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

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.