Evaluation of antidepressant-related behavioral responses in mice lacking the serotonin transporter
Evaluation of antidepressant-related behavioral responses in mice lacking the serotonin transporter
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DOI：
10.1016/s0893-133x(02)00374-3
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发表时间：
2002-12-01
影响因子：
7.6
通讯作者：
Crawley, JN
中科院分区：
文献类型：
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作者：
Holmes, A;Yang, RJ;Crawley, JN
5-羟色胺转运体（5-HTT）的抑制是许多抗抑郁药的主要初始靶点。然而，5-HTT对其治疗效果的贡献尚不完全清楚。我们利用靶向基因突变方法来研究5-HTT在抗抑郁药行为作用中的作用。5-HTT突变在两种不同的遗传背景C57 BL/6 J和129 S6上繁殖。在大体身体、神经和行为功能的初步筛选中，所有测量均正常，除了C57 BL 16 J背景的5-HTT -/-小鼠显示体重增加和转棒性能差，而129 S6背景的5-HTT -/-小鼠显示神经肌肉强度降低。在尾部悬挂试验中，129 S6背景下的5-HTT -/-小鼠显示出基线抗抑郁药样的不动性降低。相比之下，相同的小鼠在强迫游泳测试中表现出增加的不动性，可能是由于神经肌肉力量受损。5-C57 BL 16 J背景下的HTT -/-小鼠在两项测试中均未显示基线抗抑郁药相关表型。在悬尾试验中，在5-HTT突变小鼠（C57 BL 16 J背景）中测试三种抗抑郁药的行为效应。5-羟色胺再摄取抑制剂氟西汀（30 mg/kg）的抗不动作用在5-HTT -/-小鼠中被消除，证实了氟西汀的行为效应需要5-HTT基因。相比之下，5-HTT -/-小鼠对去甲肾上腺素再摄取抑制剂地昔帕明（20 mg/kg）和混合5-羟色胺/去甲肾上腺素再摄取抑制剂丙咪嗪（25 mg/kg）的抗不动作用保持敏感性。5-HTT基因敲除小鼠为描述抗抑郁药的神经精神药理学作用提供了一个有价值的工具。(C)2002年美国神经精神药理学学会。出版社：Elsevier Science Inc.
Inhibition of the serotonin transporter (5-HTT) is a principal initial target of many antidepressants. However, the contribution of the 5-HTT to their therapeutic efficacy is incompletely understood. We utilized a targeted gene mutation approach to examine the role of the 5-HTT in the behavioral actions of antidepressants. The 5-HTT mutation was bred onto two separate genetic backgrounds, C57BL/6J and 129S6. On a preliminary screen for gross physical, neurological and behavioral functions, all measures were normal with the exception that 5-HTT -/- mice on the C57BL16J background showed increased body weight and poor rotarod performance, and 5-HTT -/- mice on the 129S6 background showed reduced neuromuscular strength. On the tail suspension test, 5-HTT -/- mice on the 129S6 background showed a baseline antidepressant-like reduction in immobility. In contrast, the same mice showed increased immobility in the forced swim test, possibly due to compromised neuromuscular strength. 5-HTT -/- mice on the C57BL16J background showed no baseline antidepressant-related phenotype on either test. The behavioral effects of three antidepressants were tested in 5-HTT mutant mice (C57BL16J background) in the tail suspension test. The anti-immobility effects of the serotonin reuptake inhibitor, fluoxetine (30 mg/kg), were abolished in 5-HTT -/- mice, confirming that the 5-HTT gene is required for the behavioral effects of fluoxetine. In contrast, 5-HTT -/- mice retained sensitivity to the anti-immobility effects of the norcpinephrine reuptake inhibitor, desipramine (20 mg/kg), and the mixed serotonin/norepinephrine reuptake inhibitor, imipramine (25 mg/kg). 5-HTT knockout mice provide a valuable tool for delineating the neuropsychopharmacological actions of antidepressants. (C) 2002 American College of Neuropsychopharmacology. Published by Elsevier Science Inc.