5-HT1A autoreceptor levels determine vulnerability to stress and response to antidepressants
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Most depressed patients don't respond to their first drug treatment, and the reasons for this treatment resistance remain enigmatic. Human studies implicate a polymorphism in the promoter of the serotonin-1A (5-HT(1A)) receptor gene in increased susceptibility to depression and decreased treatment response. Here we develop a new strategy to manipulate 5-HT(1A) autoreceptors in raphe nuclei without affecting 5-HT(1A) heteroreceptors, generating mice with higher (1A-High) or lower (1A-Low) autoreceptor levels. We show that this robustly affects raphe firing rates, but has no effect on either basal forebrain serotonin levels or conflict-anxiety measures. However, compared to 1A-Low mice, 1A-High mice show a blunted physiological response to acute stress, increased behavioral despair, and no behavioral response to antidepressant, modeling patients with the 5-HT(1A) risk allele. Furthermore, reducing 5-HT(1A) autoreceptor levels prior to antidepressant treatment is sufficient to convert nonresponders into responders. These results establish a causal relationship between 5-HT(1A) autoreceptor levels, resilience under stress, and response to antidepressants.
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Reduced raphe volume may alter serotonin signaling across the brain, contributing to stress reactivity and depressive-like behavior.
“Reduced raphe volume may affect serotonin signaling throughout the brain, contributing to stress reactivity and to the development of depressive-like behavior (58).”
From Neuroanatomic differences associated with stress susceptibility and resilience (2016) · cites this paper as [58]
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Albert, P., & Fiori, L. (2014) · Current Pharmaceutical Design · doi:10.2174/13816128113196660740 · Cited by 46 · see citing works
Genetic approaches for understanding the role of serotonin receptors in mood and behavior
Donaldson, Z. R., Nautiyal, K. M., Ahmari, S. E., & Hen, R. (2013) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2013.01.011 · Cited by 42 · see citing works
Self-citationMolecular and Cellular Mechanisms of Antidepressant Action
Sharp, T. (2012) · Current Topics in Behavioral Neurosciences · doi:10.1007/7854_2012_216 · Cited by 36 · see citing works
Turcotte-Cardin, V., Vahid-Ansari, F., Luckhart, C., Daigle, M., Geddes, S. D., Tanaka, K. F., Hen, R., James, J., Merali, Z., Béïque, J.-C., et al. (2019) · The Journal of Neuroscience · doi:10.1523/jneurosci.0352-18.2018 · Cited by 36 · see citing works
“*p 0.05 (unpaired two-tailed Student’s t test). more rapid and robust FLX-induced reduction in anxiety in the NSF test (Richardson-Jones et al., 2010).”
BackgroundMethodResultInfluentialActivation of postsynaptic 5-HT1A receptors improve stress adaptation
Zhou, J., Cao, X., Mar, A. C., Ding, Y.-Q., Wang, X., Li, Q., & Li, L. (2014) · Psychopharmacology · doi:10.1007/s00213-013-3350-z · Cited by 36 · see citing works
Astrocytic TNFα regulates the behavioral response to antidepressants
Duseja, R., Heir, R., Lewitus, G. M., Altimimi, H. F., & Stellwagen, D. (2015) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2014.09.012 · Cited by 25 · see citing works
Adolescent but not adult-born neurons are critical for susceptibility to chronic social defeat
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Self-citationAstroglial Serotonin Receptors as the Central Target of Classic Antidepressants
Verkhratsky, A., Parpura, V., Scuderi, C., & Li, B. (2021) · Advances in Neurobiology · doi:10.1007/978-3-030-77375-5_13 · Cited by 19 · see citing works
- Authors
- Richardson-Jones, J. W., Craige, C. P., Guiard, B. P., Stephen, A., Metzger, K. L., Kung, H. F., Gardier, A. M., Dranovsky, A., David, D. J., Beck, S. G., Hen, R., & Leonardo, E. D.
- Affiliations
- Columbia University (US)
- Children's Hospital of Philadelphia (US)
- Université Paris-Sud (FR)
- University of Pennsylvania (US)
- Corresponding author
- Hen, René
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2010-01
- Volume
- 65
- Issue
- 1
- Pages
- 40-52
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC2941196
- OpenAlex
- W2158770881
- Cited by
- 450
- References
- 70
- Citations by year
- 2026: 14 · 2025: 18 · 2024: 20 · 2023: 20 · 2022: 22 · 2021: 32 · 2020: 21 · 2019: 27 · 2018: 23 · 2017: 29 · 2016: 26 · 2015: 26 · 2014: 35 · 2013: 32 · 2012: 32
- FWCI
- 17.54
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1329 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- AstraZeneca (CU08-8439)
- National Institutes of Health (K08 MH076083, R01 MH068542, R01 MH075047)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- 5-HT1A autoreceptors, antidepressant treatment resistance, depression, stress resilience, behavioral despair, raphe nuclei, anxiety, antidepressant response, 5-HT1A receptor
- MeSH terms
- Animals, Antidepressive Agents, Behavior, Animal, Depressive Disorder, Fluoxetine, Humans, Mice, Transgenic, Neurons, Polymorphism, Genetic, Raphe Nuclei, Serotonin, Stress, Psychological, Autoreceptors, Patch-Clamp Techniques, Receptor, Serotonin, 5-HT1A, Mice
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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