The DOI matches its Crossref record; 60 of the 60 references it cites were found in a registry or an index.
Enhancement of Spatial Reversal Learning by 5-HT2CReceptor Antagonism Is Neuroanatomically Specific
Open accessAbstract
We have recently demonstrated that systemic administration of 5-HT(2C) and 5-HT(2A) receptor antagonists significantly enhanced and impaired spatial reversal learning, respectively. In this study, the role of 5-HT(2C) and 5-HT(2A) receptor subtypes in the mediation of these opposing effects was further investigated with respect to neuroanatomical specificity. The roles of 5-HT(2C) and 5-HT(2A) receptors were examined within some of the brain regions implicated in cognitive flexibility, namely the orbitofrontal cortex (OFC), medial prefrontal cortex (mPFC), and nucleus accumbens (NAc), by means of targeted infusions of selective 5-HT(2C) and 5-HT(2A) receptor antagonists (SB 242084 and M100907, respectively). Intra-OFC 5-HT(2C) receptor antagonism produced dose-dependent effects similar to those of systemic administration, i.e., improved spatial reversal learning by reducing the number of trials (all doses: 0.1, 0.3, and 1.0 microg) and perseverative errors to criterion (0.3 and 1.0 microg) compared with controls. However, the highest dose (1.0 microg) showed a nonselective effect, as it also affected retention preceding the reversal phase and decreased learning errors. Intracerebral infusions of SB 242084 into the mPFC or NAc produced no significant effects on any behavioral measures. Similarly, no significant differences were observed with intra-OFC, -mPFC, or -NAc infusions of M100907. These data suggest that the improved performance in reversal learning observed after 5-HT(2C) receptor antagonism is mediated within the OFC. These data also bear on the issue of whether 5-HT(2C) receptor antagonism within the OFC might help elucidate the biological substrate of obsessive-compulsive disorder, offering the potential for therapeutic application.
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“In reversal tasks in which action-outcome contingencies were switched, lesions or pharmacological manipulations of serotonin neurons also resulted in impairments of adaptive behavior at the time of reversal.37–41”
From Serotonin neurons modulate learning rate through uncertainty (2022) · cites this paper as [39]
In the citing paper
“Our findings and conceptual framework, including the effect on learning from worse-than-expected outcomes, are consistent with previous observations and manipulations of serotonin neuron activity.”
From Serotonin neurons modulate learning rate through uncertainty (2022) · cites this paper as [39]
In the citing paper
“Prior research demonstrates that serotonin neurons modulate flexible behavior in changing environments.33,37–42”
From Serotonin neurons modulate learning rate through uncertainty (2022) · cites this paper as [39]
In the citing paper
“Specifically, lesioned animals continued to make the previously rewarded action.”
From Serotonin neurons modulate learning rate through uncertainty (2022) · cites this paper as [39]
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Cites
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“Without this top-down cognitive control, behavior controlled by other cortical and subcortical regions is more likely to be inflexible, dependent on simple sensory motor associations or habits (Miller and Cohen, 2001).”
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BackgroundSelf-citationMedial Frontal Cortex Mediates Perceptual Attentional Set Shifting in the Rat
Birrell, J. M., & Brown, V. J. (2000) · The Journal of Neuroscience · doi:10.1523/jneurosci.20-11-04320.2000 · Cited by 1,421 · cited 1×
“The medial region of the PFC (mPFC) has been shown to mediate behavioral flexibility in attentional set-shifting tasks, requiring the updating of attentional biases or rules (Owen et al., 1991; Dias et al., 1996; Birrell and Brown, 2000; Ragozzino and Kesner, 2001).”
BackgroundRolls, E. T., Hornak, J., Wade, D., & McGrath, J. (1994) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp.57.12.1518 · Cited by 1,005 · cited 2×
“Neuroanatomically speaking, converging evidence from a plethora of studies has implicated the orbitofrontal cortex (OFC) in efficient reversal learning, as damage to this region produces selective reversal deficits [human (Rolls et al., 1994; Hornak et al., 2004), monkey (Iversen and Mishkin, 1970; Jones and Mishkin,…”
BackgroundAmat, J., Baratta, M. V., Paul, E., Bland, S. T., Watkins, L. R., & Maier, S. F. (2005) · Nature Neuroscience · doi:10.1038/nn1399 · Cited by 931 · cited 2×
“If this regulation also results from descending influences from mPFC (Amat et al., 2005), then this may imply a descending modulation of the dorsal raphé by OFC 5-HT2C receptors.”
