Cited by 102Obsessive-Compulsive Spectrum DisordersNeurotransmitter Receptor Influence on BehaviorSchizophrenia research and treatment

Chronic reductions in serotonin transporter function prevent 5-HT1B-induced behavioral effects in mice

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Shanahan, Nancy A., Holick Pierz, Kerri A., Masten, Virginia L., Waeber, Christian, Ansorge, Mark, Gingrich, Jay A., Geyer, Mark A., Hen, Rene +1 more·2009·Biological Psychiatry

Abstract

Background Obsessive-compulsive disorder (OCD) is characterized by intrusive thoughts, images, or impulses and/or repetitive stereotypical behavior. Obsessive-compulsive disorder patients exhibit reduced prepulse inhibition (PPI) and symptom exacerbation after challenge with 5-HT1B receptor agonists. Recently, gain-of-function alleles of the serotonin transporter (5-HTT) have been associated with OCD. We tested the hypothesis that reducing 5-HTT function chronically, either genetically or via serotonin reuptake inhibitor (SRI) treatment, attenuates PPI deficits and perseverative hyperlocomotion induced by 5-HT1B agonists in mice.Methods Mice received subchronic or chronic pretreatment with the SRI fluoxetine and acute treatment with RU24969 (5-HT1A/1B agonist) or 8-OH-DPAT (5-HT1A agonist) and were assessed for PPI, locomotor activity, and spatial patterns of locomotion. The same measures were evaluated in 5-HTT wild-type (WT), heterozygous (HT), and knockout (KO) mice after RU24969 treatment. The effects of WAY100635 (5-HTA antagonist) or GR127935 (5-HT1B/D antagonist) pretreatment on RU24969-induced effects were evaluated. Finally, 5-HT1B binding and functional coupling were assessed in 5-HTT-WT, -HT, and -KO mice, and normal fluoxetine-treated mice.Results Chronic, but not subchronic, fluoxetine treatment prevented RU24969-induced PPI deficits and perseverative hyperlocomotion. These RU24969-induced effects were mediated via 5-HT1B and not 5-HT1A receptors. 5-HTT-KO mice showed no effects of RU24969, and 5-HTT-HT mice exhibited intermediate phenotypes. 5-HT1B binding and functional coupling were reduced in the globus pallidus and substantia nigra of 5-HTT-KO mice.Conclusions Our results demonstrate that chronic, but not subchronic, fluoxetine treatment and 5-HTT knockout robustly attenuate 5-HT1B agonist-induced PPI deficits and perseverative hyperlocomotion. These results may have implications for the etiology and treatment of OCD.

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Crossref · 10.1016/j.biopsych.2008.09.026

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Authors
Shanahan, N. A., Holick Pierz, K. A., Masten, V. L., Waeber, C., Ansorge, M., Gingrich, J. A., Geyer, M. A., Hen, R., & Dulawa, S. C.
Affiliations
  • University of California San Diego (US)
  • Harvard University (US)
  • Columbia University (US)
  • University of Chicago (US)
Corresponding author
Dulawa, Stephanie C.
Venue
Biological Psychiatry
Publisher
Elsevier BV
Published
2009-03
Volume
65
Issue
5
Pages
401-408
ISSN
0006-3223 (ISSN-L)
OpenAlex
W2058616430
Cited by
102
References
60
Citations by year
2026: 1 · 2025: 2 · 2024: 2 · 2023: 3 · 2022: 3 · 2021: 13 · 2020: 6 · 2019: 8 · 2018: 3 · 2017: 1 · 2016: 8 · 2015: 5 · 2014: 5 · 2013: 9 · 2012: 8
FWCI
9.29
Type
journal article
Language
en
Open access
Locations
  • Biological Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute of Mental Health (K01MH071555, R01MH079424)
  • National Institute on Drug Abuse (DA 02925, T32DA07255-15, R01DA002925, T32DA007255)
  • National Institute of Neurological Disorders and Stroke (R01NS049263, R21NS052195)
Topics
  • Social Sciences › Psychology › Clinical Psychology › Obsessive-Compulsive Spectrum Disorders
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
Keywords
serotonin transporter, 5-HT1B receptor, obsessive-compulsive disorder, prepulse inhibition, fluoxetine, serotonin reuptake inhibitors, 8-OH-DPAT, 5-HT1A receptor, globus pallidus, substantia nigra, gain-of-function alleles
MeSH terms
Animals, Female, Fluoxetine, Globus Pallidus, Indoles, Mice, Inbred BALB C, Motor Activity, Oxadiazoles, Piperazines, Pyridines, Reflex, Startle, Substantia Nigra, 8-Hydroxy-2-(di-n-propylamino)tetralin, Mice, Knockout, Receptor, Serotonin, 5-HT1B, Serotonin Plasma Membrane Transport Proteins, Mice, Serotonin 5-HT1 Receptor Agonists, Serotonin 5-HT1 Receptor Antagonists

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