Essential role for orbitofrontal serotonin 1B receptors in obsessive-compulsive disorder-like behavior and serotonin reuptake inhibitor response in mice
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Background Perseveration and sensorimotor gating deficits are core features of obsessive-compulsive disorder (OCD). Serotonin 1B receptor (5-HT1BR) agonists exacerbate OCD symptoms in patients and induce perseveration and sensorimotor gating deficits in mice. Serotonin reuptake inhibitors (SRIs), but not noradrenaline reuptake inhibitors (NRIs), reduce OCD symptoms following 4 to 8 weeks of treatment. Using mice, we compared the effects of chronic SRI versus NRI treatment on 5-HT1BR-induced OCD-like behavior and 5-HT1BR sensitivity in orbitofrontal-subcortical OCD circuits. Furthermore, we localized the 5-HT1BR population that mediates OCD-like behavior.Methods Mice chronically received the SRI clomipramine or the NRI desipramine and were examined for 5-HT1BR-induced OCD-like behavior or 5-HT1BR binding and G-protein coupling in caudate putamen, nucleus accumbens, and orbitofrontal cortex. Separate mice were tested for OCD- or depression-like behavior following 4, 14, 21, 28, or 56 days of SRI treatment. Finally, OCD-like behavior was assessed following intra-orbitofrontal 5-HT1BR agonist infusion or intra-orbitofrontal 5-HT1BR antagonist infusion coupled with systemic 5-HT1BR agonist treatment.Results Effective, but not ineffective, OCD treatments reduced OCD-like behavior in mice with a time course that parallels the delayed therapeutic onset in OCD patients and downregulated 5-HT1BR expression in the orbitofrontal cortex. Intra-orbitofrontal 5-HT1BR agonist infusion induced OCD-like behavior, and intra-orbitofrontal 5-HT1BR antagonist infusion blocked OCD-like effects of systemic 5-HT1BR agonist treatment.Conclusions These results indicate that orbitofrontal 5-HT1BRs are necessary and sufficient to induce OCD-like behavior in mice and that SRI pharmacotherapy reduces OCD-like behavior by desensitizing orbitofrontal 5-HT1BRs. Our findings suggest an essential role for orbitofrontal 5-HT1BRs in OCD pathophysiology and treatment.
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The receptors responsible for 5-HT1B agonist effects are localized to the orbitofrontal cortex.
“Further studies have localized the responsible receptors to the orbitofrontal cortex (OFC) 39”
From DISSECTING OCD CIRCUITS: FROM ANIMAL MODELS TO TARGETED TREATMENTS: Review: Dissecting OCD Circuits: Animals to Treatments (2015) · cites this paper as [39]
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- Authors
- Shanahan, N. A., Velez, L. P., Masten, V. L., & Dulawa, S. C.
- Affiliations
- University of Chicago (US)
- University of California San Diego (US)
- Corresponding author
- Dulawa, Stephanie C.
- ORCID
- Dulawa, Stephanie C.
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2011-12
- Volume
- 70
- Issue
- 11
- Pages
- 1039-1048
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC3310222
- OpenAlex
- W2075708698
- Cited by
- 72
- References
- 87
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 3 · 2023: 4 · 2022: 3 · 2021: 8 · 2020: 3 · 2019: 5 · 2018: 3 · 2017: 4 · 2016: 5 · 2015: 8 · 2014: 6 · 2013: 10 · 2012: 3
- FWCI
- 6.91
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (MH079424, MH071555)
- Topics
- Social Sciences › Psychology › Clinical Psychology › Obsessive-Compulsive Spectrum Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- obsessive-compulsive disorder, 5-HT1B receptor, orbitofrontal cortex, serotonin reuptake inhibitors, clomipramine, desipramine, perseveration, sensorimotor gating, receptor desensitization, G protein coupling, caudate-putamen, nucleus accumbens, depression-like behavior
- MeSH terms
- Acoustic Stimulation, Adrenergic beta-Antagonists, Animals, Clomipramine, Desipramine, Disease Models, Animal, Dose-Response Relationship, Drug, Drug Interactions, Exploratory Behavior, Female, Indoles, Isotopes, Mice, Inbred BALB C, Neural Inhibition, Obsessive-Compulsive Disorder, Swimming, Time Factors, Guanosine 5'-O-(3-Thiotriphosphate), Serotonin Receptor Agonists, Selective Serotonin Reuptake Inhibitors, 8-Hydroxy-2-(di-n-propylamino)tetralin, Prefrontal Cortex, Adrenergic Uptake Inhibitors, Iodocyanopindolol, Receptor, Serotonin, 5-HT1B, Mice
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