Loss of adult 5-HT1A autoreceptors results in a paradoxical Anxiogenic response to antidepressant treatment
Open accessAbstract
Selective serotonin (5-HT) reuptake inhibitors (SSRIs) are first-line antidepressants but require several weeks to elicit their actions. Chronic SSRI treatment induces desensitization of 5-HT1A autoreceptors to enhance 5-HT neurotransmission. Mice (both sexes) with gene deletion of 5-HT1A autoreceptors in adult 5-HT neurons ( 1AcKO ) were tested for response to SSRIs. Tamoxifen-induced recombination in adult 1AcKO mice specifically reduced 5-HT1A autoreceptor levels. The 1AcKO mice showed a loss of 5-HT1A autoreceptor-mediated hypothermia and electrophysiological responses, but no changes in anxiety- or depression-like behavior. Subchronic fluoxetine (FLX) treatment induced an unexpected anxiogenic effect in 1AcKO mice in the novelty suppressed feeding and elevated plus maze tests, as did escitalopram in the novelty suppressed feeding test. No effect was seen in wild-type ( WT ) mice. Subchronic FLX increased 5-HT metabolism in prefrontal cortex, hippocampus, and raphe of 1AcKO but not WT mice, suggesting hyperactivation of 5-HT release. To detect chronic cellular activation, FosB + cells were quantified. FosB + cells were reduced in entorhinal cortex and hippocampus (CA2/3) and increased in dorsal raphe 5-HT cells of 1AcKO mice, suggesting increased raphe activation. In WT but not 1AcKO mice, FLX reduced FosB + cells in the median raphe, hippocampus, entorhinal cortex, and median septum, which receive rich 5-HT projections. Thus, in the absence of 5-HT1A autoreceptors, SSRIs induce a paradoxical anxiogenic response. This may involve imbalance in activation of dorsal and median raphe to regulate septohippocampal or fimbria-fornix pathways. These results suggest that markedly reduced 5-HT1A autoreceptors may provide a marker for aberrant response to SSRI treatment. SIGNIFICANCE STATEMENT Serotonin-selective reuptake inhibitors (SSRIs) are effective in treating anxiety and depression in humans and mouse models. However, in some cases, SSRIs can increase anxiety, but the mechanisms involved are unclear. Here we show that, rather than enhancing SSRI benefits, adulthood knockout (KO) of the 5-HT1A autoreceptor, a critical negative regulator of 5-HT activity, results in an SSRI-induced anxiety effect that appears to involve a hyperactivation of the 5-HT system in certain brain areas. Thus, subjects with very low levels of 5-HT1A autoreceptors, such as during childhood or adolescence, may be at risk for an SSRI-induced anxiety response.
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A contribution of specific 5-HT receptors to various adverse effects of SSRIs has been proposed, such as sexual dysfunction (5-HT1A) or a paradoxical anxiogenic response to subchronic SSRI treatment.
“a contribution of specific 5-HT receptors to the various adverse effects of SSRIs has been proposed, such as for example sexual dysfunction [5-HT 1A ; (Olivier, 2015)] or a paradoxical anxiogenic response to subchronic SSRI treatment (Turcotte-Cardin et al., 2019).”
From Novel pharmacological targets in drug development for the treatment of anxiety and anxiety-related disorders (2019) · cites this paper as Turcotte-Cardin et al., 2019
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“Specific deletion of 5-HT1A autoreceptors in the mouse brain gives rise an anxiety response following SSRI treatment, indicating that low or no 5-HT1A autoreceptor signaling is detrimental for anxiety (Turcotte-Cardin et al., 2019).”
BackgroundЦейликман, В. Э., Tseilikman, O. B., Karpenko, M. N., Traktirov, D. S., Obukhova, D. A., Shatilov, V. A., Zhukov, M. S., Валерьевич, М. Г., Yegorov, O. N., Aristov, M. R., et al. (2024) · Biomedicines · doi:10.3390/biomedicines12112455 · Cited by 20 · see citing works
Буткевич, И. П., Михайленко, В. А., Vershinina, E. A., & Barr, G. A. (2019) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2019.00125 · Cited by 20 · see citing works
“GR are on neurons in the CNS regions classically associated with nociception and there is evidence that HPA axis directly influences nociception, particularly pre- and perinatally (Shagura et al., 2016; Zouikr et al., 2016).”
