Uncontrollable, But Not Controllable, Stress Desensitizes 5-HT1AReceptors in the Dorsal Raphe Nucleus
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Uncontrollable stressors produce behavioral changes that do not occur if the organism can exercise behavioral control over the stressor. Previous studies suggest that the behavioral consequences of uncontrollable stress depend on hypersensitivity of serotonergic neurons in the dorsal raphe nucleus (DRN), but the mechanisms involved have not been determined. We used ex vivo single-unit recording in rats to test the hypothesis that the effects of uncontrollable stress are produced by desensitization of DRN 5-HT 1A autoreceptors. These studies revealed that uncontrollable, but not controllable, tail shock impaired 5-HT 1A receptor-mediated inhibition of DRN neuronal firing. Moreover, this effect was observed only at time points when the behavioral effects of uncontrollable stress are present. Furthermore, temporary inactivation of the medial prefrontal cortex with the GABA A receptor agonist muscimol, which eliminates the protective effects of control on behavior, led even controllable stress to now produce functional desensitization of DRN 5-HT 1A receptors. Additionally, behavioral immunization, an experience with controllable stress before uncontrollable stress that prevents the behavioral outcomes of uncontrollable stress, also blocked functional desensitization of DRN 5-HT 1A receptors by uncontrollable stress. Last, Western blot analysis revealed that uncontrollable stress leads to desensitization rather than downregulation of DRN 5-HT 1A receptors. Thus, treatments that prevent controllable stress from being protective led to desensitization of 5-HT 1A receptors, whereas treatments that block the behavioral effects of uncontrollable stress also blocked 5-HT 1A receptor desensitization. These data suggest that uncontrollable stressors produce a desensitization of DRN 5-HT 1A autoreceptors and that this desensitization is responsible for the behavioral consequences of uncontrollable stress.
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Desensitization of 5-HT1A receptors is not permanent and recovers to normal within 3 days.
“Of course, the desensitization of 5-HT1A receptors is not permanent, and recovers to normal within 3 days”
From Learned helplessness at fifty: Insights from neuroscience. (2016) · cites this paper as Rozeske et al., 2011
Results, Experiment 4 (page unavailable), show impaired 5-HT1A-receptor-mediated inhibition at 24 hours but no significant difference from controls at 7 days. The paper did not test receptor function at 3 days; its reference to effects lasting 24–72 hours concerns behavior, not measured receptor recovery. Thus, recovery by 3 days is not established. (LLM, conf=0.88)
Experimental — accuracy not yet measuredInescapable shock, but not exactly equal escapable shock, desensitizes these receptors so that dorsal raphe nucleus 5-HT neurons are sensitized for a number of days and to a remarkably large extent.
“Inescapable shock, but not exactly equal escapable shock, desensitizes these receptors so that dorsal raphe nucleus5-HT neurons are sensitized for a number of days and to a remarkably large extent.”
From Learned helplessness at fifty: Insights from neuroscience. (2016) · cites this paper as Rozeske et al., 2011
These behavioral changes exist only as long as the receptors remain desensitized, which proved to be only a few days.
“Thus, these behavioral changes should exist only as long as the receptors remain desensitized, which proved to be for only a few days (Rozeske et al., 2011).”
From Learned helplessness at fifty: Insights from neuroscience. (2016) · cites this paper as Rozeske et al., 2011
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References 54 · Cited by 100
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- Authors
- Rozeske, R. R., Evans, A. K., Frank, M. G., Watkins, L. R., Lowry, C. A., & Maier, S. F.
- Affiliations
- University of Colorado Boulder (US)
- Stanford University (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2011-10-05
- Volume
- 31
- Issue
- 40
- Pages
- 14107-14115
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3207271
- OpenAlex
- W2079041682
- Cited by
- 100
- References
- 54
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 6 · 2023: 4 · 2022: 2 · 2021: 6 · 2019: 8 · 2018: 9 · 2017: 7 · 2016: 7 · 2015: 8 · 2014: 15 · 2013: 10 · 2012: 12
- FWCI
- 5.04
- 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
- National Institutes of Health
- National Institute of Mental Health (MH050479, R37MH050479, MH086539, R01MH086539, R01MH050479)
- National Institute on Drug Abuse (F31DA023329, DA023329)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- uncontrollable stress, dorsal raphe nucleus, serotonergic neurons, autoreceptors, tail shock, medial prefrontal cortex, muscimol inactivation, receptor down-regulation
- MeSH terms
- Action Potentials, Animals, Dose-Response Relationship, Drug, Electroshock, Male, Raphe Nuclei, Serotonin, Stress, Psychological, Rats, Sprague-Dawley, Receptor, Serotonin, 5-HT1A, Rats
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