Chronic Reductions in Serotonin Transporter Function Prevent 5-HT1B-Induced Behavioral Effects in Mice
Chronic Reductions in Serotonin Transporter Function Prevent 5-HT1B-Induced Behavioral Effects in Mice
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DOI：
10.1016/j.biopsych.2008.09.026
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发表时间：
2009-03-01
影响因子：
10.6
通讯作者：
Dulawa, Stephanie C.
中科院分区：
文献类型：
--
作者：
Shanahan, Nancy A.;Pierz, Kerri A. Holick;Dulawa, Stephanie C.
背景：强迫症（OCD）的特征是侵入性的想法、图像或冲动和/或重复的刻板行为。强迫症患者在接受5-HT 1B受体激动剂激发后表现出前脉冲抑制（PPI）降低和症状加重。最近，5-羟色胺转运蛋白（5-HTT）的功能获得性等位基因与强迫症有关。我们测试了这样一个假设，即通过遗传或通过5-羟色胺再摄取抑制剂（SRI）治疗慢性降低5-HTT功能，可以减弱PPI缺陷和5-HT 1B激动剂诱导的小鼠持续性过度运动。小鼠接受SRI氟西汀的亚慢性或慢性预处理和RU 24969的急性治疗（5-HT 1A/1B激动剂）或8-OH-DPAT（5-HT 1A激动剂），并评估PPI、运动活动和运动的空间模式。在RU 24969处理后，在5-HTT野生型（WT）、杂合型（HT）和敲除型（KO）小鼠中评价了相同的测量。评价WAY 100635（5-HTA拮抗剂）或GR 127935（5-HT 1B/D拮抗剂）预处理对RU 24969诱导的效应的影响。最后，在5-HTT-WT，HT，和KO小鼠，和正常的氟西汀治疗mice.Results：慢性，但不是亚慢性，氟西汀治疗预防RU 24969诱导的PPI赤字和持续性hypersomotion的5-HT 1B结合和功能耦合进行了评估。这些RU 24969诱导的作用是通过5-HT 1B而不是5-HT 1A受体介导的。5-HTT-KO小鼠未显示RU 24969的作用，5-HTT-HT小鼠表现出中间表型。5-HT 1B的结合和功能耦合减少苍白球和黑质的5-HTT-KO mice.Conclusions：我们的研究结果表明，慢性，但不是亚慢性，氟西汀治疗和5-HTT敲除稳健衰减5-HT 1B激动剂诱导的PPI赤字和持续性hypersomotion。这些结果可能对强迫症的病因学和治疗有一定的意义。
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.