Chronic Reductions in Serotonin Transporter Function Prevent 5-HT1B-Induced Behavioral Effects in Mice

• Published in: Biological psychiatry (1969) Vol. 65; no. 5; pp. 401 - 408
• Main Authors: Shanahan, Nancy A, Holick Pierz, Kerri A, Masten, Virginia L, Waeber, Christian, Ansorge, Mark, Gingrich, Jay A, Geyer, Mark A, Hen, Rene, Dulawa, Stephanie C
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2009
• Subjects: 5-HT1B receptor; 5-HTT; 8-Hydroxy-2-(di-n-propylamino)tetralin - pharmacology; Animals; antidepressant; Female; Fluoxetine - administration & dosage; Fluoxetine - pharmacology; Globus Pallidus - metabolism; Indoles - pharmacology; Mice; Mice, Inbred BALB C - genetics; Mice, Knockout; Motor Activity - drug effects; Motor Activity - genetics; OCD; Oxadiazoles - pharmacology; Piperazines - pharmacology; PPI; Psychiatry; Pyridines - pharmacology; Receptor, Serotonin, 5-HT1B - metabolism; Reflex, Startle - drug effects; Reflex, Startle - genetics; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT1 Receptor Antagonists; Serotonin Plasma Membrane Transport Proteins - drug effects; Serotonin Plasma Membrane Transport Proteins - genetics; Serotonin Plasma Membrane Transport Proteins - metabolism; Substantia Nigra - metabolism; 5-HTT; 5-HT1B receptor; PPI; OCD; antidepressant
• ISSN: 0006-3223; 1873-2402
• DOI: 10.1016/j.biopsych.2008.09.026

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.