robert L., Goldman-Rakic, Patricia S.·1998·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.95.2.735PMC PMC18490

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Abstract

To identify the cortical sites where 5-hydroxytryptamine 2A (5-HT 2A ) serotonin receptors respond to the action of hallucinogens and atypical antipsychotic drugs, we have examined the cellular and subcellular distribution of these receptors in the cerebral cortex of macaque monkeys (with a focus on prefrontal areas) by using light and electron microscopic immunocytochemical techniques. 5-HT 2A receptor immunoreactivity was detected in all cortical layers, among which layers II and III and layers V and VI were intensely stained, and layer IV was weakly labeled. The majority of the receptor-labeled cells were pyramidal neurons and the most intense immunolabeling was consistently confined to their parallelly aligned proximal apical dendrites that formed two intensely stained bands above and below layer IV. In double-label experiments, 5-HT 2A label was found in calbindin D28k-positive, nonphosphorylated-neurofilament-positive, and immuno-negative pyramidal cells, suggesting that probably all pyramidal cells express 5-HT 2A receptors. 5-HT 2A label was also found in large- and medium-size interneurons, some of which were immuno-positive for calbindin. 5-HT 2A receptor label was also associated with axon terminals. These findings reconcile the data on the receptor’s cortical physiology and localization by ( i ) establishing that 5-HT 2A receptors are located postsynaptically and presynaptically, ( ii ) demonstrating that pyramidal neurons constitute the major 5-HT 2A -receptor-expressing cells in the cortex, and ( iii ) supporting the view that the apical dendritic field proximal to the pyramidal cell soma is the “hot spot” for 5-HT 2A -receptor-mediated physiological actions relevant to normal and “psychotic” functional states of the cerebral cortex.

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The 5-HT2A receptor is expressed on dendritic shafts and dendritic spines of cortical neurons in both rodents and primates.
“The 5-HT 2A R, a common target of psychedelics, is expressed on dendritic shafts and dendritic spines of cortical neurons in both rodents and primates (Jakab and Goldman-Rakic, 1998;Miner et al., 2003;Jones et al., 2009;Weber and Andrade, 2010;Yoshida et al., 2011).”
From Psychedelics and Neural Plasticity: Therapeutic Implications (2022) · cites this paper as Jakab and Goldman-Rakic, 1998

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The distribution of 5-HT1A and 5-HT2A receptor mRNA in human brain
Burnet, P. W. J., Eastwood, S. L., Lacey, K., & Harrison, P. J. (1995) · Brain Research · doi:10.1016/0006-8993(95)00104-x · Cited by 283 · see citing works
Nonphosphorylated neurofilament protein and calbindin immunoreactivity in layer III pyramidal neurons of human neocortex.
Hayes, T. L., & Lewis, D. A. (1992) · Cerebral Cortex · doi:10.1093/cercor/2.1.56 · Cited by 80 · see citing works
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Lidow, M. S., Goldman‐Rakic, P. S., Gallager, D. W., & Rakic, P. (1989) · Journal of Comparative Neurology · doi:10.1002/cne.902800104 · Cited by 77 · see citing works

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Authors: Jakab, R. L., & Goldman-Rakic, P. S.
Affiliations: Yale University (US)
Section of Neurobiology, Yale University School of Medicine, New Haven, CT 06511
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 1998-01-20
Volume: 95
Issue: 2
Pages: 735-740
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.95.2.735
PMC: PMC18490
OpenAlex: W2004172377
Cited by: 536
References: 4
Citations by year: 2026: 20 · 2025: 21 · 2024: 18 · 2023: 15 · 2022: 15 · 2021: 19 · 2020: 11 · 2019: 11 · 2018: 18 · 2017: 12 · 2016: 7 · 2015: 19 · 2014: 10 · 2013: 19 · 2012: 17
FWCI: 11.48
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Alliance for Research on Schizophrenia and Depression
National Institutes of Health
National Institute of Mental Health (MH 44866, P50MH044866)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords: 5-HT2A receptor, cerebral cortex, macaque, prefrontal cortex, pyramidal neurons, apical dendrites, calbindin-D28k, interneurons, postsynaptic receptors, presynaptic receptors, axon terminals, hallucinogens, atypical antipsychotics, cortical layers, receptor subcellular localization
MeSH terms: Animals, Cerebral Cortex, Dendrites, Hallucinogens, Macaca mulatta, Receptors, Serotonin, Antipsychotic Agents, Pyramidal Cells

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5-Hydroxytryptamine 2A serotonin receptors in the primate cerebral cortex: Possible site of action of hallucinogenic and antipsychotic drugs in pyramidal cell apical dendrites

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