BackgroundInfluentialEffect of selective serotonin reuptake inhibitor discontinuation on anxiety-like behaviours in mice
Collins, H. M., Pinacho, R., Ozdemir, D., Bannerman, D. M., & Sharp, T. (2022) · Journal of Psychopharmacology · doi:10.1177/02698811221093032 · Cited by 15 · see citing works
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Exploring Biological Risk Factors in Treatment-Resistant Depression
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“The above results suggest that the effects of SSRIs on granule cell layer proliferation is mediated through 5-HT1A receptors [59].”
BackgroundZaky, D. A., Mehny, K. A., Abdelrahman, S. S. M., El-Yamany, M. F., & Kamel, A. S. E. D. (2024) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2024.176869 · Cited by 3 · see citing works
Unpacking the psychological, cognitive, and psycho-pharmacologic burdens of neuro-oncology
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Стрес та тривога: від нейрохімії до клініки. Що це дає лікарю-практику?
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Effect of SSRI discontinuation on anxiety-like behaviours in micePreprint
Collins, H. M., Pinacho, R., Ozdemir, D., Bannerman, D. M., & Sharp, T. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.05.29.446266
“In support of this idea, previous studies with mice reported that continuous treatment with certain SSRIs is anxiogenic on the EPM (Oh et al., 2009; Venzala et al., 2012; Turcotte-Cardin et al., 2019).”
ResultSEROTONIN 1B/1A RECEPTOR MODULATION ON BEHAVIORAL FLEXIBILITY IN C57BL/6J MICE
Oliver, B. L. (2021) · CSUSB ScholarWorks (California State University, San Bernardino)
Świderski, N., & Bielecka, A. (2026) · Annales Academiae Medicae Silesiensis · doi:10.18794/aams/211947
Role of 5-HT and BDNF in Premature Ejaculation With Anxiety or Depression
Wei, Y., Ning, B., Wang, S., Chen, W., Zhang, L., Chen, C., Qiu, J., & Hong, Z. (2026) · Journal of Integrative Neuroscience · doi:10.31083/jin45471
Brain Serotonergic System as an Effector of the Organism Temperature Homeostasis System
Ip, V. (2026) · Neurochemical Journal · doi:10.1134/s1819712426700017
Wang, Z. (2026) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2026.112169
- Authors
- 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., & Albert, P. R.
- Affiliations
- University of Ottawa (CA)
- Keio University (JP)
- New York State Psychiatric Institute (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2018-12-14
- Volume
- 39
- Issue
- 8
- Pages
- 1334-1346
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6381250
- OpenAlex
- W2904487322
- Cited by
- 36
- References
- 53
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 6 · 2023: 4 · 2022: 4 · 2021: 6 · 2020: 2 · 2019: 6
- FWCI
- 1.59
- 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)
- eCommons - AKU (Aga Khan University) (submittedVersion)
- Funders
- University of Ottawa
- Canadian Institutes of Health Research (123426_1, 115098_1)
- Japan Society for the Promotion of Science (17H06062, 15H03123)
- National Institute of Mental Health (R01MH068542)
- 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, selective serotonin reuptake inhibitors, fluoxetine, escitalopram, serotonergic neurotransmission, dorsal raphe nucleus, median raphe, FosB, novelty-suppressed feeding, elevated plus maze, serotonin metabolism, antidepressant response, entorhinal cortex, hippocampus
- MeSH terms
- Animals, Antidepressive Agents, Anxiety, Brain Chemistry, Exploratory Behavior, Feeding Behavior, Female, Fluoxetine, Hypothermia, Male, Mice, Inbred C57BL, Nerve Net, Serotonin, Swimming, Proto-Oncogene Proteins c-fos, Selective Serotonin Reuptake Inhibitors, 8-Hydroxy-2-(di-n-propylamino)tetralin, Autoreceptors, Mice, Knockout, Maze Learning, Receptor, Serotonin, 5-HT1A, Mice, Serotonergic Neurons
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