Indoleamine 2,3-dioxygenase mediates anhedonia and anxiety-like behaviors caused by peripheral lipopolysaccharide immune challenge.
Indoleamine 2,3-dioxygenase mediates anhedonia and anxiety-like behaviors caused by peripheral lipopolysaccharide immune challenge.
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DOI：
10.1016/j.yhbeh.2012.03.010
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发表时间：
2012-08
影响因子：
3.5
通讯作者：
O'Connor, Jason C.
中科院分区：
文献类型：
--
作者：
Salazar, Alexander;Gonzalez-Rivera, Bryan L.;Redus, Laney;Parrott, Jennifer M.;O'Connor, Jason C.
促炎细胞因子上调吲哚胺2，3-双加氧酶（IDO）已被认为是炎症相关情绪障碍的生物介质。关于这种神经免疫相互作用的临床报告仍然是相关的，而以机制为中心的临床前实验集中在一个相对狭窄的，有点争议的，抑郁样行为的调查，包括强迫游泳和尾巴悬挂测试。在这里，我们试图确定是否与E。目的探讨IDO在LPS诱导的抑郁样行为中的作用。C57 BL/6J小鼠腹腔内注射LPS导致探索性运动活动（eLMA）的稳健但短暂的减少，24小时后恢复至接近基线水平。与盐水处理的对照小鼠相比，LPS处理的蔗糖偏好（快感缺乏的临床前相关性）减少了20%以上，并且LPS在24小时诱导了与eLMA无关的焦虑样行为的显著增加。用IDO抑制剂1-甲基色氨酸（1MT）预处理小鼠，消除了LPS的致焦虑作用，同时对体重或eLMA的疾病相关变化没有影响。此外，1MT预处理减弱了LPS诱导的蔗糖偏好降低，这也在IDO-1敲除小鼠中得到证实。有趣的是，L-犬尿氨酸（IDO的酶产物）的急性全身给药在未处理小鼠中引起快感缺乏和焦虑作用，而对eLMA无影响。在临床前模型中，这些数据暗示IDO是LPS诱导的抑郁和焦虑样行为的关键介质。
Upregulation of indoleamine 2,3-dioxygenase (IDO) by proinflammatory cytokines has been implicated as a biological mediator of inflammation-related mood disorders. Clinical reports on this neuro-immune interaction remain correlative, while mechanism-centered preclinical experiments have focused on a relatively narrow, and somewhat controversial, survey of depression-like behaviors that include the forced swim and tail suspension tests. Here, we sought to determine whether peripheral immune challenge with E. coli, lipopolysaccharides (LPS) precipitates the development of translationally relevant depression-like behaviors and to investigate the role of IDO in mediating these LPS-induced behaviors. Intraperitoneal injection of C57BL/6J mice with LPS resulted in a robust, but transient, reduction in exploratory locomotor activity (eLMA) that returned to near baseline levels by 24h. Sucrose preference, a preclinical correlate of anhedonia, was diminished by more than 20% in LPS-treated compared to saline-treated control mice, and LPS induced a significant increase in anxiety-like behavior at 24h that was independent eLMA. Pretreatment of mice with an IDO inhibitor, 1-methyltryptophan (1MT), ablated the anxiogenic effects of LPS, while having no impact on sickness associated changes in body weight or eLMA. Additionally, 1MT pretreatment attenuated the LPS-induced reduction in sucrose preference, which was also confirmed in IDO-1 null mice. Interestingly, acute systemic administration of L-kynurenine, the enzymatic product of IDO, precipitated an anhedonic and anxiogenic effect in naïve mice without effect on eLMA. In a preclinical model, these data implicate IDO as a pivotal mediator of LPS-induced depression- and anxiety-like behavior.
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影响因子：
3.6
作者：
Kanai M;Funakoshi H;Takahashi H;Hayakawa T;Mizuno S;Matsumoto K;Nakamura T
通讯作者：
Nakamura T
影响因子：
6.1
作者：
Maes, M;Verkerk, R;Scharpé, S
通讯作者：
Scharpé, S
影响因子：
3.7
作者：
Frenois, Francois;Moreau, Maite;Castanon, Nathalie
通讯作者：
Castanon, Nathalie
影响因子：
11
作者：
O'Connor, J. C.;Lawson, M. A.;Dantzer, R.
通讯作者：
Dantzer, R.
影响因子：
10.6
作者：
Harrison NA;Brydon L;Walker C;Gray MA;Steptoe A;Critchley HD
通讯作者：
Critchley HD