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The Physiological Role of 5-HT2AReceptors in Working Memory
Open accessAbstract
Dorsolateral prefrontal cortex has an essential role in the cognitive process of working memory, dysfunction of which is considered to be a core deficit in schizophrenia. Although this cortical region is densely innervated with 5-HT 2A receptors to which atypical antipsychotic drugs bind with high affinity, little is known of the influence of this serotonin receptor subtype on prefrontal function. We addressed this issue by examining the effects of iontophoresis of selective receptor ligands on prefrontal neurons possessing spatially tuned delay activity, or “memory fields,” in monkeys performing a delayed-response task. Memory fields of putative pyramidal cells were attenuated by iontophoresis of 5-HT 2A antagonists, which primarily produced a reduction in delay activity for preferred target locations. Conversely, 5-HT 2A stimulation by α-methyl-5-HT or 5-HT itself, accentuated the spatial tuning of these neurons by producing a modest increase in activity for preferred target locations and/or a reduction in activity for nonpreferred locations. The agonist effects could be reversed by the selective antagonist MDL100,907, and were dose-dependent, such that high levels attenuated spatial tuning by profoundly reducing delay activity. A role for feedforward inhibitory circuitry in these effects was supported by the finding that 5-HT 2A blockade also attenuated the memory fields of putative interneurons. We conclude that prefrontal 5-HT 2A receptors have a hitherto unrecognized role in the cognitive function of working memory, which involves actions at both excitatory and inhibitory elements within local circuitry.
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“one study has shown that high levels of 5-HT2A receptor stimulation can suppress dorsolateral PFC neuronal firing in monkeys performing a working memory task161.”
From Stress signalling pathways that impair prefrontal cortex structure and function (2009) · cites this paper as [161]
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Metadata
- Authors
- Williams, G. V., Rao, S. G., & Goldman-Rakic, P. S.
- Affiliations
- Yale University (US)
- ORCID
- Williams, Graham V.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2002-04-01
- Volume
- 22
- Issue
- 7
- Pages
- 2843-2854
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6758292
- OpenAlex
- W1635746382
- Cited by
- 311
- References
- 87
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 13 · 2023: 7 · 2022: 7 · 2021: 9 · 2020: 8 · 2019: 5 · 2018: 10 · 2017: 10 · 2016: 14 · 2015: 14 · 2014: 13 · 2013: 12 · 2012: 10
- FWCI
- 6.76
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (MH 44866, R37MH038546, P50MH044866)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- 5-HT2A receptor, serotonin, working memory, dorsolateral prefrontal cortex, delay activity, memory field, pyramidal neurons, interneurons, feedforward inhibition, schizophrenia, atypical antipsychotics, alpha-methyl-5-HT, spatial tuning, delayed response task, iontophoresis
- MeSH terms
- Action Potentials, Animals, Cognition, Fixation, Ocular, Iontophoresis, Ligands, Macaca mulatta, Male, Memory, Short-Term, Neurons, Photic Stimulation, Reaction Time, Receptors, Serotonin, Saccades, Serotonin Antagonists, Serotonin Receptor Agonists, Prefrontal Cortex, Pyramidal Cells, Receptor, Serotonin, 5-HT2A
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