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“, 2004), monkey (Iversen and Mishkin, 1970; Jones and Mishkin, 1972; Dias et al., 1996; Clarke et al., 2008), rat (Schoenbaum et al.”
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The neural basis of reversal learning: An updated perspective
Izquierdo, A., Brigman, J. L., Radke, A. K., Rudebeck, P. H., & Holmes, A. (2017) · Neuroscience · doi:10.1016/j.neuroscience.2016.03.021 · Cited by 670
“For instance, in rats antagonism of 5-HT2A (via MDL 100-907) impairs reversal performance, while 5-HT2C antagonism (with SB 242084) facilitates performance (Boulougouris et al., 2008; Boulougouris and Robbins, 2010; Nilsson et al., 2012; Furr et al., 2012b), though there is also a report of an overall impairment after…”
BackgroundInfluentialNeurophysiology of performance monitoring and adaptive behavior
Ullsperger, M., Danielmeier, C., & Jocham, G. (2014) · Physiological Reviews · doi:10.1152/physrev.00041.2012 · Cited by 634
“In contrast, the deficit found after systemic blockade of 5HT2A receptors could not be reproduced by direct injection into either OFC, medial PFC, or nucleus accumbens (49).”
BackgroundThe serotonin system in autism spectrum disorder: From biomarker to animal models
Muller, C. L., Anacker, A. M. J., & Veenstra-VanderWeele, J. (2016) · Neuroscience · doi:10.1016/j.neuroscience.2015.11.010 · Cited by 531
“Drugs targeting serotonin receptors, particularly 5-HT1A and 5-HT2A, have shown promise for increasing social interaction or decreasing cognitive rigidity (File et al., 1996, Edwards et al., 2006, Boulougouris and Robbins, 2010, Gould et al., 2011, Amodeo et al., 2014).”
BackgroundSerotonin and dopamine: unifying affective, activational, and decision functions.
Cools, R., Nakamura, K., & Daw, N. D. (2011) · Neuropsychopharmacology · doi:10.1038/npp.2010.121 · Cited by 464
“Thus, as is the case for DA, 5-HT might have distinct effects in the ventral striatum, the amygdala, and the OFC (Clarke et al, 2008; Boulougouris and Robbins, 2010), or on functions associated with ventral versus dorsal frontostriatal circuitry (Tanaka et al, 2007).”
BackgroundDoss, M. K., Považan, M., Rosenberg, M. D., Sepeda, N. D., Davis, A. K., Finan, P. H., Smith, G. S., Pekar, J. J., Barker, P. B., Griffiths, R. R., et al. (2021) · Translational Psychiatry · doi:10.1038/s41398-021-01706-y · Cited by 356
“In animal models, 5-HT2C blockade alone has been found to enhance [30, 38] or have no impact cognitive flexibility [34].”
Background
Metadata
- Authors
- Boulougouris, V., & Robbins, T. W.
- Affiliations
- University of Cambridge (GB)
- ORCID
- Robbins, Trevor W.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2010-01-20
- Volume
- 30
- Issue
- 3
- Pages
- 930-938
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6633094
- OpenAlex
- W2090419097
- Cited by
- 136
- References
- 60
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 6 · 2023: 3 · 2022: 6 · 2021: 9 · 2020: 8 · 2019: 2 · 2018: 7 · 2017: 10 · 2016: 10 · 2015: 14 · 2014: 10 · 2013: 16 · 2012: 7
- FWCI
- 5.63
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust (076274/4/Z/04/Z, 076274/Z/04/Z)
- Medical Research Council
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- 5-HT2C receptor antagonism, 5-HT2A receptor antagonism, spatial reversal learning, cognitive flexibility, orbitofrontal cortex, medial prefrontal cortex, nucleus accumbens, SB242084, M100907, perseverative errors, obsessive-compulsive disorder
- MeSH terms
- Aminopyridines, Analysis of Variance, Animals, Brain, Brain Mapping, Conditioning, Operant, Dose-Response Relationship, Drug, Fluorobenzenes, Indoles, Male, Piperidines, Reinforcement Schedule, Reversal Learning, Serotonin Antagonists, Space Perception, Time Factors, Receptor, Serotonin, 5-HT2A, Receptor, Serotonin, 5-HT2C, Rats, Serotonin 5-HT2 Receptor Antagonists
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