5-HT2A receptors in the orbitofrontal cortex facilitate reversal learning and contribute to the beneficial cognitive effects of chronic citalopram treatment in rats
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Chronic stress is a risk factor for depression, and chronic stress can induce cognitive impairments associated with prefrontal cortical dysfunction, which are also major components of depression. We have previously shown that 5 wk chronic intermittent cold (CIC) stress induced a reversal-learning deficit in rats, associated with reduced serotonergic transmission in the orbitofrontal cortex (OFC) that was restored by chronic treatment with a selective serotonin reuptake inhibitor (SSRI). However, the mechanisms underlying the beneficial cognitive effects of chronic SSRI treatment are currently unknown. Thus, the purpose of this study was to investigate the potential modulatory influence specifically of 5-HT2A receptors (5-HT2ARs) in the OFC on reversal learning, and their potential contribution to the beneficial cognitive effects of chronic SSRI treatment. Bilateral microinjections of the selective 5-HT2AR antagonist, MDL 100,907 into OFC (0.02-2.0 nmol) had a dose-dependent detrimental effect on a reversal-learning task, suggesting a facilitatory influence of 5-HT2ARs in the OFC. In the next experiment, rats were exposed to 5 wk CIC stress, which compromised reversal learning, and treated chronically with the SSRI, citalopram (20 mg/kg.d) during the final 3 wk of chronic stress. Chronic citalopram treatment improved reversal learning in the CIC-stressed rats, and bilateral microinjection of MDL 100,907 (0.20 nmol, the optimal dose from the preceding experiment) into OFC once again had a detrimental effect on reversal learning, opposing the beneficial effect of citalopram. We conclude that 5-HT2ARs in the OFC facilitate reversal learning, and potentially contribute to the beneficial cognitive effects of chronic SSRI treatment.
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Two to five weeks of chronic intermittent cold stress results in robust deficits in the reversal learning component of the AST in rats.
“For example, two to five weeks of chronic intermittent cold stress results in robust deficits in the reversal learning component of the AST in rats (Danet et al 2010, Donegan et al 2014, Furr et al 2012, Lapiz-Bluhm et al 2009, Patton et al 2016, Wallace et al 2014).”
From Prefrontal cortex executive processes affected by stress in health and disease (2018) · cites this paper as Furr et al 2012
The 5-HT2A receptor antagonist MDL 100-907, given systemically or intra-OFC, produces reversal learning deficits in naïve rats.
“the 5-HT2A receptor antagonist MDL 100-907, administered systemically or intra-OFC, produced deficits in reversal learning in naïve rats (Boulougouris et al 2008, Furr et al 2012)”
From Prefrontal cortex executive processes affected by stress in health and disease (2018) · cites this paper as Furr et al 2012
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Faculty Opinions recommendation of The neural basis of reversal learning: An updated perspective.
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- Authors
- Furr, A., Lapiz-Bluhm, M. D., & Morilak, D. A.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- Corresponding author
- Morilak, David A.
- ORCID
- Morilak, David A.
- Venue
- The International Journal of Neuropsychopharmacology
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-10-19
- Volume
- 15
- Issue
- 09
- Pages
- 1295-1305
- ISSN
- 1461-1457 (ISSN-L)
- 1469-5111
- PMC
- PMC3454536
- OpenAlex
- W2140172277
- Cited by
- 74
- References
- 62
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 4 · 2023: 3 · 2022: 6 · 2021: 10 · 2020: 5 · 2019: 9 · 2018: 3 · 2017: 3 · 2016: 6 · 2015: 7 · 2014: 8 · 2013: 3 · 2012: 3
- FWCI
- 1.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The International Journal of Neuropsychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Mental Health (R01MH072672, R03MH083669)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Keywords
- 5-HT2A receptor, orbitofrontal cortex, reversal learning, citalopram, selective serotonin reuptake inhibitors, depression, cognitive impairment, MDL 100,907, serotonergic neurotransmission, prefrontal cortex
- MeSH terms
- 2-Hydroxypropyl-beta-cyclodextrin, Animals, Attention, Chronic Disease, Cognition, Fluorobenzenes, Male, Microinjections, Piperidines, Reversal Learning, Serotonin Antagonists, Set, Psychology, Stress, Psychological, Pharmaceutical Vehicles, Citalopram, Rats, Sprague-Dawley, Selective Serotonin Reuptake Inhibitors, Prefrontal Cortex, Receptor, Serotonin, 5-HT2A, beta-Cyclodextrins, Rats
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