GLP-1 is both anxiogenic and antidepressant; divergent effects of acute and chronic GLP-1 on emotionality
GLP-1 is both anxiogenic and antidepressant; divergent effects of acute and chronic GLP-1 on emotionality
复制标题
DOI：
10.1016/j.psyneuen.2015.11.021
复制
发表时间：
2016-03-01
影响因子：
3.7
通讯作者：
Skibicka, Carolina P.
中科院分区：
文献类型：
--
作者：
Anderberg, Rozita H.;Richard, Jennifer E.;Skibicka, Carolina P.
胰高血糖素样肽1（GLP-1），在肠道和后脑中产生，已知其葡萄糖调节和食欲抑制作用。GLP-1激动剂在临床上用于治疗2型糖尿病和肥胖症。然而，GLP-1也可能影响与情绪调节相关的大脑区域。在这里，我们的目的是表征GLP-1对焦虑和抑郁样行为的急性和慢性影响。在急性或慢性脑室内或中缝背核（DR）内应用GLP-1受体激动剂后，对大鼠进行焦虑和抑郁行为测试。在杏仁核、DR和海马体中也测量了5-羟色胺或5-羟色胺相关基因。我们证明，GLP-1和其持久的类似物，Exendin-4，诱导焦虑样行为在三个啮齿动物测试的这种行为：黑色和白色框，高架十字迷宫和开放领域的测试时，急性给药腹腔内，进入侧脑室，或直接进入DR。急性中枢GLP-1受体刺激也改变了5-羟色胺信号在杏仁核。相比之下，Exendin-4的慢性中枢给药没有改变焦虑样行为，但在强迫游泳试验中显著减少抑郁样行为。重要的是，Exendin-4的这种积极作用不是由于显著的体重减轻和食物摄入量减少，因为成对喂食Exendin-4大鼠的大鼠没有显示出情绪改变。总的来说，我们显示了中央GLP-1对情绪和杏仁核5-羟色胺信号传导的显著影响，急性与慢性GLP-1激活条件下是不同的。我们还发现DR GLP-1受体在行为调节中的新作用。这些结果可能与临床直接相关，并表明Exendin-4可能对患有抑郁症的肥胖患者特别有用。(C)2015作者爱思唯尔有限公司出版
Glucagon-like peptide 1 (GLP-1), produced in the intestine and hindbrain, is known for its glucoregulatory and appetite suppressing effects. GLP-1 agonists are in clinical use for treatment of type 2 diabetes and obesity. GLP-1, however, may also affect brain areas associated with emotionality regulation. Here we aimed to characterize acute and chronic impact of GLP-1 on anxiety and depression-like behavior. Rats were subjected to anxiety and depression behavior tests following acute or chronic intracerebroventricular or intra-dorsal raphe (DR) application of GLP-1 receptor agonists. Serotonin or serotonin-related genes were also measured in the amygdala, DR and the hippocampus. We demonstrate that both GLP-1 and its long lasting analog, Exendin-4, induce anxiety-like behavior in three rodent tests of this behavior: black and white box, elevated plus maze and open field test when acutely administered intraperitoneally, into the lateral ventricle, or directly into the DR. Acute central GLP-1 receptor stimulation also altered serotonin signaling in the amygdala. In contrast, chronic central administration of Exendin-4 did not alter anxiety-like behavior but significantly reduced depression-like behavior in the forced swim test. Importantly, this positive effect of Exendin-4 was not due to significant body weight loss and reduced food intake, since rats pair-fed to Exendin-4 rats did not show altered mood. Collectively we show a striking impact of central GLP-1 on emotionality and the amygdala serotonin signaling that is divergent under acute versus chronic GLP-1 activation conditions. We also find a novel role for the DR GLP-1 receptors in regulation of behavior. These results may have direct relevance to the clinic, and indicate that Exendin-4 may be especially useful for obese patients manifesting with comorbid depression. (C) 2015 The Authors. Published by Elsevier Ltd.