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.
BACKGROUND:Obsessive-compulsive disorder (OCD) is characterized by intrusive thoughts, images, or impulses and/or repetitive stereotypical behavior. Obsessive-compulsive disorderpatients 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.
Authors: R Delorme; C Betancur; M Wagner; M O Krebs; P Gorwood; P Pearl; G Nygren; C M Durand; F Buhtz; P Pickering; J Melke; S Ruhrmann; H Anckarsäter; N Chabane; A Kipman; C Reck; B Millet; I Roy; M C Mouren-Simeoni; W Maier; M Råstam; C Gillberg; M Leboyer; T Bourgeron Journal: Mol Psychiatry Date: 2005-12 Impact factor: 15.992
Authors: Xian-Zhang Hu; Robert H Lipsky; Guanshan Zhu; Longina A Akhtar; Julie Taubman; Benjamin D Greenberg; Ke Xu; Paul D Arnold; Margaret A Richter; James L Kennedy; Dennis L Murphy; David Goldman Journal: Am J Hum Genet Date: 2006-03-28 Impact factor: 11.025
Authors: Klaus Hoenig; Andrea Hochrein; Boris B Quednow; Wolfgang Maier; Michael Wagner Journal: Biol Psychiatry Date: 2005-05-15 Impact factor: 13.382
Authors: Shari A Steinman; Susanne E Ahmari; Tse Choo; Marcia B Kimeldorf; Rachel Feit; Sarah Loh; Victoria Risbrough; Mark A Geyer; Joanna E Steinglass; Melanie Wall; Franklin R Schneier; Abby J Fyer; H Blair Simpson Journal: Depress Anxiety Date: 2016-02-15 Impact factor: 6.505
Authors: Christopher Pittenger; Thomas G Adams; Jean-Dominique Gallezot; Michael J Crowley; Nabeel Nabulsi; Hong Gao; Stephen A Kichuk; Ryan Simpson; Eileen Billingslea; Jonas Hannestad; Michael Bloch; Linda Mayes; Zubin Bhagwagar; Richard E Carson Journal: J Affect Disord Date: 2016-02-09 Impact factor: 4.839
Authors: Summer L Thompson; Amanda C Welch; Julia Iourinets; Stephanie C Dulawa Journal: Psychopharmacology (Berl) Date: 2020-01-11 Impact factor: 4.530
Authors: Adriana M Marques; Michele V Macena; Aline R Cardoso; Camila S O Hammes; Fernanda M L Pinheiro; Newton G Castro; Gilda A Neves Journal: Psychopharmacology (Berl) Date: 2020-02-24 Impact factor: 4.530
Authors: Dennis L Murphy; Pablo R Moya; Meredith A Fox; Liza M Rubenstein; Jens R Wendland; Kiara R Timpano Journal: Philos Trans R Soc Lond B Biol Sci Date: 2013-02-25 Impact factor: 6.237
Authors: Jennifer A Steiner; Ana Marin D Carneiro; Jane Wright; Heinrich J G Matthies; Harish C Prasad; Christian K Nicki; Wolfgang R Dostmann; Carrie C Buchanan; Jackie D Corbin; Sharron H Francis; Randy D Blakely Journal: Mol Brain Date: 2009-08-05 Impact factor: 4.041