ArticleProceedings of the National Academy of Sciences of the United States of America2015
Brain 5-HT deficiency increases stress vulnerability and impairs antidepressant responses following psychosocial stress.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 65 papers.
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Who cites it
65 citing papers in PubMed, 118 citations in OpenAlex.
- An Open-Label Pilot Study of Combined Augmentation With Creatine Monohydrate and 5-Hydroxytryptophan for Selective Serotonin Reuptake Inhibitor- or Serotonin-Norepinephrine Reuptake Inhibitor-Resistant Depression in Adult Women.Journal of clinical psychopharmacology · 2017Trial
- Stress resilience is associated with transcriptional remodeling in the VTA.Cell reports · 2026Article
- Role of central and peripheral serotonin in liver physiology and diseases.Theranostics · 2026Review
- Gut-derived lactic acid enhances tryptophan to 5-hydroxytryptamine in regulation of anxiety viaGut microbes · 2025Article
- Stress resilience is associated with transcriptional remodeling in the VTA.bioRxiv : the preprint server for biology · 2025Article
- The involvement of 5-HT was necessary for EA-mediated improvement of post-stroke depression.Translational psychiatry · 2025Article
- Global, regional and national burdens of major depression disorders and its attributable risk factors in adolescents and young adults aged 10-24 years from 1990 to 2021.BMC psychiatry · 2025Article
- Sex-specific and developmental effects of early life adversity on stress reactivity are rescued by postnatal knockdown of 5-HTNeuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2025Article
- Employment-dependent associations of serum biomarkers with short- and long-term antidepressant treatment outcomes.Frontiers in psychiatry · 2025Article
- Optogenetics and chemogenetics: key tools for modulating neural circuits in rodent models of depression.Frontiers in neural circuits · 2025Review
- Synergistic effect between citalopram and muscimol upon induction of anxiolytic- and antidepressant-like effects in male mice: An isobologram analysis.IBRO neuroscience reports · 2024Article
- The basal forebrain to lateral habenula circuitry mediates social behavioral maladaptation.Nature communications · 2024Article
- Synergistic antidepressant-like effect of citicoline and CB 1 agonist in male mice.Psychopharmacology · 2024Article
- A neural circuit associated with anxiety-like behaviors induced by chronic inflammatory pain and the anxiolytic effects of electroacupuncture.CNS neuroscience & therapeutics · 2024Article
- The Neuroanatomy of the Habenular Complex and Its Role in the Regulation of Affective Behaviors.Journal of functional morphology and kinesiology · 2024Review
- The protective role of ginsenoside Rg3 in heart diseases and mental disorders.Frontiers in pharmacology · 2024Review
- Psychopharmacological Approaches for Neural Plasticity and Neurogenesis in Major Depressive Disorders.Advances in experimental medicine and biology · 2024Review
- Article
- Organic cation transporter 2 contributes to SSRI antidepressant efficacy by controlling tryptophan availability in the brain.Translational psychiatry · 2023Article
- Dysfunctional serotonergic neuron-astrocyte signaling in depressive-like states.Molecular psychiatry · 2023Article
5 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
3 authors at 1 institution in 2 countries.
Funding
Abstract
Brain serotonin (5-HT) deficiency and exposure to psychosocial stress have both been implicated in the etiology of depression and anxiety disorders, but whether 5-HT deficiency influences susceptibility to depression- and anxiety-like phenotypes induced by psychosocial stress has not been formally established. Most clinically effective antidepressants increase the extracellular levels of 5-HT, and thus it has been hypothesized that antidepressant responses result from the reversal of endogenous 5-HT deficiency, but this hypothesis remains highly controversial. Here we evaluated the impact of brain 5-HT deficiency on stress susceptibility and antidepressant-like responses using tryptophan hydroxylase 2 knockin (Tph2KI) mice, which display 60-80% reductions in brain 5-HT. Our results demonstrate that 5-HT deficiency leads to increased susceptibility to social defeat stress (SDS), a model of psychosocial stress, and prevents the fluoxetine (FLX)-induced reversal of SDS-induced social avoidance, suggesting that 5-HT deficiency may impair antidepressant responses. In light of recent clinical and preclinical studies highlighting the potential of inhibiting the lateral habenula (LHb) to achieve antidepressant and antidepressant-like responses, we also examined whether LHb inhibition could achieve antidepressant-like responses in FLX-insensitive Tph2KI mice subjected to SDS. Our data reveal that using designer receptors exclusively activated by designer drugs (DREADDs) to inhibit LHb activity leads to reduced SDS-induced social avoidance behavior in both WT and Tph2KI mice. This observation provides additional preclinical evidence that inhibiting the LHb might represent a promising alternative therapeutic approach under conditions in which selective 5-HT reuptake inhibitors are ineffective.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.