Department of Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
Horm Behav. 2012 Aug;62(3):202-9. doi: 10.1016/j.yhbeh.2012.03.010. Epub 2012 Mar 31.
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 Escherichia 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.
促炎症细胞因子可诱导吲哚胺 2,3-双加氧酶（IDO）表达上调，被认为是与炎症相关的情绪障碍的生物学介质。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则侧重于相对狭窄且存在一定争议的抑郁样行为调查，其中包括强迫游泳和悬尾试验。在这里，我们试图确定外周免疫挑战大肠杆菌、脂多糖（LPS）是否会引发翻译相关的抑郁样行为，并研究 IDO 在介导这些 LPS 诱导的行为中的作用。腹腔内注射 LPS 可使 C57BL/6J 小鼠产生强烈但短暂的探索性运动活动（eLMA）减少，24 小时后恢复接近基线水平。与生理盐水处理的对照组相比，蔗糖偏好（快感缺失的临床前相关物）降低超过 20%，LPS 在 24 小时诱导显著增加焦虑样行为，而与 eLMA 无关。用 IDO 抑制剂 1-甲基色氨酸（1MT）预处理可消除 LPS 的焦虑作用，而对与疾病相关的体重或 eLMA 变化没有影响。此外，1MT 预处理可减轻 LPS 诱导的蔗糖偏好降低，在 IDO-1 缺失小鼠中也得到了证实。有趣的是，急性全身给予 IDO 的酶产物 l-犬尿氨酸可在没有影响 eLMA 的情况下引起快感缺失和焦虑样效应。在临床前模型中，这些数据表明 IDO 是 LPS 诱导的抑郁和焦虑样行为的关键介质。
